Dear All I’m not impressed with your answer regarding the level of evidence of this article. Many of you copied the answer from each other. See the diagram and answer the question regarding the level of evidence
Level 5 narrative review ( comprehensive, critical and objective analysis of the current knowledge on a topic).
Alyaa Ali
2 years ago
Allograft rejection is a complex process with the involvement of different cellular and molecular pathways that cause allograft injury.Antibody ligation to human leukocyte antigen (HLA) or blood antigens expressed on the endothelium, can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/macrophage– mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
Diagnostic criteria using Banff classification Acute Antibody-Mediated Rejection According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
Histologic evidence of acute tissue injury
Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum .
Chronic Antibody-Mediated Rejection . According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
Histologic evidence of chronic tissue injury
Histologic evidence of antibody interaction with vascular endothelium
Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes of Antibody-Mediated Rejection
according to 2011 Banff report, 2 principal phenotypes of acute AMR were defined. Phenotype 1: occurs in the presensitized patient and occurs in the early post-transplant period. Phenotype 2: develops from the emergence of de novo DSAs in the late post-transplant period and is thought to be related primarily to non adherence or inadequate immunosuppression. Paradigms in antibody mediated rejection
Subclinical Antibody-Mediated Rejection : histologic evidence of antibody-mediated injury in protocol biopsy despite stable creatinine .if left untreated, increased the risk of allograft loss.
C4d-Positive and C4d-Negative Rejection :55% of patients can have a C4d-negative rejection with evidence of microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs.
Antibody-Mediated Vascular Rejection :usually , endarteritis has been associated with cellular rejection; however, a population-based study demonstrated that vasculitis belongs to both T cell– mediated rejection and AMR.
Non-HLA Antibody-Mediated Rejection: Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies.the complement-binding capacity of anti-HLA antibodies played a role in kidney allograft failure.
Transplant Glomerulopathy: is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. The prevalence of transplant glomerulopathy is 5%-20% , increasing to 55% in high-risk cohorts, causes progressive allograft failure with a poor prognosis and eventual allograft loss in 40%-70%of patients.
Antibody removal for highly sensitized patients
High-Dose Intravenous Immunoglobulin ,IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
Intravenous Immunoglobulin and Rituximab: Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Immunoadsorption for Rapid Crossmatch Conversion
Treatment of antibody mediated rejection
The goal for the treatment of AMR is to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without compromising the normal immune responses that protect patients from serious infections.
Plasmapheresis: is considered a standard part of therapy in most protocols developed for the treatment of AMR
Intravenous Immunoglobulin The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
Rituximab
Proteasome Inhibitor (Bortezomib),: removing plasma cells that generate antibodies , it has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR
Complement Inhibition(Eculizumab)
Prevention of antibody mediated rejection
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival
Background: Chronic antibody mediated injury is a serious threat to allograft outcomes and may cause graft failure. Recent advances in molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However still ABMR is the main cause for graft failure.
Methods: The reviewed the current diagnostic criteria for AMR; AMR paradigms; and desensitization, treatment, and prevention strategies.
Introduction:
Allograft rejection is a complex process that involves different cellular and molecular pathways that cause a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis). Antibody against human leukocyte antigen (HLA) or blood antigens, including non-HLA antigens expressed on the endothelium, can activate the complement system, leading to recruitment of leukocytes and facilitation of NKC or monocyte/macrophage mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
Allograft rejection can be hyperacute due to high levels of preformed antibodies, early acute occurring days to weeks after transplantation, late acute occurring 3 months after transplantation, or chronic occurring months to years after transplantation. Rejection also can be classified as per histopathological picture o TCM and ABMR.
The Banff classification for allograft rejection pathology has made a dramatic improvement in detection, standardizing, and incorporating histologic, immunohistochemical, and serologic factors that all causing improve sensitivity in the diagnosis of allograft rejection and in providing good idea regarding outcome data in terms of allograft survival.
Acute Antibody-Mediated Rejection According to the Banff 2013 classification: all the following 3 features are required for the diagnosis of acute AMR: 1. Histologic evidence of acute tissue injury:One of the following a. Glomerulitis or peritubular capillaritis b. Intimal or transmural arteritis c. Acute thrombotic microangiopathy (TMA) d. Acute tubular injury. 2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum.
Chronic Antibody-Mediated Rejection: According to the revised Banff 2013 classification the diagnosis of chronic, active AMR requires 3 features: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis 2. Histologic evidence of antibody interaction with vascular endothelium a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum.
Antibody-Mediated Rejection phenotypes:
There are 2 principal phenotypes of acute AMR:
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
C4d-Positive and C4d-Negative Rejection: C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation.
Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies. They include angiotensin type I receptor and endothelin type A receptor antibodies
Transplant Glomerulopathy
Transplant glomerulopathy is characterized by glomerular basement membrane duplication, double contouring, or splitting.The electron microscopy provides the best tool for the early diagnosis of transplant glomerulopathy and should be incorporated into the definition of chronic glomerulopathy.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
High-Dose Intravenous Immunoglobulin
Intravenous Immunoglobulin and Rituximab
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Immunoadsorption for Rapid Crossmatch Conversion Compared to PLEX,
TREATMENT OF ANTIBODY-MEDIATED REJECTION
Plasmapheresis PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR
Intravenous Immunoglobulin
Rituximab
Proteasome Inhibitor: Bortezomib has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
Complement Inhibition:The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.Only limited data, usually single cases, are available on the efficacy of eculizumab in patients with severe AMR.
Chronic Antibody-Mediated Rejection Treatment: PREVENTION OF ANTIBODY-MEDIATED REJECTION
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are strategies used to reduce or early diagnose AMR and improve allograft survival.
In summary, a reduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure.
Wee Leng Gan
2 years ago
Antibody Mediated Rejection.
This article is a narrative review with level 5 evidence for the AMR current diagnostic criteria and paradigms. Besides, it emphasizes the AMR desensitization protocol, treatment, and prevention strategies. AMR diagnosis criteria.
1. Evidence of chronic tissue injury in renal HPE as defined by at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known aetiology.
2. Histology evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury.
3. Detection of DSAs (HLA or non-HLA) in the serum.
In the 2011 Banff report 2 principal phenotypes of acute AMR.
Phenotype 1 occurs in the pre sensitized kidney transplant recipient and occurs in the early post-transplant period.
Phenotype 2 develops from the development of de novo DSAs in the late posttransplant period due to poor compliance or inadequate immunosuppression. AMR Paradigms.
a) Subclinical Antibody-Mediated Rejection
-Poor graft survival.
b) C4d-Positive and C4d-Negative Rejection
-Poor marker for AMR.
c) Antibody-Mediated Vascular Rejection
-The risk of graft loss is greater in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
d) Non-HLA Antibody-Mediated Rejection
-Increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
e) Transplant Glomerulopathy
-Lead to progressive allograft failure. Poor prognosis and eventual contribute to 40%-70% allograft loss.
Desensitizing protocol.
a) Intravenous immunoglobulin (IVIG).
b) IV Rituximab. May combine with IVIG for more effective desensitization. However, larger trial needed.
c) Plasmapheresis, Intravenous Immunoglobulin, and Rituximab. High-dose IVIG is inferior to combination therapy.
d) Immunoadsorption for Rapid Crossmatch Conversion.
Treatment of AMR.
a) Plasmapheresis.
-Removes preformed antibodies.
b) Intravenous Immunoglobulin.
c) Rituximab.
d) Proteasome Inhibitor. Bortezomib. Has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with good outcome.
e) Complement Inhibition. Eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH).
Chronic Antibody-Mediated Rejection Treatment
a) Steroid and IVIG. Rigorous and potent immunosuppressive agents might not be feasible.
Prevention of AMR.
Pregnancies, blood transfusions, patient nonadherence and previous organ transplantation are major risk factors for recipient sensitization and AMR.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies.
Conclusion.
Alloimmune response remains crucial for successful long-term allograft function. Banff classification histology criteria remain useful for the diagnosis of AMR. Plasmapharesis and IVIG are still considered mainstay therapies for the treatment of AMR. Further evidence needed for newer therapy for AMR.
Nandita Sugumar
2 years ago
Summary
Introduction
Different cellular and molecular processes lead to rejection. This causes injury to the allograft, such as acute tubular injury, glomerulitis, capillarities, and fibrinoid necrosis.
There are different types of allograft rejection with respect to period of occurrence post transplant – these include :
hyper acute – within minutes following vascular anastomosis
acute – Days to weeks post transplant
late acute – 3 months post transplant
chronic – months to years post transplant
CAMR can present with transplant glomerulopathy with basement membrane duplication, double contouring or splitting as typical histological features for identification. Clinically, proteinuria and increase in creatinine will be seen.
Diagnostic criteria
SAB or single antigen bead testing are sensitive for identification of anti HLA antibodies and consequently AMR.
Banff classification 2013 is used for differentiating features of acute and chronic AMR.
Acute AMR :
Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
Intimal or transmural arteritis (v >0)
Acutethromboticmicroangiopathy(TMA)ofnoother obvious cause
Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium, defined by at least one of
the following:
Linear C4d staining in the peritubular capillaries
At least moderate microvascular inflammation (g þ
ptc >2)
Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic AMR :
Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
Transplantglomerulopathy(cg>0)intheabsenceof
chronic TMA
Severe peritubular capillary basement membrane
multilayering identified by electron microscopy
New-onset arterial intimal fibrosis with no other
known etiology
2. Histologicevidenceofantibodyinteractionwithvascular
endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes
Phenotype 1 :
Occurs in presensitized patient
Early post transplant period
Phenotype 2 :
De novo DSAs in late post transplant period
Related to non adherence
Could be due to inadequate immunosuppression regimen
Treatment
Treatment options for AMR include the following
Antibody depletion with PLEX or plasma pheresis
Immunoadsorption
Immunomodulation with IVIG
T cell or B cell depleting agents
Bortezomib and eculizumab (anti C5 monoclonal antibody) are used for difficult rejections.
PLEX removes preformed antibodies. Outcome is better with a combination of PLEX and IVIG versus PLEX alone.
Rituximab along with PLEX also gives good outcome, possibly better than PLEX and IVIG.
Bortezomib can be used in a regimen of PLEX, IVIG, Rituximab can work against AMR.
Prevention
C1q binding assay can be a predictor for allograft loss
Careful monitoring of DSA in high risk sensitized patients with history of pregnancy, blood transfusion, previous organ transplant, is useful in assessing for AMR. This is because DSA can be present before allograft dysfunction is detected, and thus repeat testing is crucial.
Check for non adherence because it is a major risk factor for DSA formation
Patient education regarding importance of immunosuppression in the post transplant period and for life.
Lower intensity of CNis in late post transplant phase needs to be avoided to prevent late rejection.
Conclusion
Alloimmune response is the major barrier to successful organ transplant. AMR, whichever period it occurs in, can result in significant harm to the graft or even graft loss, if not detected early and treated sufficiently. Early detection can be done with proper followup and repeat DSA testing. Necessary precautions for prevention of rejection include identifying non-adherence, and maintaining adequate immunosuppression through the lifetime of the patient. Patient awareness regarding immunossive regimen dose, frequency, and importance is paramount to long term success of transplant and graft as well as patient survival.
Level of Evidence
This is a narrative review. Level of evidence 5.
ahmed saleeh
2 years ago
The histology of acute and chronic AMR overlaps
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum
Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g were associated with an increased risk of allograft loss. The authors concluded that chronic AMR was associated with poor graft survival after diagnosis.
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cellmediated rejection (88%) and no-rejection (90%) groups (P<0.001)
In addition to complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility make C4d a poor marker for the diagnosis of AMR.
No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive
angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies
agreed that electron microscopy unequivocally provides the best tool for the early diagnosis of transplant glomerulopathy and should be incorporated into the definition of chronic glomerulopathy.
🏣level 5
Evidence
Manal Malik
2 years ago
Summary of Antibody-mediated rejection: Introduction:
Allograft rejection is a complex process that involves different cellular and molecular pathway which can cause a broad range of allograft injury .
Classification of allograft rejection based on the time of rejection:
1. Hyperacute (occurring minutes after the vascular anastomosis)
2. Acute (days to weeks after transplantation)
3. Late acute (occurring 3 months after transplantation)
4. Chronic (occurring months to years after transplantation)
Rejection classification based on the pathophysiological events:
1. Cellular
2. AMR
3. Both Current diagnostic criteria:
Despite the major advances in molecular biology and gene rearrangement the diagnosis of AMR is still depend on histological finding Acute antibody-mediated rejection:
Banff 2013 classification all of the following 3features are required for the diagnosis of a cute AMR:
1. Histological evidence of acute tissue injury defined by the presence of one or more of the following
A. Glomerulitis or peritubular capillaritis
B. Intimal or transmural arteritis
C. Acute thrombotic microangiopathy
D. Acute tubular injury
2. Histological evidence of current antibody interaction with vascular endothelium
3. Detection of DSA (HLA or non HLA) in the serum Chronic antibody-mediated rejection:
Banff 2013 classification the diagnosis of chronic active AMR require 3 features:
1. Histological evidence of chronic tissue injury defined by the presence of at least one of the following:
A. TG
B. Multi-layering of peritubular capillary basement membrane
C. New onset arterial intimal fibrosis with no other known aetiology
2. Histological evidence of antibody interaction with vascular endothelium
3. Detection of DSAs (HLA or non HLA )in the serum Phenotype of antibody-mediated rejection:
In Baff 2011 report 2 phenotypes of acute AMR:
1. Phenotype 1
Occurs in the pre-sensitized patients
Occur early post renal transplant period
2. Phenotype 2
Occur from de novo DSAs
Occur in late post renal transplant period
Related to non-adherence or inadequate immunosuppression Paradigms in antibody-mediated rejection: Subclinical antibody-mediated rejection
Protocol biopsy identified a sub-group of patients with histological evidence of antibody-mediated injury despite creatinine stable
Lack of long term follow up data has prevented the development of strong guidelines for effective therapeutic intervention
Subclinical AMR if left untreated increased the risk of allograft loss C4d-positive and c4d-negative rejection:
Banff 2013 classification included others marker for endothelial activation and injury such as:
Increased expression of endothelial activation and injury transcripts or other gene expression markers of endothelial injury in the tissue biopsy
C4d-Negative AMR:
Microvascular injury (glomerulitis, peritubular capllaritis, TMA) in the presence of DSAs and absence of c4d deposition in PTC
Present later compare to c4d positive AMR
Less common than c4d positive AMR
Increase risk of allograft loss in c4d positive compare to c4d negative AMR Antibody-mediated vascular rejection:
Population based study demonstrated that vasculitis belong to T-cell mediated rejection and AMR hence the risk of graft loss 9 times in AMR vascular rejection these T-cell mediated rejection without vasculitis Non-HLA antibody-mediated rejection:
Non-HLA antibodies are 2 types
1. Alloantibodies against polymorphic antigens
2. Antibodies that recognize self-antigens or auto-antibodies
Eg:
a-angiotensin type 1 receptor
b-endothelium type A receptor antibodies
Transplant glomerulopathy:
Glomerular basement membrane
Late stage of antibody mediated injury which associated with poor graft survival High-dose intravenous immunoglobulin:
Mechanism of IVIG:
1. Inhibition of T-cell proliferation
2. Inhibition of cytokines synthesis
3. Inhibition of complement activation
4. Ant idiotypic blockade of alloantibodies
Some of studies conclude IVIG was better in replacing anti-HLA antibody levels and improving transplantation rate in highly sensitized patients with ESRD Intravenous immunoglobulin and Rituximab:
The researchers concluded that the combination of IVIG and Rituximab was effective as desensitization regimens
Plasmapheresis, intravenous immunoglobulin, and Rituximab
The researcher concluded that high dose IVIG is inferior to combination therapy Immunoadsorption for rapid crossmatch conversion:
Treatment consisted of a single session of immediate pretransplant IA(protein) followed by posttransplant IA
Conclusion that IA is an effective strategy for rapid desensitization in deceased-donor transplantation Treatment of antibody-mediated rejection:
Optimization of baseline immunosuppression (CNI+ antiproliferative agents, +steroid)
Pulse steroid
Rabbit ATG
PLEX, IVIG
B-cell depleting agents Plasmapheresis:
Rapidly removed performed antibodies
PLEX and IVIG was superior to PLEX alone Intravenous immunoglobulin:
Better allograft outcome in combination therapy PLEX and Rituximab Rituximab:
Combination of Rituximab, PLEX and IVIG
Graft survival was better in this control group Protease inhibitors:
Removing plasma cells
Bortezomib approved for the treatment of multiple myeloma
Has been used in combination with PLEX, IVIG, or Rituximab Complement inhibition:
Eculizumab (anti C5 monoclonal antibody) and C1 esterase inhibitor (C1-INH)
Early use of eculizumab before advanced change in kidney injury are identified can improved responses and allograft survival Chronic antibody mediated rejection treatment:
Therapy has been used for the treatment of chronic AMR data are limited Prevention of antibody-mediated rejection:
To prevent AMR:
1. Avoid transplant for highly sensitized patients
2. Enrolling highly sensitized patients in approved. Kidney exchange programme
3. Participating in special programme such as Euro transplant Acceptable MB match programme
4. Combined kidney paired exchange programme with desensitization protocol
5. Maintain de novo DSAs using class 11 HLA epitopes matching and performing protocol biopsy Conclusion:
Alloimmune response remains an important barrier for successful long term allograft function
Histological criteria driven by Banff classification has helped standardized the diagnosis of AMR
Treatment of AMR are PLEX and IVIG
More research is required in the field of AMR
2- level of evidence is 5
Abdullah Raoof
3 years ago
Please summarise this article
Antibody-Mediated Rejection: A Review
Allograft rejection can be
-hyperacute (occurring within minutes after the vascular anastomosis),
-acute (occurring days to weeks after transplantation), – late acute (occurring 3mmonths after transplantation), or
– chronic (occurring months to years after transplantation).
Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
Because of current improvement in immunossuppresion treatment ,It is not uncommon for rates of acute rejection to be < 15%. CURRENT DIAGNOSTIC CRITERIA Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the
following 3 features are required for the diagnosis of acute
AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis or peritubular capillaritis
b. Intimal or transmural arteritis
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy ) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Redfield et al conducted a study of 123 -The authors concluded that chronic AMR was associated with poor graft survival after diagnosis. Moderate Microcirculatory Changes
Microcirculatory changes were introduced in the revised Banff 2013 classification and are recognized as highly suspicious for antibody injury. Only the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
Phenotypes of Antibody-Mediated Rejection
2 principal phenotypes of acute AMR were defined. Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION Subclinical Antibody-Mediated Rejection
Patients with subclinical AMR had the poor graft survival Post transplant compared with the subclinical T cell – mediated rejection and no-rejection. Orandi and colleagues reported that subclinical AMR, if left untreated, increased the risk of allograft loss. C4d-Positive and C4d-Negative Rejection
In 1993, Feucht et al were the first to report the presence of C4d deposition in peritubular capillaries and the correlation with allograft loss.
C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation.
C4d-negative rejection was not different from C4d-positive rejection in any baseline characteristic. Compared to patients with C4d-negative rejection, patients with C4d-positive AMR were more likely to present earlier post transplantation and were more common. Graft survival in C4d-negative AMR patients was better in C4d-positive AMR patients . C4d-negative AMR was associated with a 2.56-fold increased risk of allograft loss compared with AMR-free matched controls.
No clinical characteristic could distin guish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group. Antibody-Mediated Vascular Rejection
Traditionally, endarteritis has been associated with cellular rejection; however, a population-based study demonstrated that vasculitis belongs to both T cell – mediated rejection and AMR.the result of one study, the risk of graft loss was 9.07 times higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis. Non-HLA Antibody-Mediated Rejection
Patients with complement binding DSA after transplantation had a lower graft survival compared with patients with non-complement-binding DSA and patients without DSA antibodies .
These antibodies were associated with an increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
Transplant Glomerulopathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring,
or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
Transplant glomerulopathy causes progressive allograft failure with a poor prognosis and eventual allograft loss and is considered a histologic feature associated with chronic AMR that results from recurrent events of endothelial activation injury and repair.
-electron microscopy unequivocally provides the best tool for the early diagnosis of transplant glomerulopathy High-Dose Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent.
Several mechanisms of IVIG action have been proposed, including
§ the inhibition of T cell proliferation,
§ the inhibition of cytokine synthesis,
§ The inhibition of complement activation,
§ the antiidiotypic blockade of alloantibodies.
In one study The authors concluded that IVIG was better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease. Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventualmaturation to antibody-forming plasma cells . Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Lefaucheur et al compared the outcome of a plasmapheresis (PLEX)-, IVIG-, and rituximab-based protocol vs IVIG alone. The researchers concluded that high-dose IVIG is inferior to combination therapy. Immunoadsorption for Rapid Crossmatch Conversion
Compared to PLEX, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. TREATMENT OF ANTIBODY-MEDIATED REJECTION
Because of current immunosuppressive medications, the rates of acute rejection and 1-year graft survival have substantially improved . The threat of hyperacute rejection has been completely eliminated.
The treatment of subclinical AMR and its potential benefits are still under investigation.
Subclinical AMR was independently associated with a increased risk of allograft loss compared to matched controls but was not different from clinical AMR. Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
In an observational study, the auther found that the combination of PLEX and IVIG was superior to PLEX alone.
One study patients receives treatment with PLEX alone,compared to received treatment with a combination of PLEX and IVIG (0.5 g/kg). One-year graft survival was significantly higher in the PLEX plus IVIG group than in the PLEX-alone group. Similarly, patient survival was higher in the PLEX plus IVIG group vs the PLEX-alone group. Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab. Proteasome Inhibitor
Removing plasma cells that generate antibodies is therationale behind using a proteasome inhibitor (PI) as therapy for AMR.
has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results. This large experience with PI based AMR therapy demonstrated that it provides effective AMR reversal, including substantial reductions in DSA levels. Complement Inhibition
The FDA has approved 2 agents, for complement inhibition
· eculizumab (an anti-C5 monoclonal antibody) and
· a C1 esterase inhibitor (C1-INH),
-Eculizumab was approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
-C1-INH was approved for use in patients with hereditary angioedema. Only limited data, usually single cases, are available on the efficacy of eculizumab in patients with severe AMR.
In a 2014 study, found that eculizumab was not effective in severe oliguric early-onset AMR. The researchers con cluded that splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR. Chronic Antibody-Mediated Rejection Treatment
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited. Because of the slow progression of chronic AMR compared to acute AMR, subjecting patients to rigorous and potent immunosuppressive agents might not be feasible. despite the best available therapies, patients experienced poor graft survival. PREVENTION OF ANTIBODY-MEDIATED REJECTION
1-avoiding transplantation for highly sensitized patients,
2-better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening,
3- enrolling highly sensitized patients in a paired kidney exchange program, 4-Monitoring de novo DSAs,
5- using class II HLA epitope matching,
6- performing protocol biopsies .
What is the level of evidence provided by this article?
level 5
AMAL Anan
3 years ago
Please summarise this article :
* The first description of acute AMR identified neutrophils in peritubular capillaries and de novo donor-specific antibodies (DSAs).
* C4d, a degradation product of the complement pathway that binds covalently to the endothelium, was identified as marker of endothelial injury and hence of antibody activity.
* B cells and plasma cells produce DSAs that interact with the endothelium, which activates the cellular pathways responsible for the development of microcirculatory changes and tissue injury.
* Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
* CURRENT DIAGNOSTIC CRITERIA :
– Single-antigen bead testing .
– Complement-dependent cyto- toxicity .
– Electron microscopy is routinely used for the biopsies of transplant recipients.
* Acute Antibody-Mediated Rejection :
– 1. Histologic evidence of acute tissue injury .
– 2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium.
– 3. Detection of DSAs (HLA or non-HLA) in the serum.
* Chronic Antibody-Mediated Rejection:
– – 1. Histologic evidence of acute tissue injury .
– 2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium.
– 3. Detection of DSAs (HLA or non-HLA) in the serum.
* Phenotypes of Antibody-Mediated Rejection:
– Phenotype 1 occurs in the presensi- tized patient and occurs in the early posttransplant period.
– Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to non-adherence or inadequate immuno- suppression.
* PARADIGMS IN ANTIBODY-MEDIATED REJECTION Subclinical Antibody-Mediated Rejection:
– Patients with subclin- ical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell– mediated rejection (88%) and no-rejection (90%) groups (P<0.001).Orandi and colleagues reported that subclin- ical AMR, if left untreated, increased the risk of allograft loss.
– C4d-negative AMR, defined by microvascu- lar injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
* Non-HLA Antibody-Mediated Rejection:
– angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies.
* Transplant Glomerulopathy:
– It is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. The prevalence of transplant glomerulopathy is 5%-20% in most series, increasing to 55% in high-risk cohorts.
* Intravenous Immunoglobulin and Rituximab:
– The researchers concluded that the combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
– IA is an effective strategy for rapid desensitization in deceased-donor transplantation.
– The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune respons- es that protect patients from serious infections.
* Treatment of ANTIBODY- Mediated rejection:
– Plasmapheresis.
– IVIG .
– Protesome inhibitors .
– complement Inhibition .
* PREVENTION OF ANTIBODY-MEDIATED REJECTION:
Djamali et al proposed several strategies to prevent AMR, including avoiding transplantation for highly sensitized patients, better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desen- sitization protocols.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
REFERENCES
1. Terasaki PI. A personal perspective: 100-year history of the humoral theory of transplantation. Transplantation. 2012 April 27;93(8):751-756. doi: 10.1097/TP.0b013e3182483713.
2. Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014 Feb;14(2):255-271. doi: 10.1111/ajt.12589.
3. Mauiyyedi S, Pelle PD, Saidman S, et al. Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol. 2001 Mar;12(3):574-582.
4. Farkash EA, Colvin RB. Diagnostic challenges in chronic antibody-mediated rejection. Nat Rev Nephrol. 2012 Mar 27; 8(5):255-257. doi: 10.1038/nrneph.2012.61.
5. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant. 2010 Feb;15(1):42-48. doi: 10.1097/MOT.0b013e3283352a50.
It is a narrative review and level of evidence 5 Diagnoses of acute AMR: -Evidence of acute tissue injury at the histology level defined by the presence of one or more of the following: *Glomerulitis (g >0) or peritubular capillaritis (ptc >0) *Intimal or transmural arteritis (v >0) *Acute thrombotic microangiopathy(TMA) with no obvious cause *Acute tubular injury with no obvious cause -Evidence of current or recent antibody reaction with vascular endothelium, defined by at least one of the following: * C4d staining (in linear pattern) in the peri tubular capillaries *At least moderate microvascular inflammation *Increased expression of tissue gene transcripts -Presence of DSAs in the serum either HLA or non-HLA. Diagnosis of Chronic AMR : As per revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features: – Evidence of chronic tissue injury, defined by the presence of at least one of the following: *Transplant glomerulopathy without chronic TMA * Multi layering in peritubular capillary basement membrane by electron microscopy *Arterial intimal fibrosis of new onset without known etiology – Evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: * Linear C4d staining in the peritubular capillaries * Moderate microvascular inflammation * Increased expression of tissue gene transcripts indicative of endothelial injury -Presence of DSAs in the serum either HLA or non-HLA. Treatment of AMR: -Plasmapheresis: to removes the antibodies. – IVIG. – Rituximab. – Proteasome Inhibitor. Bortezomib. – Complement Inhibition. Eculizumab
CARLOS TADEU LEONIDIO
3 years ago
Please summarise this article
Antibody-Mediated Rejection: A Review
Allograft rejection is a complex process that involves the interplay of different cellular and molecular pathways that cause a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis). Antibody ligation to human leukocyte antigen (HLA) or blood antigens, including non-HLA antigens expressed on the endothelium, can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/macrophage– mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
With the introduction of T cell–depleting drugs, calcineurin inhibitors (CNIs), and antiproliferative agents, the field of transplantation has experienced exceptional improvement in allograft survival. Other progress was recognition of the role of DSAs, such as new techniques to detect antibodies, the use of desensitization protocols, and the introduction of new agents that interfere with complement-mediated allograft injury.
1 – CURRENT DIAGNOSTIC CRITERIA:
The Banff classification for allograft pathology has made considerable progress during the last 2 decades in capturing, standardizing, and incorporating histologic, immunohistochemical, and serologic factors believed to improve sensitivity in the diagnosis of allograft rejection and in providing outcome data in terms of allograft survival.
The 12th Banff Conference on allograft pathology was held in Brazil in August 2013. Different working groups presented their findings to reach consensus on the diagnosis of AMR: – presence and absence of a C4d stain;
– role of microcirculatory inflammation,
including thresholds for glomerulitis;
– the role of intimal arteritis;
– comparisons of different methodologies for evaluating interstitial fibrosis;
– role of implantation biopsies in terms of allograft outcomes.
Despite the major advances in molecular biology and gene rearrangement, the diagnosis of AMR is still dependent on histologic findings
1.A – Moderate Microcirculatory Changes
The Banff renal pathologists involved with the evaluation of kidney biopsies established the presence of glomerulitis and graded this finding based on the complete occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement
1.B – Phenotype of Antibody-mediated rejection
The 2011 Banff report, 2 principal phenotypes of acute AMR were defined.13 Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
2 – PARADIGMS ANTIBODY-MEDIATED REJECTION
2.A – Subclinical Antibody-Mediated Rejection
Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell– mediated rejection (88%) and no-rejection (90%) groups (P<0.001). If left untreated, increased the risk of allograft loss.
2.B – C4d positive and C4d negative rejection
C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation
2.c – Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies.23,24 Non-HLA antibodies use different pathways to cause endothelial injuries that do not involve the presence of integrins, as with HLA antibodies
2.d- Transplant Glomerulypathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. Transplant glomerulopathy causes progressive allograft failure with a poor prognosis and eventual allograft loss in 40%-70% of patients and is considered a histologic feature associated with chronic AMR that results from recurrent events of endothelial activation injury and repair.
Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome (graft loss of 92% vs 33%, P< 0.005) and is strongly associated with preexisting or de novo DSAs.
3 – ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Approximately one-third of patients awaiting a deceased donor kidney transplant have circulating anti-HLA antibodies, and almost 15% have a high degree of sensitization to potential kidneys. Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
3.A – High-Dose Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
3.B – Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complemente dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen. The researchers concluded that the combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
3.C – Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Assay compared the outcome of a plasmapheresis (PLEX)-, IVIG-, and rituximab-based protocol vs IVIG alone. The researchers concluded that high-dose IVIG is inferior to combination therapy
3.D – Immunoadsorption for Rapid Crossmatch Conversion
Compared to PLEX, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. Three or more plasma exchanges can be processed during a single session. Some authors have proposed that this technique may provide rapid and selective antibody depletion in a few hours. At 5 years, overall graft survival, death-censored graft survival, and patient survival were 63%, 76%, and 87%, respectively, without any differences among crossmatch-positive, crossmatch-negative/DSA-positive, and crossmatch-negative/DSA-negative recipientes.
4 – TREATMENT OF ANTIBODY-MEDIATED REJECTION
4.A – Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. Pascual et al evaluated the role of PLEX and tacrolimus (TAC)-mycophenolate rescue therapy for AMR. Slatinska et al found that the combination of PLEX and IVIG was superior to PLEX alone.
4.B – Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
4.C – Rituximab
4.D – Proteasome Inhibitor
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor (PI) as therapy for AMR. Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
4.E – Complement Inhibition
The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition. Wongsaroj et al reported on the efficacy and safety of eculizumab in treating patients with severe AMR episodes unresponsive to standard treatment with IVIG plus rituximab with or without PLEX.
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited
5 – PREVENTION OF ANTIBODY-MEDIATED REJECTION
Choosing donors with lower sensitization to recipients, as well as avoiding reduced immunosuppression, appear to be the actions with the best result to avoid rejection.
What is the level of evidence provided by this article?
This article is a narrative review – evidence level 5.
AMAL Anan
3 years ago
What is the level of evidence provided by this article?
Level 5 narrative review
MOHAMED Elnafadi
3 years ago
Antibody-Mediated Rejection: A Review
before ABMR was adisaster unknown ghost that led to graft loss,The first description of acute AMR identified neutrophils in peritubular capillaries and de novo donor-specific antibodies (DSAs). C4d, a degradation productof the complement pathway that binds covalently to the endothelium, was identified as marker of endothelial injury and hence of antibody activity. CURRENT DIAGNOSTIC CRITERIA.
single-antigen bead testing (SAB)used to detect anti-HLA antibodies,current technique of choice used to identify antibodies that can injure the allograft .
graft biopsy could be done by electron microscopy .
cdc nowdays is not the technique of choice. Acute Antibody-Mediated Rejection
Banff 2013 classification
all of the following 3 features are required for the diagnosis of acute AMR
A. Histologic evidence of acute tissue injury as Glomerulitis or peritubular capillaritis Intimal or transmural arteritis ,tubular injury with out obvious cause.
B. Histologic evidence of current/recent antibody interaction with vascular endothelium
need only one of the following C4d staining in the peritubular capillaries,moderate microvascular inflammation,endothelial injury.
C. positive DSA. Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification, the diagnosis ofchronic, active AMR requires 3 features:
A. evidence of chronic tissue injury in the form of Transplant glomerulopathy in the absence of chronic TMA , Severe peritubular capillary basement membrane
multilayering identified by electron microscopy, arterial intimal fibrosis with out obvious cause.
B. Histologic evidence of antibody interaction with vascular endothelium requires one of the following C4d staining in the peritubular capillaries,moderate microvascular inflammation,endothelial injury.
C.positive DSA.
Antibody removal for highly sensitized patients
High dose Intravenous immunoglobulin (IVIG) immunomodulatory agent Inhibits complement activation, T cell proliferation, cytokine release.
It was found to be better than placebo with efficacy of 52%(9/17) in reducing anti-HLA antibodies in sensitized patients.
IVIG and Rituximab
Rituximab is an ati-CD20 monoclonal antibody Causes B cell lysis and blocks B cell activation. Does not affect already formed plasma cells which lack CD20.
Has been found to be effective in desensitization a regimen when combined with IVIG.
PPS, IVIG, and Rituximab this combination lead to graft survival at 36 months of 91.7% in vs 50% with IVIG alone.
Immunoadsorption for Rapid Crossmatch Conversion appears to be better than plasmapheresis with faster clearance immunoglobulins.
What is the level of evidence provided by this article? narrative review level 5
Drtalib Salman
3 years ago
Summarise this article:
Allograft rejection can be hype acute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation).
Complement-dependent cytotoxicity is still considered the gold standard for the detection of preformed antibodies. Electron microscopy is routinely used for the biopsies of transplant recipients because early changes cannot always be detected with light microscope .
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.
the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
2 principal phenotypes of acute AMR were defined .Phenotype 1 occurs in the presensitized patient . Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group.
The risk of graft loss was 9.07 times higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
Patients with complement binding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graft survival (54%) compared with patients with non-complement-binding donor-specific anti HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%).
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting30 and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome (graft loss of 92% vs 33%) and is strongly associated with preexisting or de novo DSAs.
treatment of highly sensitizing patients, high-dose Intravenous immunoglobulin, intravenous immunoglobulin and rituximab, plasmapheresis, intravenous immunoglobulin, and rituximab, combination therapy is superior to other.
by immunoabsorption, three or more plasma exchanges can be processed during a single session, this technique may provide rapid and selective antibody depletion in a few hours.
treatment of acute Ab mediated rejection
-Plasmapharesis .
-IVIg.
-Rituximab
-Bortezomib.
-eculizumab.
-in chronic antibody-mediated rejection treatment the previously mentioned therapies have been used for the treatment of chronic AMR although data are limited.
-The 5-year graft survival for patients with no DSAs, non–C1q-binding DSAs, and C1q-binding DSAs was 94%, 93%, and 54%, respectively.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
What is the level of evidence provided by this article?
Honestly in the first I think it is Level 2 but after read of diagram of Professor Ahmed Halawa it is LEVEL 5.
Esmat MD
3 years ago
This article is a narrative review with the level 5 of evidence.
Introduction: the development of antibodies against HLA and non-HLA antibodies and their binding to HLA antigens and non-HLA antigens on the endothelium is essential in the allograft rejection that lead to complement system activation and subsequent recruitment of leukocytes, initiation of NK cells and macrophage mediated cytotoxicity. Ultimately interplay of different cellular and molecular pathways lead to endothelial damage and increased coagulation, and consequently allograft rejection. Allograft rejection can be hyperacute, early acute, late acute and chronic. It also can be cellular and, or Antibody mediated. With the significant progression in the field of recognition of the roles of DSAs, new techniques of detection of DSAs, development of new drugs and desensitization protocols result in decline in the rate of acute rejection less than 15%.
Current diagnostic criteria
These days single antigen bead testing is the final step in detection of DSA, monitoring of transplant recipients and also utilize as a tool for diagnosis of AMR. Electron microscopy integrate the light microscopy findings of transplant recipient’s kidney biopsy findings for diagnosis of rejection. The Banff classification by incorporating histologic, immunological and serologic factors for pathologic diagnosis of allograft rejection has been in progress in recent decades.
Acute ABMR
In accord with Banff 2013 classification all of these three features are required for the diagnosis of acute AMR: histologic evidence of acute tissue injury, histologic evidence of current or recent antibody interaction with endothelium, detection of DSA in the serum.
Chronic AMR
There are overlaps between histologic evidence of acute and chronic AMR. And acute AMR is a risk factor for chronic AMR. For diagnosis of chronic, active AMR 3 features are required including histologic evidence of chronic tissue injury, histologic evidence of antibody interaction with endothelium, detection of DSA in the serum.
In one study, chronicity scores>8, DSA>2500 MFI, ser Cr> 3 mg/dl, and urine Pr/Cr ratio more than 1 gr/gr were correlated with higher risk for graft loss.
Moderate microcirculatory changes
It is recognized as a highly suspicious for antibody mediated injury and defined in the presence of vasculitis and high number of inflammatory cells in the microcirculation which is associated with poor outcome.
Phenotypes of AMR
Two principle phenotypes of AMR are phenotype 1 is related to preexisting DSA and occurs in early post transplantation, phenotype 2 is related to de novo DSA that occurs later and is associated with non-adherence and low level of immunosuppression.
Subclinical AMR
It is defined as histologic evidence of AMR and normal serum Cr. It is associated with poorer graft survival compared with subclinical TCM rejection and no rejection and if it is not treated appropriately, will lead to increased rate of rejection.
C4d-positive and C4d negative rejection
C4d positivity in the absence of evidence of allograft injury was reported, and on the other hand, up to 55% of patients with acute AMR can be C4d-negative. Thus, other markers of endothelial injury such as injury transcripts incorporate in Banff classification. C4d-negative AMR has been defined as microvascular injury in the presence of DSAs. In one study, comparison between C4d-positive and C4-d negative DSA demonstrated that similar baseline and clinical characteristics, similar DSAs and poorer graft survival in the C4d positive group.
Antibody mediated vascular rejection
Endarteritis is associated with both AMR and TCM rejection, but in correlation with AMR is related to significant increased risk of graft loss.
Non-HLA AMR
Non-HLA antibodies are either alloantibodies directed against polymorphic antigens such as angiotensin type 1 receptor and endothelin type A receptors antibodies or autoantibodies. Presence of complement fixing anti HLA DSAs is associated with poorer graft survival compared with non-complement binding DSAs.
Transplant glomerulopathy
Transplant glomerulopathy that is characterized by duplication and splitting of GBM is considered the histologic finding of late stage of AMR, with prevalence of 5-20%, and correlated with graft loss. It is associated with heavy proteinuria and electron microscopy is the best tool for diagnosis. Risk stratification based on serum Cr, proteinuria, and chronic inflammatory scores may provide guidance for prognosis and treatment.
Antibody removal for highly sensitized patients
One third of patients in waiting list for deceased donor have circulating DSAs, and 15% are highly sensitized. Thus, different immunomodulatory strategies are utilized for decreasing the level of these antibodies consist of IVIG, rituximab, plasmapheresis, and immunoadsorption. IVIg can plat its immunomodulatory role by different mechanism including inhibition of T cell proliferation, cytokine synthesis, and complement activation, and blockade of alloantibodies.
Rituximab, induce CD20+ B cell lysis and block B cell activation but does not affect on plasma cells. It is reported that combination of Rituximab and IVIG can be effective as desensitization protocol. The combination of IVIG, Rituximab, and plasmapheresis may be better than IVIG as desensitization protocol. Immunoadsorption provide more specific and more effective clearance of circulating alloantibodies and lead to rapid and selective antibody removal on a few hours. As a result, IA can be an effective strategy for rapid desensitization.
Treatment of AMR
Protocol biopsy and DSA monitoring has been considered for follow up of kidney transplant recipients. If subclinical AMR leave untreated it may progress to transplant glomerulopathy. There is uncertainty about the treatment of subclinical AMR, and it is required large randomized clinical trials. Untreated subclinical AMR may be associated with more than 2-3 fold increased risk of allograft loss. Plasmapheresis is a part of standard treatment of AMR, but the results about its efficacy is conflicting. Combination of PLEX and IVIG is more effective than PLEX alone or IVIG alone in treatment of AMR. Rituximab in addition to IVIG and PLEX has been associated with good graft survival in AMR (>90%). Another option with encouraging result for treatment of AMR is bortezomib (by removing plasma cells) in combination with IVIG, PLEX, and/or rituximab. Inhibition of complement system by eculizumab in severe and unresponsive AMR has been reported in few case reports, that was especially effective in cases with TMA. One study suggested splenectomy in combination with eculizumab can be effective in treatment of acute early AMR.
Chronic AMR
Administration of mentioned medication for treatment of chronic AMR because of its slow rate of progression is not widely accepted. Although , the studies are conflicting.
Prevention of AMR
Presence of C1q-fixing DSAs is considered as an independent predictor of graft loss. Some strategies were proposed for prevention of AMR, such as avoiding transplantation in highly sensitized patients, utilizing sensitive anti-HLA DSA screening test, enrolling highly sensitized patients in paired donation programs alone or in combination with desensitization protocols and monitoring of de novo DSAs, anti-class II HLA, and protocol biopsy for early diagnosis of AMR. Even low level of DSAs and suboptimization of immunosuppressive drugs are associated with poor graft survival.
Radwa Ellisy
3 years ago
Identification of molecular and histologic changes allowed AMR therapeutic intervention
AMR is a major enemy threating allograft function
(DSAs).
DSA come from both B cell and plasma cell, injure the endothelium and microcirculatory changes after activation of cellular pathways.
CURRENT DIAGNOSTIC CRITERIA
Current diagnostic criteria :
Biopsy: light microscopy with immunohistochemistry for C4d , C1q (Banff classification)and EM to examine early detection not detected by light microscopy
Detection of DSA : CDC ,single antigen bead
Acute Antibody-Mediated Rejection
Acute ABMR diagnosed according to the Banff 2013 classification with all of the 3 features
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
While chronic ABMR diagnosed with at least one of the following: 1. histologic features of tissue injury
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum Phenotype of ABMR: Type 1: with the persistence of preformed DSA, occur early Type 2: de novo DSA, later on Paradigm of ABMR
1. Subclinical ABMR:
Diagnosed with protocol biopsy and associated with poorer outcome in means in graft survival 56% vs 90% in patients without it
Intravenous Immunoglobulin
Not alone with RTX or plasmapharesis Rituximab
Manty studies showed acceptable graft survival with ppx and IVIG either in 500mg/m2 or 375/m2/w Proteasome Inhibitor
To remove plasma cell producing and memorizing DSAs
In a dose (1.3 mg/m2/dose 3-4 doses) with IVIG and rtx showed promising results in histological reversal of the rejection. Complement Inhibition
Two monoclonal abs are approved now eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH),
Scarce data are available for their use in reversal of AMR (not in early oliguric sever AMR) and ttt of TMA Chronic Antibody-Mediated Rejection Treatment
The aggressive IS used in management of acute ABMR may not be feasible in chronic AMR being slowly progressive.
Data supporting the use of RTX, IVIG are limited and of low evidence(case series) PREVENTION OF ANTIBODY-MEDIATED REJECTION
Prediction:
1- C1q-fixing DSAs Prescence predict allograft loss level 5 evidence
Theepa Mariamutu
3 years ago
Antibody-Mediated Rejection: A Review
This is a narrative review with class 5 evidence
ABMR can be either hyperacute, acute, late acute or chronic based on timing of rejection and cellular and/ or AMR with reference to the phenotype. DSA has an important role rejection
AMR diagnosis:
kidney biopsy (with histopathological examination and C4d staining)
single antigen bead testing – to detect DSA
Banff classification for AMR includes Acute AMR and Chronic AMR whereby 3 features are required for the diagnosis.
Detection of DSA (HLA or non-HLA) in the serum with histological evidence of antibody interaction with the vascular endothelium (linear C4d staining in peritubular capillaries, at least moderate microvascular inflammation or increased expression of tissue gene transcripts pointing towards endothelial injury) are common features in acute and chronic AMR.
ABMR -histological evidence of acute tissue injury must be there in form of either glomerulitis or peritubular capillaritis, intimal or transmural arteritis, acute thrombotic microangiopathy (TMA) or acute tubular injury of no other cause
CABMR -evidence of chronic tissue injury like transplant glomerulopathy, severe peritubular capillary basement membrane multilayering on electron microscopy or new-onset arterial intima fibrosis is seen.
Graft survival has been shown to be inferior in patients with AMR as compared to those without rejection. Patients with chronic AMR have poor graft prognosis with approximately 80% graft loss in 1.9 years post-diagnosis.
AMR phenotypes:
phenotype 1 -occurring early due to pre-formed DSAs
phenotype 2, presenting late, due to de novo DSAs formed usually due to non-adherence or under-immunosuppression
Patients with subclinical AMR has worst graft survival as compared to those with subclinical T cell mediated rejection or no rejection, and hence should be treated. C4d negative AMR is also quite common, up to 55%, is due to complement-independent pathways and has 2.5 times increased risk of graft loss than those without AMR. C4d positive AMR presents earlier, has worse allograft outcomes, and has clinical features like C4d negative AMR. Complement binding DSAs are associated with increased risk of AMR and graft loss, more severe graft injury, more C4d deposition, more micro-circulatory inflammation, and worse graft survival.
Vasculitis in AMR can be seen in up to 21% patients and is associated with 9 times increased graft loss than vasculitis in T cell mediated rejection. Non-HLA antibodies like anti angiotensin type 1 receptor and anti-endothelin type A receptor antibodies also have role in AMR. Transplant glomerulopathy, presenting as double contouring on electron microscopy, usually causes proteinuria and is seen in late stage of AMR indicating irreversible damage leading to graft loss.
AMR prevention pre-transplant:
involves either including the patients in a paired transplant program or desensitization (removal of antibodies to get a negative crossmatch) in a highly sensitized patient.
Various protocols utilized include
High dose intravenous immunoglobulin (IVIG), by anti-idiotypic blockade of alloantibodies and by inhibiting T cell proliferation, cytokine synthesis and complement activation, helps in reducing anti-HLA antibody levels thereby increasing chances of transplantation.
IVIG and rituximab has also been shown to improve chances of transplantation in highly sensitized patients.
Plasmapheresis, IVIG and rituximab combination has been shown to be superior to IVIG alone
Immunoadsorption, with its fast and selective removal of antibodies, helps in rapid desensitization and early transplant.
AMR treatment:
involves
reducing inflammation in the graft
removing factors causing inflammation
prevention of further antibody formation
Subclinical AMR, if not treated, leads to poor graft outcomes.
The treatment modalities used in AMR include:
Plasmapheresis: removes antibodies rapidly, but studies have shown mixed results with plasmapheresis alone. Plasmapheresis with IVIG is superior to plasmapheresis alone.
IVIG: monotherapy not useful, better results when used in association with plasmapheresis and rituximab.
Rituximab in combination with PLEX and IVIG
Proteasome inhibitor bortezomib: Useful if used in conjunction with plasmapheresis, IVIG and rituximab.
Complement inhibitor Eculizumab and C1 esterase inhibitor: Splenectomy with Eculizumab have been shown to be helpful in early severe, refractory AMR.
AMR prevention post-transplant:
protocol biopsies
post-transplant DSA monitoring for early detection and treatment
Under-immunosuppression, due to non-adherence or drug minimization/withdrawal, should be avoided.
Ben Lomatayo
3 years ago
Introduction ;
AMR is complex process that result in micro-vascular inflammation, compliment activation, recruitment of macrophages/monocytes and endothelial damages[5] Willicombe et al showed that AMR was associate with inferior allogratf survival compared to non-rejection[7]. This paper reviewed the current diagnostic criteria for AMR, AMR paradigms, de-sensitization, treatment & preventive strategies
Current diagnostic criteria ; Base on Banff 2013, all 3 required for diagnosis of AMR
Evidence of acute tisssue injury ; one or more of the following
Glomerulitis(g>0) or peritubular capillaritis(ptc>0)
Intimal or transmural arteritis(V>0)
Acute TMA, no other causes
ATI , no other cause
2.Evidence of recent/current antibody interaction with vascular endothelium; at least one of the following
Linear C4d deposition in ptc
At least moderate microvascular inflammation(g + ptc>0)
High expression of tissue gene transcipt = endothelial injury
3. Presence of DSA in the serum(HLA & non-HLA)
Chronic Antibody-Mediated Rejection ; Acute AMR is the major risk factors for
Chronic active AMR. The histology overlaps, based on Banff 2013 Chronic active AMR requires 3 features ;
1.Evidence chronic tissue injury, at least one of the following
Transplant glomerulopathy(cg >0) in absence of TMA
Severe ptc basement membrane multi-layering on EM
New onset arterial intimal fibrosis, on other causes
2.Evidence of antibody interaction with vascular endothelium; at least one of the fellowing
Linear C4d deposition on the ptc
At least moderate microvascular inflammation(cg + ptc >2)
Risk factors ; non-adherence or inadequate immunosuppression
Paradigms in AMR ;
1.Sub-clinical AMR ;
Diagnose by protocol biopsies
Associated with poor graft outcome if left untreated[14,15]
No long-term data that help the development of guidelines for effective therapy.
2.C4d positive Rejection ;
C4d is a split product of complement C4 activation, a marker to antibody injury [18]
C4d deposition in ptc correlates with allograft rejection[16]
C4d deposition with no evidence of AMR has been reported[17]
C4d positivity varies from place to another and the methodology for defecting C4d is also varies from center to another
C4d +ve AMR present early post-transpalnt
Complement-dependent mechanism
Associated with poorer outcome than C4d -ve AMR[17]
3.C4d negative Rejection ;
C4d is negative in 55% of with AMR( -ve C4d with evidence of microvascular inflammation plus DSAs)[18]
C4d -ve AMR present late post-transplant
Complement-independent mechanism
Summary ;
C4d is a poor marker for diagnosis of AMR due to ;
Low sensitivity ( 50-60%)
It has a lot of variations = reproducibility
3.The presence of complement-independent pathway for AMR
Solutions ; due to problems of C4d , Banff 2013 introduced gene expression markers e.g.endothelial transcript into the diagnosis of AMR to compensate for C4d[8]
Antibody-Mediated Vascular rejection ;
Vascular lesions occur in both TCMR & AMR[22]
Vascular lesions of AMR is associated with inferior outcomes compared with those of TCMR[22]
Non-HLA AMR ; Two main groups[23,24]
1.Allo-antibodies ; to antigen other than HLA 2.Auto-antibodies ; against self-antigen Mechanism of injury does not involve integrins as in HLA-Abs
Examples ; angiotensin type I receptor antibodies[25-27]
Complement fixing DSA is associated with lower 5 year graft survival rate compared with non-complement binding DSA & those without DSA. This may due to more severe phenotype of allograft injury, more C4d deposition , & aggressive microvascular inflammation[28]
Transplant glomerulopathy ;
Prevalence 5-20%, may high in sensitized patient ~ 55%
EM is essential for early diagnosis; ptc multi-layering
Poor prognostic features( late signs) are ;
1.Glomerular basement membrane duplication 2.Double contouring or splitting
Prognostic index/score[35] ; based on Cr, protenuria, chronicity on Bx ;
Low risk group(Median survival >60 months from the diagnosis)
Medium risk group = 19 months
High risk group = 1.6 months
Anti-body removal for highly sensitized patients ;
High dose IVIG(2g/kg) ; inhibition of T & B cells proliferation, inhibition of cytokine and complements, anti-idiotypic blockage of allo-antibodies
Better than placebo in reducing HLA DSA in highly sensitized pt[41]
2.IVIG & Rituximab :
Rituximab induces B cell lysis through complement-dependent cyto-toxicity & antibody dependent cellular cyto-toxicity
Blocks B cell actiavtion and their development into plasma cells
No effect on the existing plasma cells because they don’t express CD20
Combination of IVIG + Rituximab was effect desensitization protocol butv more studies are needed in this area[43]
3.IVIG + Rituximab + plasmpheresis(pp) ;
Allograft survival was superior( 92% vs 50%) with these combination comapred to IVIG alone[44]
4.Immuno-adsorption for rapid cross-match conversion ;
This is an effective method for quick desensitization in deceased donor transplant[14]
Compared to plasmpheresis it is more specific, more effective, and not associated with side effect of substitution of FFP or albumin[45,46]
Treatment of Antibody-Mediated Rejected ; Goals of treatments are 1. Decrease inflammation in the allograft 2. Remove factors associated with inflammation 3. Prevent antibody formation without interference with normal immune mechanisms that protect the host against infection
Current options are ; Combinations of ATG, methyl pred, PP, IVIG, B cell deleting agents
RCT is needed to show superiority of the treatment, large sample size, & prolonged follow up[51]
PP ; remove circuating anibodies[42]. It has to be used with other therapies e.g IVIG
IVIG
Rituximab
Proteasome inhibitor
Complement inhibitor e.g Eculizumab, CI esterase inhibitor
Chronic AMR treatment ;
Combination of pulse steroids + Rituximab + IVIG[66]
Participation in Euro-transplant Acceptable mismatch programme
Combination of paired exchange donation + de-sensitization
post-transplantion morning of DSAs
Protocol biopsies for those positive DSAs
Other measures ;
Avoid reduction of immuno-suppression
Patient education & proper financial assessment prior to transplantation
Conclusion ;
Alloimmune responses are the major obstacle to transplantation
AMR diagnosis is based on Banff 2013
Treatment of AMR involve combination of therapies(PP, IVIG, Rituximab, pulse steroid) but no RCT compared the efficacy of each treatment
To prevent AMR ; avoid transplanting sensitized patients, DSA screening & monitoring, protocol biopsies, avoid reduction of immuno-suppression, Desensitization & paired exchange donation
Level of evidence is 5 ; narrative review
Hinda Hassan
3 years ago
this is a narative review so the level is 5
Ferrari, Rossella. (2015). Writing narrative style literature reviews. Medical Writing. 24. 230-235. 10.1179/2047480615Z.000000000329.
Hinda Hassan
3 years ago
This is a review of AMR current diagnostic criteria, paradigms and treatment. For diagnosing acute/ Chronic active Antibody-Mediated Rejection( Banff 2013), 3 features are required. 2 features are common in both acute and chronic active AMR 1-histologic evidence of current/recent antibody interaction with vascular endothelium(at least one of linear peritubular C4d staining , moderate microvascular inflammation (g þ ptc >2) or Increased expression of tissue gene transcripts ) 2- detection of DSAs. The third feature is histologic evidence of tissue injury. In acute it is defined by one or more of the following: a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0) b. Intimal or transmural arteritis (v >0) c. Acute thrombotic microangiopathy (TMA) of no other obvious cause d. Acute tubular injury of no other obvious cause in the chronic active the chronic tissue injury is defined by one or more of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology Hence the diagnosis of AMR is mainly dependent on histologic findings. The principal phenotypes of acute AMR were : Phenotype 1 ( presensitized patient in the early posttransplant period) and Phenotype 2 (de novo DSAs in the late posttransplant period related primarily to nonadherence or inadequate immunosuppression).Clinical manifestations of AMR include proteinuria and a rise in serum creatinine. Current treatment of AMR include antibody removal with plasmapheresis , immunoadsorption , immunomodulation with intravenous immunoglobulin , and lymphocytes depleting agents. Strategies include combinations of these modalities with different success rate.
Dalia Ali
3 years ago
Antibody mediatedrejection
the development of antibodies plays a critical-
role.
and antibodies are considered a major cause of allograft failure.
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
CURRENT DIAGNOSTIC CRITERIA
Single-antigen bead testing, which is used to detect antiHLA antibodies, is the final step in the current techniques used to identify antibodies that can injure the allograft
Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
2. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.
According to the revised Banff 2013 classification
the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Moderate Microcirculatory Changes
the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
The Banff renal pathologists involved with the evaluation of kidney biopsies established the presence of glomerulitis and graded this finding based on the complete occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement.
Phenotypes of Antibody-Mediated Rejection
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION Subclinical Antibody-Mediated Rejection
Protocol biopsies have identified a subgroup of patients with histologic evidence of antibody-mediated injury despite stable creatinine.
Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cellmediated rejection (88%) and no-rejection (90%) groups (P<0.001).
C4d-Positive and C4d-Negative Rejection
C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation.
C4d a poor marker for the diagnosis of AMR
C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
C4d-negative rejection was not different from C4d-positive rejection in any baseline characteristic. Compared to patients with C4d-negative rejection, patients with C4d-positive AMR were more likely to present earlier posttransplantation (median of 14 days vs 46 days for C4d-negative rejections
No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection
demonstrated that vasculitis belongs to both T cellmediated rejection and AMR.
Non-HLA Antibody-Mediated Rejection
into 2 primary categories:
alloantibodies directed against polymorphic antigens that differ between the recipient and donor
and antibodies that recognize self-antigens or autoantibodies.
Patients with complementbinding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graft survival (54%) compared with patients with non-complement-binding donor-specific antiHLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P2.5 g/d is associated with a worse outcome
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
High-Dose Intravenous Immunoglobulin
Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
Intravenous Immunoglobulin and Rituximab
It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen.
combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
high-dose IVIG is inferior to combination therapy.
Immunoadsorption for Rapid Crossmatch Conversion
IA is an effective strategy for rapid desensitization in deceased-donor transplantation
immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin.
Three or more plasma exchanges can be processed during a single session.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune responses that protect patients from serious infections.
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR
Currently, strategies for the treatment of non-HLA antibodies are based on the same principle used for AMR, which mainly involves extracorporeal techniques to remove antibodies, including PLEX or IA
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
Rituximab
In a pilot study of 7 AMR patients treated using PLEX and IVIG at 100 mg/kg/d for 3 days, then 3 times per week for 2-4 weeks, then rituximab 500 mg/m2 for 1 dose if AMR was ongoing at week 4
Proteasome Inhibitor
Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
bortezomib (1.3 mg/m2/dose 3 4 doses) preceded by a single rituximab dose and PLEX prior to each bortezomib dose.
Complement Inhibition
the early use of eculizumab before advanced changes in kidney injury are identified can improve responses and allograft survival.
Chronic Antibody-Mediated Rejection Treatment
series conducted by Fehr et al of 4 adult patients who received steroid pulse and rituximab (375 mg/m2) followed by IVIG (0.4 g/kg/d for 4 days) showed improved kidney allograft function.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
it is well recognized that pregnancies, blood transfusions, and previous organ transplantation are major risk factors for recipient sensitization and AMR.
The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss
However, the C1q binding assay currently is neither widely available nor validated
donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
Patients received IVIG monthly for 4 months with additional infusions at 12 and 24 months or the equivalent volume of placebo. IVIG significantly reduced PRA levels, and more patients in the IVIG group were transplanted (35% vs 17%).
In summary, a reduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure. Education for patients and community nephrologists is advised, as well as appropriate financial evaluations prior to transplantation. Lack of financial support is a major barrier for adherence to the long-term use of immunosuppressive medications. Community physicians tend to lower the dose of CNIs and/or antiproliferative agents based on the longevity of the allograft without considering potential late rejection.
2- level 5
Weam Elnazer
3 years ago
According to the Banff 2013 categorization, all three of the following characteristics must be present for the diagnosis of acute AMR to be established:
1. The presence of one or more histologic features of acute tissue damage on histological examination.
a) At least one histologic demonstration of current or recent antibody interaction with the vascular endothelium
3) Detection of DSAs in the blood (HLA or non-HLA).
Evidence of acute tissue damage on histologic examination: a. Glomerulitis (g > 0) or peritubular capillaritis (ptc > 0)
V > 0 indicates intimal or transmural arteritis.
In the absence of any other clear reason, acute thrombotic microangiopathy (TMA) occurs.
tubular harm that occurs suddenly with no apparent reason (d).
Recent/current antibody contact with the vascular endothelium as shown by histologic findings:
a. C4d staining in the peritubular capillaries with a linear pattern
(g ptc >2) Microvascular inflammation is present in at least moderate amounts.
c. Increased expression of gene transcripts in the tissue that are suggestive of endothelial injury
Identification of Chronic AMR; According to the updated Banff 2013 categorization, three characteristics are required for the identification of chronic, active AMR:
a histologic characteristic indicating chronic tissue damage, or the presence of at least one such feature
A histologic finding indicating an antibody interaction with the vascular endothelium is required in this case.
3) Detection of DSAs in the blood (HLA or non-HLA).
Chronic tissue damage manifests itself histologically as: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA; and b. Transplant glomerulopathy in the presence of chronic TMA.
By using electron microscopy, it was discovered that there was severe peritubular capillary basement membrane multilayering.
c. New-onset arterial intimal fibrosis with no known underlying cause.
The following are examples of histologic evidence of antibody interactions with vascular endothelium: a. Linear C4d staining in the peritubular capillaries; and b. Linear C4d staining in the peritubular capillaries.
(g ptc >2) Microvascular inflammation is present in at least moderate amounts.
c. Increased expression of gene transcripts in the tissue that are suggestive of endothelial injury.
Desensitization to HLA antibodies is achieved by the use of immunomodulating agents.
treatments aimed at lowering levels of anti-HLA antibodies in order to improve kidney function
Transplantation is an option that is viable.
Immunoglobulin administered intravenously at a high dose
An agent that has immunomodulatory properties.
IVIG’s mechanisms of action
T cell growth is one of the things that is inhibited.
Inhibition of cytokine synthesis is the term used.
Complement activation is prevented from occurring.
Alloantibodies are blocked by anti-idiotypic antibodies.
Intravenous Immunoglobulin and Rituximab Rituximab is a kind of immunoglobulin that is given intravenously.
A chimeric monoclonal antibody directed against the CD20 antigen promotes B cell lysis via the activation of the CD20 receptor.
Complement-dependent cytotoxicity and antibody-mediated cellular cytotoxicity are two types of cellular cytotoxicity.
The investigators came to the conclusion that the combination of IVIG and rituximab was effective.
as a desensitization strategy that is successful
Plasmapheresis, intravenous immunoglobulin, and Rituximab are all treatments for leukaemia.
Immunoadsorption for Crossmatch Conversion in a Short Time:
IA is a successful technique for achieving fast desensitization in deceased-donor patients.
transplantation.
The following is the treatment for ANTIBODY-MEDIATED REJECTION:
Plasmapheresis:
PLEX is a fast-acting antibody remover that is considered a typical element of immunotherapy.
Therapy is included in the majority of AMR treatment regimens that have been devised.
When it is effective
in combination with IVIG
The one-year graft survival rate in the PLEX + IVIG group was considerably greater than in the control group.
in comparison to the PLEX alone group (90.9 per cent vs 46.2 per cent, P14.044).
Immunoglobulin administered intravenously:
IVIG is anticipated to be ineffective as a monotherapy for AMR due to its low effectiveness. Allograft performance is improved.
Combination treatment with PLEX and rituximab has shown promising results in several studies.
Inhibitor of the proteasome:
Bortezomib, which is now licensed for the treatment of multiple myeloma, has been approved for the treatment of other cancers as well.
Rescue treatment for AMR is utilized in conjunction with other drugs such as PLEX, IVIG, or rituximab.
as well as some favourable outcomes
Inhibition of the Complement System:
On the effectiveness of Eculizumab, very few data are available, most of which are from single instances.
in individuals suffering from severe AMR
Treatment for Chronic Antibody-Mediated Rejection (CARM):
Chronic pain has been successfully treated using the methods listed above for many years.
AMR, despite the fact that data is scarce.
ASSISTANCE IN PREVENTING ANTIBODY-MEDIATED REJECTION
AMR prevention strategies include the following:
In the case of severely sensitive individuals, transplantation should be avoided.
Using sensitive donor-specific anti-HLA antibodies, we can better stratify immunologic risk.
-LEVEL of evidence 5
Innocent lule segamwenge
3 years ago
Antibody-Mediated Rejection: A Review Introduction
Allograft injury can cause tubulitis, glomerulitis, fibrinoid necrosis and capillaritis.
Antibodies can be produce against HLA-molecules, non-HLA antigens on endothelial cells or against blood antigens
Antibodies cause damage by activating complement, recruitment of leukocytes leading to natural killer cell or macrophage mediated injury
Pathology; Endothelial injury, loss of vascular integrity and coagulation.
Hyperacute rejection: Occurs within minutes of releasing anastomotic clamps.
Acute; Days to weeks, Late acute: 3 months after transplantation.
Chronic rejection: Months to years
Diagnosis of Acute AMR
3 features required
1. Histological evidence of tissue injury defined by any of; glomerulitis, peritubular capillaritis, intimal or transmural arteritis, TMA of no other cause, tubular injury of no other cause.
2. Histological Evidence of current or recent antibody interaction with vascular endothelium e.g C4d staining of ptc,
3. Detection of DSA in serum
Chronic AMR
3 features
1. Histological evidence of chronic tissue injury any of; Transplant glomerulopathy without chronic TMA, severe capillary basement multilayering, new onset intimal fibrosis.
2. Similar to acute AMR for 2&3.
Phenotypes of Antibody-Mediated Rejection
Phenotype 1- occurs due to preformed DSA, in the early transplant period.
Phenotype 2- occurs due to de novo DSA, in the late transplant period.
Paradigms in AMR
1.Subclinical Antibody-Mediated Rejection; Identified on protocol biopsies, patients have stable creatinine with histological evidence of AMR.
2. Non-HLA AMR- could be due antibodies against polymorphic antigens differing between donor and transplant or due to autoantibodies.
3. Transplant glomerulopathy; double contour, GBM duplication or splitting.
A feature of chronic AMR, occurs with proteinuria of more than 2.5 g/day
Requires electron microscopy to diagnose
Antibody removal for highly sensitized patients
High dose Intravenous immunoglobulin (IVIG)
Works as an immunomodulatory agent
Inhibits complement activation, T cell proliferation, cytokine release.
It was found to be better than placebo with efficacy of 52%(9/17) in reducing anti-HLA antibodies in sensitized patients.
IVIG and Rituximab
Rituximab is an ati-CD20 monoclonal antibody
Causes B cell lysis and blocks B cell activation.
Does not affect already formed plasma cells which lack CD20.
Has been found to be effective in desensitization a regimen when combined with IVIG.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
This combination lead to graft survival at 36 months of 91.7% in vs 50% with IVIG alone.
Immunoadsorption for Rapid Crossmatch Conversion
Appears to be better than plasmapheresis with faster clearance immunoglobulins.
Treatment of antibody-mediated rejection
Plasmapheresis
Removes preformed antibodies.
Has been found to be beneficial in randomized controlled trials.
Intravenous Immunoglobulin
Useful in combination with other modalities.
Rituximab
Main concern is infections.
Proteosome inhibitors
Removes plasma cells that produce antibodies.
Bortezomib has been used as rescue therapy for AMR in combination with IVIG, PLEX and rituximab.
Complement Inhibition
Eculizumab a C5a inhibitor and C1-INH
Mixed results with use of Eculizumab in AMR.
Chronic Antibody-Mediated Rejection Treatment
Similar agents have used in the treatment of chronic AMR.
Data is limited due to the slow progression of chronic AMR
What is the level of evidence provided by this article?
This is a review article.
It is not an ideal to consider it as level of evidence. It has discussed a few studies on the different treatment aspects.
I would rank it between level IV and V.
Mohamed Mohamed
3 years ago
I. Antibody-Mediated Rejection: A Review Please summarise this article
Introduction AMR is a well recognized cause of allograft failure. Complex interactions between cellular & molecular processes cause a range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, & fibrinoid necrosis). Complement system is activated when antibody binds to HLA-or ABO-antigens, & non-HLA antigens expressed on the endothelium. This leads to recruitment of leukocytes & facilitation of NK cell–mediated or macrophage–mediated cytotoxicity, that leads to endothelial damage, loss of vascular integrity, & increased coagulation. Allograft rejection classified as:
– Hyper-acute (within minutes after transplant)
– Acute (after days to weeks)
– Late acute (3 months after transplant)
– Chronic (months to years). Pathophysiologically rejection is classified as cellular &/or AMR. AMR occurs in 10% & graft survival is inferior to those with no rejection (Willicombe et al). Graft survival is improving with new advances in immunology & use of new drugs. This article reviews the current diagnostic criteria for AMR, its treatment, & prevention modalities. Current diagnostic criteria Although CDC is still present in many centers, SAB is now widely used to detect anti-HLA antibodies, monitor recipients & as a diagnostic tool for AMR. LM cannot detect early changes in many biopsies & EM is therefore being increasingly used. The Banff classification believed improved sensitivity survival.in the diagnosis & data about allograft vV& Acute antibody-mediated rejection (banff 2013) All of the following are required for the diagnosis: (1). Histologic evidence of acute tissue injury defined by 1 or more of the following: a. Glomerulitis (g >0) or PTC (ptc >0) b. Intimal or transmural arteritis (v >0) c. Acute TMA of no other cause d. Acute tubular injury of no other cause (2). Histologic evidence of antibody/vascular endothelium interaction, defined by one of the following: a. Linear C4d staining in the PTCs b. At least moderate MVI (g+ptc >2) c. Increased tissue gene transcripts 3. Detection of DSAs (HLA or non-HLA) in the serum Chronic antibody-mediated rejection (Banff 2013) Diagnosis requires 3 features: 1. Histologic evidence of chronic tissue injury, defined by at least 1 of the following: a. TG (cg >0) in the absence of chronic TMA b. Severe PTC BM multilayering (by EM) c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by at least 1 of the following: a. Linear C4d staining in the PTCs b. At least moderate MVI (g+ ptc >2) c. Increased expression of tissue gene transcripts 3. Detection of DSAs (HLA or non-HLA) in the serum
Increased risk of allograft loss was associated with:
– Chronicity scores >8
– DSA >2,500 MFI
– S. creatinine >3 mg/Dl
– Urine PCR >1 g/g Phenotypes of AMR (2011 Banff report):
– Phenotype 1: early posttransplant in presensitized patients.
– Phenotype 2 due to de novo DSAs: occurs late posttransplant; related to nonadherence or inadequate IS. Subclinical antibody-mediated rejection
– Diagnosed by protocol biopsy.
– Evidence of AMR despite stable creatinine.
– No strong guidelines of therapeutic interventions due to lack of long-term follow-up.
– Poorest graft survival at 8 years compared with the subclinical TCMR & no-rejection groups
– Risk of allograft loss if left untreated (Orandi et al) C4d-positive & C4d-negative Rejection
– C4d is split product of C4 activation
– No known biologic action
– Variable frequency depending on methods of detection, positivity threshold & prevalence of highly sensitized patients.
– Isolated C4d positivity without allograft injury has been reported.
– C4d is a poor marker for the diagnosis of AMR due to: @ Low sensitivity (50%-60%) @ 55% can have a C4d-ve rejection @ Presence of complement-independent pathways @ Poor reproducibility
– Owing to its low sensitivity, Banff 2013 included increased expression of endothelial activation & injury transcripts in the tissue biopsy.
– C4d-negative AMR are reported both in on cause & protocol biopsies.
– Orandi et al compared C4d-ve with C4d+ve in terms of the risk of allograft loss: – Similar baseline characteristics. – C4d+ve AMR presented earlier. – C4d +ve AMR 3 times more common. – Better graft survival at 1 & 2 years in C4d-ve AMR. – C4d-ve AMR has increased risk of graft loss compared to no-AMR. – Anti-HLA DSA class was not different between the 2 groups Antibody-Mediated Vascular Rejection Seen in both TCMR & AMR. Non-HLA Antibody-Mediated Rejection
– Classified into: – Alloantibodies (recognize polymorphic antigens that differ between the recipient & donor) – Autoantibodies (recognize self-antigens)
– Not well defined by available tests
– Not included in the revised Banff 2013 classification.
– AT1R & ET type A receptor antibodies are implicated as markers of endothelial injury. Role of complement-binding anti-HLA antibodies in kidney allograft failure (Loupy et al):
– Lower 5-year graft survival compared with non-complement-binding DSAs & non-DSA.
– Increased risk of allograft loss
– Increased rate of AMR
– More severe graft injury phenotype with increased microcirculatory inflammation
– C4d deposition. Transplant Glomerulopathy
– GBM duplication, double contouring, or splitting
– A late stage of irreversible antibody-mediated injury
– Indicator of poor graft survival.
– Prevalence: 5%-20%; 55% in high-risk cohorts (T cell CDC-XM).
– Proteinuria >2.5 g/d is associated with a worse outcome.
– Strongly associated with preexisting or de novo DSAs.
– EM is the best tool for early diagnosis(Banff 2013 meeting)
– A prognostic index may guide prognosis & treatment (Patri et al). Desensitization to HLA antibodies: A. Immunomodulating agents- high-dose IVIG:
– Inhibit T cell proliferation
– Inhibit cytokine synthesis
– Inhibit complement activation
– Anti-idiotypic blockade of alloantibodies
– Better than placebo in highly sensitized (Jordan et al) B. IVIG & Rituximab:
– Rituximab induces B cell lysis via CDC & antibody-mediated cellular cytotoxicity.
– Plasma cells not affected (no expression of CD20 antigen).
– Combination of IVIG & rituximab was fo C. Plasmapheresis, IVIG, & Rituximab vs IVIG alone:
– High-dose IVIG was inferior to this combination(Lefaucheur et al). D. IA for Rapid XM Compared to PLEX:
– More specific & effective removal of circulating Igs without S/Es of FFP or albumin.
– Rapid (few hours) & selective antibody depletion.
– Effective for rapid desensitization in deceased-donor transplantation(Bartel et al). Studies looking into the effect of treatment in patients with DSA-associated AMR: 1. No change in DSA levels or histopathology with monthly high dose IVIG, & pulse steroids (Wiebe et al). 2. Archdeacon et al described 13 case series & controlled trials using different treatment modalities: – AMR is less common than acute TCM – Incidence of AMR exceeds 25% in highly sensitized patients , & more severe injuries leading to late allograft failure. 3. Orandi et al compared 219 patients with AMR to matched controls: – Subclinical AMR was associated with increased risk of allograft loss but was not different from clinical AMR. – Treated subclinical AMR patients had no difference in graft loss compared to matched controls 4. Plasmapheresis rapidly removes preformed antibodies: – An RCT by Bonomini et al found it to be beneficial. – Two controlled trials by Blake et al & Allen et al found no benefit. – Kirubakaran et al found potential harm with PLEX. – PLEX significantly decreased DSAs to pretransplant levels in 4 of 5 patients, & improved renal function in all patients (Pascual et al) – Slatinska et al: combination of PLEX & IVIG was superior to PLEX alone in terms of 1 year graft & patient survival. 5. Rituximab: – Faguer et al, reported a 75% graft survival at 10-month with 50% infectious complications. – Mulley et al found 100% graft survival at 21-month using PLEX, IVIG & rituximab. – Kaposztas et al retrospectively studied 54 AMR patients compared with historic control: Graft survival was better treatment group. 6. Proteasome Inhibitor (e.g. Bortezomib): Woodle & colleagues: Used as rescue therapy in combination with PLEX, IVIG, or rituximab demonstrated effective AMR reversal. 7. Complement Inhibition – Wongsaroj et al: 7 TMA patients showed full or partial recovery vs 100% graft failure in TMA patients treated with IVIG, rituximab, & PLEX. – Orandi et al found that eculizumab was not effective in severe oliguric early-onset AMR. – The authors reported different rescue therapies in 24 patients with AMR including splenectomy (n=14), eculizumab (n=5), or splenectomy + eculizumab (n=5), in addition to PLEX: Splenectomy + eculizumab may be effective for rescuing & preserving allograft function in early severe AMR.
– Eculizumab, if used early, can improve responses & allograft survival (Yelken et al). Chronic antibody-mediated rejection treatment Slow progressive nature might not allow the use of potent & aggressive immunosuppressives. Fehr et al, in a series of 4 patients who received steroid pulse, rituximab & IVIG, showed improved allograft function. Redfield et al retrospectively reviewed 123 patients with biopsy-proven chronic AMR, treated with steroids/IVIG, & reported improved graft survival. Prevention of antibody-mediated rejection Stratification & prediction of allograft outcomes are not well charachterized. Loupy et al differentiated DSAs by C1q binding(as a measure of the ability to fix complement). The 5-year graft survival was least for C1q-binding DSAs (54%) compared to no-DSAs (94%) & non–C1q-binding DSAs (93%). C1q binding assay is not widely available & not validated. Djamali et al proposed several strategies to prevent AMR:
– Avoid transplanting highly sensitized patients
– Better immunological risk stratification.
– Use of sensitive DSA screening methods.
– PKE program
– Participation in special programs such as the Eurotransplant Acceptable Mismatch Program
– Combining PKE programs with desensitization protocols.
– Monitoring de novo DSAs, using class II HLA epitope matching.
– Performing protocol biopsies Conclusion Alloimmune response is a barrier for successful long-term allograft function. Banff classification criteria has helped standardize the diagnosis of AMR. Treatment of AMR with current therapies has produced a variety of results PLEX & IVIG are the main therapies for the treatment of AMR. RCTs are needed to find surrogate markers & improve the efficacy of therapy. What is the level of evidence provided by this article? Level V: A narrative review; a summary of literature in a way which is not explicitly systematic
Asmaa Khudhur
3 years ago
Summary //
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
The understanding of renal allograft rejection has paralleled new discoveries in human immu- nology and the development of new drugs and biologic products. It is not uncommon for rates of acute rejection to be 0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c.Acutethromboticmicroangiopathy(TMA)ofnoother obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium, defined by at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.10 According to the revised Banff 2013 classification,8 the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplantglomerulopathy(cg>0)intheabsenceof
chronic TMA
b. Severe peritubular capillary basement membrane
multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other
known etiology
2.Histologicevidenceofantibodyinteractionwithvascular
endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes of Antibody-Mediated Rejection
Phenotype 1 occurs in the presensi- tized patient and occurs in the early posttransplant period.
Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immuno- suppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECT
Subclinical Antibody-Mediated Rejection
C4d-Positive and C4d-Negative Rejection
Antibody-Mediated Vascular Rejection
Non-HLA Antibody-Mediated Rejection
Transplant Glomerulopathy
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Desensitization to HLA antibodies involves treatment with immunomodulating therapies de- signed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option
1-High-Dose Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
2-Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement- dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen.
3-Plasmapheresis, Intravenous Immunoglobulin, and Rituximab.
5-Immunoadsorption for Rapid Crossmatch Conversion
TREATMENT OF ANTIBODY-mediated rejection:
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and Rituximab
Rituximab
Proteasome Inhibitor
Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combina- tion with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
Complement Inhibition
The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.
Chronic Antibody-Mediated Rejection Treatment
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited.
Level of evidence 5 / narrative study
Professor Ahmed Halawa
Admin
3 years ago
Dear THOSE WHO THINK IT IS LEVEL I/II EVIDENCE It is level 5 It is a narrative review not a systematic review. Looks you have not read it properly
Heba Wagdy
3 years ago
Rejection involves different cellular and molecular pathways causing allograft injury which may e hyperacute, acute, late acute or chronic and classified into cellular and/or AMR. Current diagnostic criteria: According to Banff 2013 classification Acute antibody mediated rejection:
3 features are required: Histologic evidence of acute tissue injury. Histologic evidence of current/recent antibody interaction with vascular endothelium Detection of DSAs (HLA or non-HLA) in serum. Chronic antibody mediated rejection:
3 features are required: Histologic evidence of chronic tissue injury. Histologic evidence of antibody interaction with vascular endothelium Detection of DSAs (HLA or non-HLA) in serum
Chronic AMR is associated with poor graft survival. Moderate microcirculatory changes:
They are considered highly suspicious for antibody injury.
Vasculitis and high rate of inflammatory cells in microcirculation were associated with poor outcome.
Presence of glomerulitis is determined by occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement Phenotypes of AMR: Phenotype 1: occur in pre-sensitized patient and early post transplant. Phenotype 2: occur due to emergence of de novo DSA in late post transplant period and is related to non-adherence or inadequate immunosuppression. Paradigms in AMR: Subclinical AMR:
Presence of histologic evidence of AMR in protocol biopsy with stable graft function
No guidelines available for treatment, A study showed that untreated subclinical rejection increases the risk of graft loss. C4d positive and C4d negative rejection:
They are similar in baseline characteristics and can’t be differentiated clinically
Now, C4d is not considered mandatory for diagnosing AMR due to presence of independent complement pathway and its low sensitivity.
C4d positive group have poorer graft outcome. Antibody mediated vascular rejection:
Itis associated with higher risk of graft loss than TCMR without vasculitis. Non-HLA antibody mediated rejection:
Non-HLA antibodies are either alloantibodies against polymorphic antigens different between donor and recipient or antibodies recognizing self antigens (autoantibodies).
they are associated with high risk of graft loss, increased rate of AMR and more severe graft injury. Transplant glomerulopathy:
Manifest as basement membrane duplication, double contouring or splitting, electron microscopy provides best tool for diagnosis.
Considered irreversible, indicates poor graft survival.
Frequently causes proteinuria and is associated with chronic AMR. Antibody removal for highly sensitized patients:
Desensitization involves treatment with immunomodulating therapy to decrease level of anti-HLA antibodies to allow transplantation. High dose IVIG IVIG and rituximab Plasmapheresis, IVIG and rituximab Immunoadsorption for rapid crossmatch conversion:
It provides more specific and effective clearance of circulating immunoglobulins without side effects of plasmapheresis
Effective strategy for rapid desensitization in deceased donor transplant Treatment of AMR:
Treatment of subclinical rejection and its benefits are still under investigation, also the effect of treatment on DSA associated AMR is understudied. Plasmapheresis:
Considered standard part of therapy in most protocols, It rapidly removes preformed antibodies. IVIG Rituximab:
A study showed that patients with AMR treated with plasmapheresis, IVIG then rituximab had 100% graft survival at 21-months follow up. Proteasome inhibitor Complement inhibition
Eculizumab and C1 esterase inhibitor are approved for complement inhibition but limited data are available on efficacy in severe AMR Treatment of chronic AMR:
Potent immunosuppression agents may be not feasible due to its slow progression compared to acute AMR.
Treatment with steroids and IVIG was associated with improved graft survival.
Further studies are needed to improve graft survival in chronic AMR. Prevention of AMR:
Avoiding transplantation of highly sensitized patients or enrolling them in special programs, using sensitive DSA screening for better risk stratification, kidney paired donation and desensitization protocols
Monitoring de novo DSA and performing protocol biopsy for early detection and treatment of AMR to improve graft survival.
Avoiding reduction of immunosuppression (intended or due to non adherence)
Ensuring presence of financial support prior to transplantation.
Definitions & histological changes:
Allograft rejection can be classified according to onset to hyperacute, acute, late acute or chronic. Also, Rejection can be classified according to the pathophysiologic event: cellular and/or AMR.
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR
.
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum.
Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g were associated with an increased risk of allograft loss.
Moderate Microcirculatory Changes are highly suspicious for antibody injury and have been associated with poor outcomes.
Phenotypes of Antibody-Mediated Rejection In the 2011 Banff report, 2 principal phenotypes of acute AMR were defined. Phenotype 1 occurs in the pre-sensitized patient and occurs in the early post-transplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late post-transplant period and is thought to be related primarily to non-adherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
· Subclinical AMR: Patients with Subclinical AMR had the poorest graft survival at 8 years post-transplant compared with the subclinical T cell– mediated rejection and no-rejection groups.
· C4d-Positive and C4d-Negative Rejection: C4d was considered a marker for antibody injury; however, up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation. No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group, also patients with C4d-positive AMR were more likely to present earlier post-transplantation.
· Antibody-Mediated Vascular Rejection: The risk of graft loss was higher in antibody-mediated vascular rejection than in T cell–mediated rejection without Vasculitis.
· Non-HLA Antibody-Mediated Rejection: Angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies. Patients with complement binding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graft survival compared with patients with non-complement-binding donor-specific anti HLA antibodies.These antibodies were associated with an increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition. Transplant Glomerulopathy
Transplant glomerulopathy causes progressive allograft failure with a poor prognosis and eventual allograft loss in 40%-70% of patients and is considered a histologic feature associated with chronic AMR that result from recurrent events of endothelial activation injury and repair.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
· High-Dose Intravenous Immunoglobulin used as immunomodulatory agent.
· Intravenous Immunoglobulin and Rituximab
· Plasmapheresis, Intravenous Immunoglobulin, and Rituximab : Combination therapy is superior to a high-dose IVIG alone.
· Immunoadsorption for Rapid Crossmatch Conversion IA was shown in one study as an effective strategy for rapid desensitization in deceased-donor transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
The treatment of subclinical AMR and its potential benefits are still under investigation.Treated subclinical AMR patients had no difference in graft loss compared to matched controls, but untreated subclinical AMR patients had a 3.34-fold higher risk of graft loss compared to matched controls.
Treatment of antibody-mediated rejection includes:
· Plasmapheresis PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.However, the results of the different analyses are conflicting results.
· Intravenous Immunoglobulin The efficacy of IVIG as monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
· Currently, strategies for the treatment of non-HLA antibodies are based on the same principle used for AMR.
· Proteasome Inhibitor as Bortezomib, demonstrate effective AMR reversal, including substantial reductions in DSA levels.
· Eculizumab (an anti-C5 monoclonal antibody)
For Chronic Antibody-Mediated Rejection the previously mentioned therapies have been used for the treatment of chronic AMR although data are limited.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
Several strategies are proposed to prevent AMR, including:
· Avoiding transplantation for highly sensitized patients,
· Better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening,
· Enrolling highly sensitized patients in a paired kidney exchange program,
· Monitoring de novo DSAs,
· Performing protocol biopsies.
· Patient’s education regarding adherence to medications.
· Appropriate financial evaluations and support prior to transplantation.
· Education to Community physicians who tend to lower the dose of CNIs and/or anti-proliferative agents based on the longevity of the allograft without considering potential late rejection.
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. The presence of one or more Histologic feature of acute tissue injury .
2. At least one Histologic evidence of current/recent antibody interaction with vascular endothelium.
3. Detection of DSAs (HLA or non-HLA) in the serum. Histologic evidence of acute tissue injury : a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0) b. Intimal or transmural arteritis (v >0) c. Acute thrombotic microangiopathy (TMA) of no other obvious cause d. Acute tubular injury of no other obvious cause
Histologic evidence of current/recent antibody interaction with vascular endothelium: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury.
Diagnosis of Chronic AMR;
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features: 1. the presence of at least one Histologic feature of chronic tissue injury.
2. the presence of at least one Histologic evidence of antibody interaction with vascular endothelium .
3. Detection of DSAs (HLA or non-HLA) in the serum.
Histologic features of chronic tissue injury are;
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multi layering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology.
Histologic evidence of antibody interactions with vascular endothelium are; a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury.
Phenotypes of Antibody-Mediated Rejection;
1-Phenotype 1 occurs in the pre sensitized patient and occurs in the early post transplant period. 2-Phenotype 2 develops from the emergence of de novo DSAs in the late post transplant period and is thought to be related primarily to non adherence or inadequate immunosuppression.
Types of AMR; 1-Subclinical Antibody-Mediated Rejection 2-C4d-Positive and C4d-Negative Rejection
3-Antibody-Mediated Vascular Rejection 4-Non-HLA Antibody-Mediated Rejection 5- Transplant Glomerulopathy; PREVENTION OF ANTIBODY-MEDIATED REJECTION
1- better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening. 2-The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss. 3- enrolling highly sensitized patients in a paired kidney exchange program . 4- combining kidney paired exchange programs with desensitization protocols. 5-Monitoring de novo DSAs, using class II HLA epitope matching . 6- performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
Antibodies removal for highly sensitized patients
The following protocols are used in desensitization;
1- High-Dose Intravenous Immunoglobulin .
2- Intravenous Immunoglobulin and Rituximab . 3-Plasmapheresis, Intravenous Immunoglobulin, and Rituximab .
4-Immunoadsorption for Rapid Crossmatch Conversion .
Treatment of AMR ;
The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune responses that protect patients from serious infections. Treatment of subclinical AMR; Treated subclinical AMR patients had no difference in graft loss compared to matched controls , but untreated subclinical AMR patients had a higher risk of graft loss compared to matched controls. Treatment Chronic AMR; The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited. Because of the slow progression of chronic AMR compared to acute AMR, subjecting patients to rigorous and potent immunosuppressive agents might not be feasible.
Medication used in the desensitization and treatment of AMR ;
1- Intravenous Immunoglobulin;
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies. The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
2- Rituximab ;
A chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complementdependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20. The combination of IVIG and rituximab was effective as a desensitization regimen .
3-Bortezomib; Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor (PI) astherapy for AMR. Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
4-Complement Inhibition; Eculizumab was approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.Only limited data, usually single cases, are available on the efficacy of eculizumab in patients with severe AMR.Wongsaroj et al reported on the efficacy and safety of eculizumab in treating patients with severe AMR episodes unresponsive to standard treatment with IVIG plus rituximab with or without PLEX. Splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR. The early use of eculizumab before advanced changes in kidney injury are identified can improve responses and allograft survival. 5- Plasmapheresis; PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. Currently, strategies for the treatment of non-HLA antibodies are based on the same principle used for AMR, which mainly involves extracorporeal techniques to remove antibodies, including PLEX or IA.
6-Immunoadsorption for Rapid Crossmatch Conversion; Compared to PLEX, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. IA is an effective strategy for rapid desensitization in deceased-donor transplantation.
What is the level of evidence provided by this article?
The level of evidence is 5( a narrative review).
.
.
Amit Sharma
3 years ago
Antibody-Mediated Rejection: A Review
Please summarise this article
Graft rejection can be either hyperacute, acute, late acute or chronic on the basis of timing of rejection and cellular and/or antibody mediated rejection (AMR) with reference to the phenotype. Donor specific antibodies (DSA) have an important role in AMR. AMR diagnosis: AMR diagnosis has evolved over years. Currently, kidney biopsy (with histopathological examination and C4d staining) and single antigen bead testing, to detect DSA are the two important components essential for diagnosing AMR. Banff classification for AMR includes Acute AMR and Chronic AMR whereby 3 features are required for the diagnosis. Detection of DSA (HLA or non-HLA) in the serum with histological evidence of antibody interaction with the vascular endothelium (linear C4d staining in peritubular capillaries, at least moderate microvascular inflammation or increased expression of tissue gene transcripts pointing towards endothelial injury) are common features in acute and chronic AMR. In acute AMR, histological evidence of acute tissue injury must be there in form of either glomerulitis or peritubular capillaritis, intimal or transmural arteritis, acute thrombotic microangiopathy (TMA) or acute tubular injury of no other cause. In chronic AMR, evidence of chronic tissue injury like transplant glomerulopathy, severe peritubular capillary basement membrane multilayering on electron microscopy or new-onset arterial intima fibrosis is seen. Graft survival has been shown to be inferior in patients with AMR as compared to those without rejection. Patients with chronic AMR have poor graft prognosis with approximately 80% graft loss in 1.9 years post-diagnosis. AMR phenotypes: There are two phenotypes of AMR: phenotype 1, occurring early due to pre-formed DSAs and phenotype 2, presenting late, due to de novo DSAs formed usually due to non-adherence or under-immunosuppression. Patients with subclinical AMR has worst graft survival as compared to those with subclinical T cell mediated rejection or no rejection, and hence should be treated. C4d negative AMR is also quite common, upto 55%, is due to complement-independent pathways and has 2.5 times increased risk of graft loss than those without AMR. C4d positive AMR presents earlier, has worse allograft outcomes and has clinical features similar to C4d negative AMR. Complement binding DSAs are associated with increased risk of AMR and graft loss, more severe graft injury, more C4d deposition, more micro-circulatory inflammation and worse graft survival. Vascultis in AMR can be seen in upto 21% patients and is associated with 9 times increased graft loss than vascultis in T cell mediated rejection. Non-HLA antibodies like anti angiotensin type 1 receptor and anti endothelin type A receptor antibodies also have role in AMR. Transplant glomerulopathy, presenting as double-contouring on electron microscopy, usually causes proteinuria and is seen in late stage of AMR indicating irreversible damage leading to graft loss. AMR prevention pre-transplant: AMR prevention involves either including the patients in a paired transplant program or desensitization (removal of antibodies to get a negative crossmatch) in a highly sensitized patient. Various protocols utilized include 1) High dose intravenous immunoglobulin (IVIG), by antiidiotypic blockade of alloantibodies and by inhibiting T cell proliferation, cytokine synthesis and complement activation, helps in reducing anti-HLA antibody levels thereby increasing chances of transplantation. 2) IVIG and rituximab has also been shown to improve chances of transplantation in highly sensitized patients. 3) Plasmapheresis, IVIG and rituximab combination has been shown to be superior to IVIG alone. 4) Immunoadsorption, with its fast and selective removal of antibodies, helps in rapid desensitization and early transplant. AMR treatment: AMR treatment involves reducing inflammation in the graft, removing factors causing inflammation and prevention of further antibody formation. Subclinical AMR, if not treated, leads to poor graft outcomes. The treatment modalities used in AMR include: 1) Plasmapheresis: removes antibodies rapidly, but studies have shown mixed results with plasmapheresis alone. Plasmapheresis with IVIG is superior to plasmapheresis alone. 2) IVIG: monotherapy not useful, better results when used in association with plasmapheresis and rituximab. 3) Rituximab: 4) Proteasome inhibitor bortezomib: Useful if used in conjunction with plasmapheresis, IVIG and rituximab. 5) Complement inhibitor Eculizumab and C1 esterase inhibitor: Splenectomy with Eculizumab have been shown to be helpful in early severe, refractory AMR. AMR prevention post-transplant: It involves protocol biopsies and post-transplant DSA monitoring for early detection and treatment. Under-immunosuppression, due to non-adherence or drug minimization/withdrawal, should be avoided.
What is the level of evidence provided by this article?
Antibody-Mediated rejection: A Review Level Narrative review
antibody-mediated rejection was a destructive event that cause allograft loss. recently with the evolving knowledge in molecular and histologic changes accompanying this event, therapeutic interventions as well, evolving. antibodies are the major cause of allograft failure. These (DSAs) are produced by B-cells and plasma cells, interact with (HLA) or blood antigens that include non-HLA antigens expressed on the endothelium, leading to activation of the complement system, leading to cell-mediated cytotoxicity that result in endothelial damage and increase coagulation. The allograft injuries include; acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis.
Rejection classification by time:
1- Hyperacute rejection occurring within minutes after vascular anastomosis nowadays it becomes very rare
2- Acute rejection occurs days to weeks after transplantation
3- Late acute occurring 3 months after transplantation
4- Chronic occurring months to years after transplantation
Rejection classification by pathophysiologic event:
1- Cellular
2- AMR
3- Mixed
With the recognition of the role of DSAs, new techniques to detect them, the use of desensitization protocols, and the induction of new drugs, significant progress has been made in an improvement of graft survival.
This article gives describes the classification of AMR and gives the spotlight on the available treatment options
The phenotypes of AMR are:
a- Phenotype 1: due to pre-sensitized recipient, occurs in the early post-transplant period.
b- Phenotype 2: due to emerging de novo DSAs and occurs in the late post-transplant period likely due to non-adherence or low immunosuppression. CURRENT DIAGNOSTIC CRITERIA
Identification of DSAs is the cornerstone step in the prevention of AMR
§ Complement dependent cytotoxicity is still considered the gold standard method for the detection of preformed antibodies.
§ Single-antigen bead test now used to monitor transplant recipients and used as a diagnosed tool for AMR.
§ Electron microscopy is routinely used to examine allograft biopsy to detect early changes.
For diagnosis of allograft pathology; Banff classification has been used, which depend on histologic, immunohistochemical, and serologic factors to increase the sensitivity of the diagnosis and provide outcome data in term of allograft survival.
Despite the major advances in molecular biology and gene rearrangement, the diagnosis of AMR is still dependent on histologic findings (Glomerulitis, intimal arteritis, interstitial fibrosis).
A- Acute AMR: its diagnosis according to Banff 2013 needs the presence of all of the following features:
§ Histologic evidence of acute tissue injury is defined by the presence of one or more of the following:
a- Glomerulitis (g>0) or peritubular capillaritis (ptc> 0)
b- Intimal or transmural arteritis (v>0)
c- C- Acute thrombotic microangiopathy (TMA) of no other obvious cause
d- Acute tubular injury of no other obvious cause
§ Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of
the following:
a- Linear C4d staining in the peritubular capillaries
b- At least moderate microvascular inflammation (g + ptc>2)
c- An increased expression of tissue gene transcripts indicative of endothelial injury (What does mean??//)
§ Detection of DSAs (HA or non-HLA).
B- Chronic AMR: The diagnosis of chronic active AMR requires 3 features: According to revised Banff 2013 to which vascular changes had been added (vasculitis) 1- Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a- Transplant glomerulopathy (cg>0) in the absence of chronic TMA
b- Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c- New-onset arterial intimal fibrosis with no other known aetiology 2- Histological evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a- Linear C4d staining in the peritubular capillaries b- At least moderate microvascular inflammation (g + ptc >2) c- An increased expression of tissue gene transcripts indicative of endothelial injury 3- Detection of DSAs (HLA or nono-HLA) in the serum
The histology of acute and chronic AMR overlaps significantly, and acute AMR is a major risk factor for chronic AMR
The g score was determined based on the per cent of involved glomeruli (occlusion of at least one glomerular capillary by infiltrated leucocytes or endothelial cell enlargement)
g 1 ——1% – 25% of the glomeruli are involved
g 2 —–26% – 50%
g 3 > 50% Types of AMR: A- Subclinical AMR:
Protocol biopsy has identified histological evidence of AMR in spite of normal serum creatinine in the subgroup of patients, which carry a high risk of graft loss if left untreated
B- C4d-Positive and C4d-Negative Rejection
§ C4d is a split product of C4 activation. C4d has no known biological action. It is a marker of antibody injury. The frequency of its positivity varies between centres due to differences in the method used to detect it, the prevalence of highly sensitized patients, and the threshold for C4d positivity (low sensitive marker)
§ It is a poor marker for diagnosis of AMR, because its absence does not exclude AMR. up to 55% of patients can have C4d negative rejection.
§ Positive C4d without evidence of allograft injury has been reported. C4d positive AMR presents earlier and has poorer graft outcome as compared to C4d negative one, although both have the same baseline characteristics.
Therefore, Banff classification 13 has incorporated increased expression of injury transcripts or other gene expression markers of endothelial injury on biopsy. C- Antibody-mediated vascular injury
§ Vasculitis belongs to both T cell-mediated rejection and AMR.
§ The risk of graft loss is higher in antibody-mediated vascular rejection than in T-cell mediated rejection without vasculitis
D- Non-HLA Antibody-Mediated Rejection: it is of two primary types
1- Alloantibodies directed against polymorphic antigens that differ between the recipient and donor
2- Antibodies that recognize self-antigens or autoantibodies
§ Examples of non-HLA antigens are angiotensin type 1 receptor and endothelin type A receptor antibodies.
§ These antibodies currently are not well characterized by the available assays.
§ Complement binding antibodies are more dangerous than non-complement binding.
E- Transplant Glomerulopathy
§ Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting. Electron microscopy should be incorporated into the definition of chronic glomerulopathy according to Banff 2013
§ considered to be a late stage of antibody-mediated injury that is usually irreversible
§ it is of poor graft survival, ultimately lead to graft loss
§ frequent cause of proteinuria.
§ strongly associated with preexisting or de novo DSAs. ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS 1- High-Dose Intravenous Immunoglobulin Mechanism of action includes inhibition of T cell proliferation, inhibition of cytokine synthesis, inhibition of complement activation, and anti-idiotypic blockade of alloantibodies.
IVIG was better than placebo in reducing anti-HLA antibody levels and improving the transplantation rate in highly sensitized patients. 2- Intravenous Immunoglobulin and Rituximab
It induces B cell lysis via complement-dependent cytotoxicity and antibody-mediated cellular cytotoxicity. Also, block B cell activation and maturation to plasma cells that produce antibodies. But it has no effect on pre-existing plasma cells (these cells do not express CD 20) 3- Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
This combination is better than IVIG alone 4- Immunoadsorption for Rapid Crossmatch Conversion
IA allows more specific and effective clearance of the DSAs compared to PLEX
It gives rapid desensitization in deceased-donor transplantation TREATMENT OF ANTIBODY-MEDIATED REJECTION 1- Plasmapheresis
It removes preformed antibodies and is considered part of any protocol for the treatment of AMR.
2- Intravenous Immunoglobulin
Monotherapy with IVIG is of limited efficacy in AMR therapy. Combination therapy with PLEX and rituximab carry better graft outcome
3- Rituximab
A combination of PLEX and IVIG carries a better outcome
4- Proteasome Inhibitor (PI) ,, Bortezomib,, Acts by removing plasma cells (the cells producing antibodies)
Treatment protocols that include Bortezomib provide effective AMR reversal, including substantial reductions in DSA levels.
5- Complement Inhibition
v Eculizumab (an anti-C5 monoclonal antibody) FDA approved treatment for PNH and Atypical HUS
v C1 esterase inhibitor (C1-INH) approved for hereditary angioedema
There is limited data about its use. Some reports early use of eculizumab before progressive changes in kidney injury are identified can improve responses and allograft survival. Chronic Antibody-Mediated Rejection Treatment
Limited data about its treatment PREVENTION OF ANTIBODY-MEDIATED REJECTION Possible strategies are:
· avoiding transplantation for highly sensitized patients,
· better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening,
· enrolling highly sensitized patients in a paired kidney exchange program,
· participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols.
· Monitoring de novo DSAs, using class II HLA epitope.
· performing protocol biopsies
· appropriate immunosuppression dose and avoid unnecessary reduction
· education of the patient with emphasis about drug adherence
The level of evidence is 4 (like a narrative review)
In this article, the author reviewed the AMR in detail
summary:
contrary to past, now we have understood more about molecular basis of AMR. this resulted in less frequent rejection or graft loss compared to the era before this understanding wich also was poor in respect to late novel immune suppressions like Tacrolimus. recognition of cd4 despoistion which is degradation of complement pathway as endothelial injury marker helped in early detection of AMR before even elevation of creatinine level. Rejection is a complexinreplay of multiple pathways. rejection can be hyper acute, acute, late accute or chronic. while chronic occursa months to years post transplantation, late acute is usually seen 3 months after transplantation. even if treated, AMR cases have low survival rates compared ton no rejection cases (wellcomb etal).
current diagnostic criteria:
SAB is now used as diagnostic tool for AMR. CDC is still a gold standard fo preformed DSA’s. electron microscopy is preferrable to light microscopy (not all centres have).
since BANFF2003 criteria the acute cellular rejection was differentiated from AMR. Histologic features still the backbone of diagnosis
Acute AMR/Chronic AMR:
both should have histologic evidence of defines by linear staining of cd4 in pericapillar tubules , at least moderate microvascular inlamamtion (g+>2) in addition to detection of DSAs (either HLA on non-HLA). The main difference is that we have histologic acute tissue injury (golemrulitis, inteimal or transmural arterits and unexplained TMA) in acute AMR while in chronic AMR we have transplant glomerulopathy with chronic TMA, newonset arterial intima fibrosis and severe severe multilayering of peritubular capillary basement membranes defined by electron microscopy)
Phenotypes of AMR:
two phenotypes where defined in BANFF 2011: type one is seen in presensitized patients while phenotype 2 occurs in case of de novo DSA.
…
protocol biopsies defines AMR cases even with stable creatinine level
although cd4 positivity was defined in 1993 as marker of ABM rejection, up to %55 may have negative cd4.
although endarteritis was considered as feature of cellular ejection, it was found with AMR.
NON-HLA AMR:
complement fixing antibodies cause more graft loss compared to non-fixing. non-HLA antibodies alike angiotensin type 1 receptor and endothelin type A may have potential endothelial injury as shown in case reports.
Transplant Glomerulopathy:
TG a late stage of AMR is defined as doubling of glomerular basement membrane. is considered late stage may present with proteinurea and have worse prognosis leading to earlier graft loss
Antibody removal for highly sensetized patients:
High dose IVIG
IVIG isan immune modulator that is thought te have role in T cell iprofileration and cytokine nhibition as well.
IVIG and Rituximab:
was found helpful but still we need confirmation trials
plasmapheresis, IVIG and Rituximab:
was found better than IVIG alone
Immunoadsorption for rapid crossmach conversion:
Immunoadsorption has the advantage of removal of antibodies without need for plasma or albumin load. and maybe more effective in terms of circulating antibody removal
AMR treatment:
plasmapheresis helps in removal of preformed antibodies
IVIG is better when combined with PLEX and Rituximab
Bortezomib (proteasome inhibitor) was shown to be helpfull
complement inhibition with Eculizumab is controvertial
Thanks Mahmud
It is level 5. This is better than your colleagues who said level 1
MICHAEL Farag
3 years ago
level of evidence is 5 as it is a Review
the summary of the article Introduction
In the past AMR was a catastrophic event in kidney post-transplant which eventually leads to graft loss. However, the recent years after advancement of the diagnostic and therapeutic tools, AMR becomes a possible treatable condition but still has its negative impact on the graft survival so the prevention of it still has the priority in kidney transplant era.
The first description of acute AMR identified neutrophils in peritubular capillaries and de novo donor-specific antibodies (DSAs). Almost concomitantly, C4d, a degradation product
of the complement pathway that binds covalently to the endothelium, was identified as marker of endothelial injury and hence of antibody activity. the correlation between DSAs and diffuse C4d deposition (>50%) as diagnostic markers for AMR. A recent research has indicated that B cells and plasma cells produce DSAs that interact with the endothelium, which activates the
cellular pathways responsible for the development of microcirculatory changes and tissue injury.
Current Diagnostic Criteria
– Complement-dependent cytotoxicity is still considered the gold standard for the
detection of preformed antibodies
– Electron microscopy is routinely used for the biopsies of transplant recipients because early changes cannot always be detected with light microscopy.
– The Banff classification for allograft pathology
– Single-antigen bead testing, which is used to detect anti-HLA antibodies, is the final step in the current techniques used to identify antibodies that can injure the allograft
Acute Antibody-Mediated Rejection According to the Banff 2013 classification,8 all of the following 3 features are required for the diagnosis of acute AMR: 1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following: a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause 2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following: a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g> 2, ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum Chronic Antibody-Mediated Rejection The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.10 According to the revised Banff 2013 classification,8 the diagnosis of chronic, active AMR requires 3 features: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum Phenotypes of Antibody-Mediated Rejection
– Phenotype 1 occurs in the pre-sensitized patient and occurs in the early posttransplant period.
– Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression
Can AMR diagnosed although C4d deposition is negative?
Yes
Up to 55% of patients can have a C4d-negative rejection with obvious evidence of
microcirculatory inflammation.
Why? Because, in addition to complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility make C4d a poor marker for the diagnosis of AMR.
Antibody-Mediated Vascular Rejection Traditionally, endarteritis has been associated with cellular rejection; however, a population-based study demonstrated that vasculitis belongs to both T cell– mediated rejection and AMR.
Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are:
– alloantibodies directed against polymorphic antigens that differ between the recipient and donor
– autoantibodies antibodies that recognize self-antigens
Although they are not well characterized by current available tests or included in the revised Banff 2013 classification, angiotensin type I receptor and endothelin type A receptor antibodies
have been implicated as markers of potential endothelial injury in case reports and clinical studies. New specific assays to identify these antibodies would facilitate the understanding and diagnosis of allograft dysfunction and would likely identify molecular pathways for effective
treatment. Transplant Glomerulopathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
It is considered a histologic feature associated with chronic AMR that results from recurrent events of endothelial activation injury and repair.
Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome.
It is strongly associated with preexisting or de novo DSAs
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS A) High-Dose Intravenous Immunoglobulin
It is an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the anti-idiotypic blockade of alloantibodies.
B) Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen.
The researchers concluded that the combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
C)Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
This combination has more potent effect D) Immunoadsorption (IA) for Rapid Crossmatch Conversion
Compared to plasmapheresis, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. this technique may provide rapid and selective antibody depletion in a few hours.
Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by
posttransplant IA.IA is an effective strategy for rapid desensitization in deceased-donor transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
Protocol biopsies and DSA monitoring at predetermined intervals are gaining wide acceptance, primarily at centers that perform HLA- and ABO-incompatible transplants. The treatment of subclinical AMR and its potential benefits are still under investigation.
1- Plasmapheresis (PLEX)
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. The combination of PLEX and IVIG was superior to PLEX alone.
2- Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab
3- Rituximab 4- Proteasome Inhibitor
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor (PI) as therapy for AMR. Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for
AMR with some encouraging results
5- Complement Inhibition
The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.
the efficacy and safety of eculizumab in treating patients with severe AMR episodes unresponsive to standard treatment with IVIG plus rituximab with or without PLEX.
CHRONIC ANTIBODY-MEDIATED REJECTION TREATMENT
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited
PREVENTION OF ANTIBODY-MEDIATED REJECTION
– Avoiding transplantation for highly sensitized patients
– better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening
– enrolling highly sensitized patients in a paired kidney exchange program
– Monitoring de novo DSAs, using class II HLA epitope matching,
– and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and
improve allograft survival
– ensure adherence to Is medications
# Please summarise this article
# Allograft rejection is a complex process that involves the interplay of different cellular and molecular pathways that
cause allograft injuries.
# Allograft rejection can be
– hyperacute: occurring within minutes after the vascular anastomosis .
– acute: occurring days to weeks after transplantation .
– late acute: occurring 3
months after transplantation .
– chronic: occurring months to years after transplantation .
# Rejection can also be
classified according to the pathophysiologic event: cellular or AMR.
# Diagnostic criteria
– Single antigen bead testing
to detect antiHLA antibodies, a diagnostic tool for AMR.
– Complement dependent cytotoxicity
is gold standard for the detection of preformed antibodies.
– Electron microscopy used for the biopsies
– The Banff classification for allograft pathology has improve sensitivity in the diagnosis of rejection and the outcome of allograft survival
# Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
# Chronic Antibody Mediated Rejection
* Acute AMR has been shown to be a major risk factor for the development of chronic AMR.
* According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
# Moderate Microcirculatory Changes
– Introduced in the revised Banff 2013 classification as highly suspicious for antibody injury.
– Only the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcome.
# Phenotypes of Antibody-Mediated Rejection
In the 2011 Banff defined, 2 phenotypes of acute AMR.
* Phenotype 1: occurs in the early posttransplant period in presensitized patient
* Phenotype 2: occurs in the late posttransplant period due to de novo DSA and is thought to be related to non adherence or inadequate immuno- suppression.
# PARADIGMS IN ANTIBODY-MEDIATED REJECTION
*Subclinical Antibody Mediated Rejection
– Protocol biopsies identified patients
with histologic evidence of antibody mediated injury despite stable creatinine.
– Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant .
# C4d-Positive and C4d-Negative Rejection
– The frequency of C4d positivity varies
from center to center because of the methodology used, prevalence of highly sensitized patients, and the threshold for C4d positivity.
– C4d was considered a marker for antibody injury also many patients have a C4d-negative rejection with microcirculatory inflammation.
– The low sensitivity make C4d a poor marker for the diagnosis of AMR,
for this reasons Banff 2013 classification increased expression of endothelial activation and injury transcripts or gene expression markers of endothelial injury in the biopsies.
– C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the
presence of DSAs.
– patients with C4d positive AMR were more likely to present earlier posttransplantation than C4d negative patient.
# Antibody Mediated Vascular Rejection
Endarteritis has been associated with
cellular rejection, however, study
demonstrated that vasculitis belongs to both T cell mediated rejection and AMR.
# Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified
into 2 categories:
* Alloantibodies directed against
polymorphic antigens that differ between the recipient and donor
* Antibodies that recognize self antigens or autoantibodies.
– Angiotensin type I receptor and endothelin type A receptor antibodies
have been implicated as markers of potential endothelial injury
– Patients with complement binding DSA after transplantation had a lower 5-year graft survival compared with patients with non complement binding DSA and patients without DSA
# Transplant Glomerulopathy
* Manifested as glomerular basement membrane duplication, double contouring, or splitting.
* Glomerulopathy causes proteinuria.
associated with a worse outcome
and is strongly associated with preexisting or de novo DSAs.
* late stage of antibody mediated injury that is usually irreversible and an
indicator of poor graft survival.
# ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
* Desensitization to HLA antibodies
involves treatment with immunomodulating therapies to reduce levels of anti-HLA antibodies to make
kidney transplantation a feasible option.
#High Dose Intravenous Immunoglobulin
(IVIG) is considered an immunomodulatory agent. It cause inhibition of T cell proliferation, cytokine synthesis, complement activation, and the antiidiotypic blockade of alloantibodies.
* IVIG reducing anti HLA antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease.
# Intravenous Immunoglobulin and – Rituximab
– Rituximab a chimeric monoclonal antibody against the
CD20
– Induces B cell lysis via complement dependent cytotoxicity and antibody mediated cellular cytotoxicity.
– It blocks B cell activation and maturation to antibody forming plasma cells
– It does not affect existing plasma cells
– Combination of IVIG and rituximab was effective as a desensitization regimen
# Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
* Study conducting that combination of plasmapheresis , IVIG, and rituximab superior to high dose IVIG alone.
# Immunoadsorption for Rapid Crossmatch Conversion
* Compared to PLEX, immunoadsorption (IA) allows more specific and effective clearance of circulating immunoglobulins without the side effects associated with fresh frozen plasma or albumin.
* They concluded that it is an effective strategy for rapid desensitization in deceased donor transplantation.
# TREATMENT OF ANTIBODY-MEDIATED
REJECTION
* Different treatment modalities including – rabbit antithymocyte globulin -methylprednisolone
– Plasmapheresis (PLEX )
rapidly removes preformed antibodies and isconsidered a standard part of therapy in most protocols
*combination of PLEX and IVIG superior to PLEX alone.
– Intravenous Immunoglobulin
* The efficacy of IVIG as a mono-
therapy for AMR is likely limited.
* Better allograft outcomes if used in-
combination therapy with PLEX and rituximab.
– Rituximab
– Proteasome Inhibitor
* Removing plasma cells that generate antibodies .
– Bortezomib has been used in combination with PLEX, IVIG, or rituximab for AMR
– Complement Inhibition
* Eculizumab ( anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH),for complement inhibition.
* Eculizumab was used in treating
patients with severe AMR episodes unresponsive to IVIG plus rituximab with or without PLEX.
* patients had AMR with TMA recovered fully or partially after eculizumab compared with graft failure in TMA positive patients treated with IVIG, rituximab and PLEX
* Eculizumab was found not effective in severe oliguric early onset AMR.
* The researchers concluded that splenectomy plus eculizumab may provide an effective intervention for preserving allograft function for patients with early severe AMR.
* The early use of eculizumab before advanced changes in kidney injury are identified can improve responses and
allograft survival.
– B cell depleting agents, muromonab
and maintenance therapy with CNIs, antiproliferative agents,and oral steroid
* Subclinical AMR was independently associated with a risk of allograft loss .
# Chronic Antibody Mediated Rejection Treatment
* Patients who received steroid pulse and rituximab followed by IVIG showed improved kidney allograft function.
* Biopsy proven chronic AMR
treatment with steroids/IVIG was associated with improved graft survival.
#PREVENTION OF ANTIBODY MEDIATED
REJECTION
* The presence of C1q fixing DSAs has emerged as an independent predictor of allograft loss.
* They recognized that pregnancies, blood transfusions, and previous organ transplantation are major risk factors for recipient sensitization and AMR.
* To prevent AMR avoiding transplantation for highly sensitized
patients, better stratifying immunologic risk by using sensitive DSA screening, enrolling highly sensitized patients in a paired kidney exchange program.
* Monitoring de novo DSAs, using class II HLA epitope matching and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
* Reduction of immunosuppression whether physician driven or because of patient nonadherence, is a well recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure.
# What is the level of evidence provided by this article?
level of evidence is I
Not impressed It is level 5 It is a narrative review not a systematic review. Looks you have not read it properly
Tahani Ashmaig
3 years ago
☆ Antibody-Mediated Rejection:
This reviews the current diagnostic criteria for antibody mediated rejection (AMR); AMR paradigms; and desensitization, treatment, and prevention strategies.
INTRODUCTION:
*Allograft rejection:
Is a complex process that involves the interplay of different cellular and molecular pathways that cause a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis).
Types:
_______
1. Hyperacute (occurring within minutes after the vascular anastomosis)
2. Acute (occurring days to weeks after transplantation)
3. Late acute (occurring 3 months after transplantation)
4. Chronic (occurring months to years after transplantation).
☆Classified according to the pathophysiologic event:
1. Cellular
2. AMR
3. Cellular + AMR
CURRENT DIAGNOSTIC CRITERIA for AMR:
____________________________________________
1) Single-antigen bead testing (used to detect antiHLA antibodies) is currently used to:
i. Monitor transplant recipients
ii. Diagnose AMR.
2) Complement-dependent cytotoxicity is still considered the gold standard for the
detection of preformed antibodies.
3) Electron microscopy for the biopsies.
▪︎Banff has differentiated acute cellular rejection from AMR since 2003.
▪︎ In the 12th Banff Conference(2013) different findings were presented to reach consensus on the diagnosis of AMR in the presence and absence of a C4d stain
▪︎The diagnosis of AMR is dependent on histological findings.
*Acute and chronic Antibody-Mediated Rejection:
____________
▪︎Can be diagnosed according to the Banff 2013 classification
▪︎Their histology overlaps.
▪︎Acute AMR has been shown to be a major risk factor for the development of chronic AMR.
▪︎Moderate Microcirculatory Changes is highly suspicious for antibody injury.
▪︎The presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
▪︎The biopsies according to Banff is graded into g1, g2, and g3.
Phenotypes of Acute AMR ( 2011 Banff report):
__________
1) Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.
2) Phenotype 2 develops from the emergence of de novo DSAs in the late post transplant period and is thought to be related primarily to non-adherence or inadequate immunosuppression.
☆PARADIGMS IN ANTIBODY-MEDIATED REJECTION
*Subclinical AMR:
____________________
▪︎Histologic evidence of antibody mediated injury despite stable creatinine.
▪︎These patients had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell– mediated rejection (88%) and no-rejection (90%) groups
▪︎ If left untreated, increased the risk of allograft loss.
*C4d-Positive and C4d-Negative Rejection:
_____________________________________________
▪︎C4d deposition in peritubular capillaries correlates with allograft loss.
▪︎ C4d is split product of C4 activation and has no known biologic action
▪︎C4d positivity without other evidence of allograft injury has been reported.
▪︎ C4d-negative rejection with obvious evidence of microcirculatory inflammation can occur in 55% of patients.
▪︎C4d is a poor marker for the diagnosis of AMR due complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility.
▪︎Because of the low sensitivity of C4d, the Banff 2013 classification incorporates increased expression of endothelial activation and injury transcripts or other gene expression markers of endothelial injury in the tissue biopsy.
▪︎C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies
performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
▪︎ No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome is worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection
__________________________________________
▪︎Vasculitis belongs to both T cell–mediated rejection and AMR.
▪︎The risk of graft loss is higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis
Non-HLA Antibody-Mediated Rejection
__________________________________________
▪︎Are classified into 2 primary categories:
1) Alloantibodies directed against polymorphic antigens that differ between the recipient and donor.
2) Antibodies that recognize self-antigens or autoantibodies.
▪︎Non-HLA antibodies use different pathways to cause endothelial injuries that do not involve the presence of integrins, as with HLA antibodies.
▪︎Angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury.
Transplant Glomerulopathy:
_______________________________
▪︎There is glomerular basement membrane duplication, double contouring, or splitting
▪︎Is considered to be a late stage of AMR that is usually irreversible and an indicator of poor graft survival.
▪︎A frequent cause of proteinuria and is strongly associated with preexisting or de
novo DSAs
▪︎ Diagnosis: by electron microscopy.
▪︎Prognostic index based on the risk factors for allograft failure within 5 years of diagnosis. (The factors considered in the score included serum creatinine, level of proteinuria, and chronic inflammation score at biopsy based on the Banff classification.
▪︎The risk stratification may provide guidance for prognosis and treatment.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS:
___________________________
These includes:
1) High-Dose Intravenous Immunoglobulin
2) Intravenous Immunoglobulin and Rituximab.
3) Plasmapheresis, Intravenous Immunoglobulin, and Rituximab: Superior to high-dose IVIG.
4) Immunoadsorption: This is an effective strategy for rapid desensitization in deceased-donor transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
______________
These include:
1) Plasmapheresis: rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
2) Intravenous Immunoglobulin: The efficacy is better in combination therapy with PLEX and rituximab.
3) Rituximab
4) Proteasome Inhibitor to remove plasma cells: Bortezomib in combination with PLEX, IVIG, or rituximab.
5) Complement Inhibition: Eculizumab and a C1 esterase inhibitor (C1-INH). The early use of eculizumab before advanced changes in kidney injury are identified can improve responses and allograft survival. Splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR.
TREATMENT OF CHRONIC AMR:
__________________
▪︎ Steroid pulse and rituximab (375 mg/m2) followed
by IVIG (0.4 g/kg/d for 4 days)
▪︎Steroids/IVIG was associated with improved graft survival despite the limitations of the review.11
▪︎ Further studies are needed
PREVENTION OF AMR:
_________________________
▪︎Avoiding transplantation for highly sensitized patients.
▪︎Stratifying immunologic risk by using sensitive DSA screening
▪︎Enrolling highly sensitized patients in a paired kidney exchange program
▪︎ Monitoring de novo DSAs
▪︎Using class II HLA epitope matching
▪︎Performing protocol biopsies to early diagnose AMR (DSAs are present before the detection of allograft dysfunction).
▪︎Avoiding reduction of immunosuppression, whether physician driven or because of patient nonadherence.
Not impressed It is level 5 It is a narrative review not a systematic review. Looks you have not read it properly
Reem Younis
3 years ago
-Antibody-mediated rejection (AMR) is considered a major cause of allograft failure.
-C4d, a degradation product of the complement pathway that binds covalently to the endothelium, was identified as a marker of endothelial injury and hence of antibody activity.
-Antibody for HLA or blood antigens, including non-HLA antigens expressed on
the endothelium can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/ macrophage– mediated cytotoxicity, leading to endothelial damage, loss
of vascular integrity, and increased coagulation.
-Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation).
-Rejection can also be classified according to the pathophysiologic event: cellular
and/or AMR.
– One study showed allograft survival was inferior in the AMR group compared with the nonrejection group . CURRENT DIAGNOSTIC CRITERIA
-Single-antigen bead testing, is currently used to monitor transplant recipients and used as a diagnostic tool for AMR.
-Complement-dependent cytotoxicity is still considered the gold standard for the
detection of preformed antibodies.
-The Banff classification improves sensitivity in the diagnosis of allograft rejection and in providing outcome data in terms of allograft survival. -Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury is defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction
with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g +ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification,8 the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g +ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
– The presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes. Phenotypes of Antibody-Mediated Rejection
– Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.
-Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression. PARADIGMS IN ANTIBODY-MEDIATED REJECTION Subclinical Antibody-Mediated Rejection
-Protocol biopsies have identified a subgroup of patients with histologic evidence of antibody-mediated injury despite stable creatinine. C4d-Positive and C4d-Negative Rejection
– C4d has no known biologic action, and it is a split product of C4 activation. C4d
positivity without other evidence of allograft injury has been reported.
-55% of patients can have a C4d-negative rejection with obvious evidence of
microcirculatory inflammation.
-C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies
performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
-No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group. Antibody-Mediated Vascular Rejection
-Vasculitis belongs to both T cell– mediated rejection and AMR. Non-HLA Antibody-Mediated Rejection
– Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and
donor and antibodies that recognize self-antigens or autoantibodies. Transplant Glomerulopathy
– Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splittingand is considered to be a late stage of
antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
-Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
1.High-Dose Intravenous Immunoglobulin
2.Intravenous Immunoglobulin and Rituximab
3.Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
4.Immunoadsorption for Rapid Crossmatch Conversion TREATMENT OF ANTIBODY-MEDIATED REJECTION
-The treatment of subclinical AMR and its potential benefits are still under investigation.
1.Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
2.Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
3.Rituximab
4.Proteasome Inhibitor
-Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for
AMR with some encouraging results.
5.Complement Inhibition
-Eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition Chronic Antibody-Mediated Rejection Treatment
-Biopsy-proven chronic AMR, treatment with steroids/IVIG was associated with improved graft survival despite the limitations of the review. PREVENTION OF ANTIBODY-MEDIATED REJECTION
-The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss.
-Pregnancies, blood transfusions, and previous organ transplantation are major
risk factors for recipient sensitization and AMR.
-Strategies to prevent AMR, including :
-avoiding transplantation for highly sensitized patients, better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, and
combining kidney paired exchange programs with desensitization protocols.
-Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and
improve allograft survival.
-Areduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft
failure.
In the past, AMR was inevitably leading to allograft loss. Mauiyyedi et al described the correlation between DSAs and diffuse C4d deposition (>50%) as diagnostic markers for AMR. Recently, its evidenced that B cells and Plasma cells activate cellular pathways when interacting with the endothelium developing microcirculatory changes and tissue injury.
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
The development of t cell-depleting drugs, calcineurin inhibitors and anti-proliferative drugs has
significantly improved graft survival and decrease the risk of acute rejection to less than 15%
with the introduction of T cell–depleting drugs, calcineurin inhibitors (CNIs), and
antiproliferative agents, the field of transplantation has experienced exceptional improvement in
allograft survival, which was considered impossible in the
Diagnostic criteria of AMR
Despite the major advances in molecular biology and gene rearrangement, the diagnosis of AMR is still dependent on histologic findings.
Acute Antibody-Mediated Rejection
Banff 2013 diagnstic criteria, all of the following are needed:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other
obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g + ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
Acute AMR is a risk factor for chronic AMR, Banff 2013 diagnostic criteria, all of the following
are needed:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g + ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Redfield et al concluded that chronic AMR was associated with poor graft survival after diagnosis, poor prognostic features included: Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g
Moderate Microcirculatory Changes
Microcirculatory changes that are highly suspicious for antibody injury and poor graft outcome, includes: vasculitis and the high rate of inflammatory cells in the microcirculation
The g score was determined based on the percent of involved glomeruli: 1%-25%, 26%-50%, and >50% equate to g scores of g1, g2, and g3, respectively. Glomerulitis was graded depending on the finding of complete occlusion of one or more glomerular capillary by leukocytes infiltration and endothelial enlargement.
Phenotypes of Antibody-Mediated Rejection
Phenotype 1 occurs in the pre-sensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
Subclinical Antibody-Mediated Rejection
A subgroup of patients has histologic evidence of AMR despite of normal creatinine level. Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell–mediated rejection (88%) and no-rejection (90%) groups.
C4d-Positive and C4d-Negative Rejection
C4d has no known biologic action, and it is a split product of C4 activation. C4d positivity varies from center to center because of the methodology used to detect C4d, the prevalence of highly sensitized patients, and the threshold for C4d positivity. C4d positivity is a poor marker for the diagnosis of AMR.
C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies performed because of graft dysfunction and in protocol biopsies of grafts with stable function C4d negative AMR present later than C4d positive AMR (No clinical characteristic could distinguish C4d-negative from C4d-positive rejection,) and 2.5X increased risk of graft loss compared to AMR negative patients.
Antibody-Mediated Vascular Rejection
Vasculitis is not exclusive for AMR, it occurs with TCMR also. Antibody-mediated vascular rejection has 9 times more risk of graft loss than in T cell–mediated rejection without vasculitis
Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies. Non-HLA Abs include angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies.
complement-binding capacity of anti-HLA antibodies played a role in kidney allograft failure, patients with complement binding DSAs have increased risk of allograft lost at 5 years follow up compared to non-compliment binding DSAs and no DSAs at all. Also, they were associated with an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
Transplant Glomerulopathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome (graft loss of 92% vs 33%,P<0.005) and is strongly associated with preexisting or de novo DSAs.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED
PATIENTS
Approximately one-third of patients awaiting a deceased donor kidney transplant have circulating anti-HLA antibodies, and almost 15% have a high degree of sensitization to potential kidneys. Desensitization reduces levels of anti-HLA antibodies to make kidney transplantation a feasible option. Options include: High dose IVIG, IVIG and Rituximab, Plasmapheresis with Intravenous Immunoglobulin and Rituximab, Immunoadsorption for Rapid Crossmatch Conversion
High-Dose Intravenous Immunoglobulin
Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the ant idiotypic blockade of alloantibodies IVIG was better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease
Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen. the combination of IVIG and rituximab was effective as a desensitization regimen, but needs larger trials to evaluate the efficacy of this intervention.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
The triple therapy has a better outcome than high dose IVIG on graft survival but larger studies are needed.
Immunoadsorption for Rapid Crossmatch Conversion
immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin compared to plasmapheresis. Immunoadsorption is an effective strategy for rapid desensitization in deceased-donor transplantation
TREATMENT OF ANTIBODY-MEDIATED REJECTION
The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune responses that protect patients from serious infections.
Only a few studies to date have reported on the effect of treatment in patients with DSA associated AMR. Wiebe et al reported no impact on DSA levels or histopathology from optimization of baseline immunosuppression, monthly high dose IVIG, and pulse steroids
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. The data is debatable with some studies show benefits of PLEX, others no benefits and others considered PLEX as harmful!
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
Rituximab
Rituximab solely for AMR has inferior results than combination of Rituximab, IVIG and PLEX.
Proteasome Inhibitor
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor. experience with PI-based AMR therapy demonstrated that it provides effective AMR reversal, including substantial reductions in DSA levels
Complement Inhibition
Eclizumab treatment for patients with TMA has superior results than IVIG, Rituximab and PLEX combination. Splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR
Chronic Antibody-Mediated Rejection Treatment
The previous treatment modalities are harmful to apply for long periods on patients with chronic AMR.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
few tools are available that can be used to stratify and predict allograft outcomes or patients at risk for allograft failures.
The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss pregnancies, blood transfusions, and previous organ transplantation are major risk factors for recipient sensitization and AMR.
Proposed strategies to prevent AMR, include: avoiding transplantation for highly sensitized patients, better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols, Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies a reduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure.
Finally, there is no straightforward algorithm to treat AMR, treatments modalities need larger well controlled studies and may need to be individualized for each patient apart!
The level of evidence is II (a review article)
Shereen Yousef
3 years ago
It is a review article, level 2 evidence ,
INTRODUCTION
Allograft rejection is a complex process
Antibody ligation to human leukocyte antigen (HLA) or blood antigens, including non-HLA antigens expressed on the endothelium,can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/macrophage– mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
CURRENT DIAGNOSTIC CRITERIA
*Acute Antibody-Mediated Rejection
According to the Banff 2013 classification all of the following 3 features are required for the diagnosis of acute AMR:
1 Histologic evidence of acute tissue injury with one or more of the following:
Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
Intimal or transmural arteritis (v >0)
Acute thrombotic microangiopathy (TMA) of no other obvious cause
Acute tubular injury of no other obvious cause
2 Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
Linear C4d staining in the peritubular capillaries
At least moderate microvascular inflammation (g þ ptc >2)
Increased expression of tissue gene transcripts indicative of endothelial injury
3 Detection of DSAs (HLA or non-HLA) in the serum.
*Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1 Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
Transplant glomerulopathy (cg >0) in the absence of chronic TMA
Severe peritubular capillary basement membrane multilayering identified by electron microscopy
New-onset arterial intimal fibrosis with no other known etiology
2 Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
Linear C4d staining in the peritubular capillaries
At least moderate microvascular inflammation (g þ ptc >2)
Increased expression of tissue gene transcripts indicative of endothelial injury
3 Detection of DSAs (HLA or non-HLA) in the serum
chronic AMR was associated with poor graft survival after diagnosis.
●Moderate Microcirculatory Changes
presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
Presence of glomerulitis is established in biopsy when there is complete occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement.
2 principal phenotypes of acute AMR were defined.
*Phenotype 1 occurs in the presensi-tized patient in the early posttransplant period. *Phenotype 2 due to de novo DSAs in the late posttransplant period primarily to nonadherence or inadequate immuno-suppression.
Paradigm in antibody mediated rejection
●Subclinical Antibody-Mediated Rejection
protocol biopsies was done in some Patients with stable creatinine showed evidence of AMR they had the poorest graft survival at 8 years compared with the subclinical TCR or no rejection ,subclinical AMR, if left untreated, increased the risk of allograft loss.
●C4d-Positive and C4d-Negative Rejection
the Banff 2013 classification incorporates increased expression of endothelial activation and injury transcripts or other gene expression markers of endothelial injury in the tissue biopsy. C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs .
patients with C4d-positive AMR were more likely to present earlier in posttransplantation ,C4d-negative AMR patients had better survival thsn c4d positive receipts.
●Antibody-Mediated Vascular Rejection
vasculitis belongs to both T cell– mediated rejection and AMR.
graft loss was higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
●Non-HLA Antibody-Mediated Rejection
Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graf survival. These antibodies were associated with an increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
●Transplant Glomerulopathy
It is manifested as glomerular basement membrane duplication, double contouring, or splitting it is a late stage of antibody-mediated injury that is usually irreversible lead to poor graft survival.
Transplant glomerulopathy is a frequent cause of proteinuria and is strongly associated with preexisting or de novo DSAs.
▪︎ ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
*High-Dose Intravenous Immunoglobulin
IVIG reducing anti-HLA antibody and improving transplantation rates in highly sensitized patients
*Intravenous Immunoglobulin and Rituximab
combination of IVIG and rituximab was effective as a desensitization regimen but more studies are needed
*Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
combination of the three agents is considered better than the IVIG alone.
*Proteasome Inhibitor.
used in combination with PL EX, IVIG, or rituximab as therapy for AMR with good results.
*Complement Inhibition.
still need more studies
Prevention of AMR
Proper matching for receiptnt and
Doner
avoiding transplanting highly sensitized receptient
Encourge paired exchange for proper matching and better allocationof graft
monitoring of DSA after transplantion and protocol biopsy.
Chronic antibody mediated rejection ( AMR) is a serious disorder and significantly contributes to the limited survival of renal grafts. therefore, it is an area of active research.
Despite there was a better understanding AMR and the potential therapeutic approaches in recent years, several pathways are still unknown about the pathophysiology of AMR. therefore, there is a lack of efficacy of currently available agents
This article was a review study of the current diagnostic criteria for AMR and also the related management.
The results of this review study was as following :
1- AMR results in transplant glomerulopathy, manifested by basement membrane duplication or splitting.
2- the clinical manifestations of AMR include proteinuria and increased S. creatinine.
3- treatment modalities include the following :
a- plasmapharesis.
b- immunoadsorption.
c- immunomodulation with IVIG.
d- T-cell or B-cell depleting agents.
e- Rituximab.
f- Bortezomab : – proteosome inhibitor, of low significant benefits as documented in most recent studies.
g- Eculizomab.
The conclusion :
1- AMR is an area of active research.
2- allo-immune reaction remains a significant barrier for successful long-term graft function despite advanced techniques in allo-antibody detection.
3- new therapies are promising but high-powered studies are still awaited for confirming efficacy
What is the level of evidence provided by this article?
the level of evidence is II
Ban Mezher
3 years ago
Level of evidence 1
AMR considered as dangerous complication of solid organ transplantation leading to graft loss. Now after better understanding of causes & pathogenesis of rejection with improvement in IS used for treatment, there was an improvement in graft survival.
DSA is the most important factor in development of AMR. Acute rejection can be classified according to the time of occurrence (hyper acute, acute, late acute, & chronic) or according to the histopathological events ( cellular, & humoral)
The incidence of AR decline dramatically (<15%) after development of T cell depleting agent, CNI, & anti proliferative.
Banff classification can differentiate between ACR & AMR.
Features of AMR according Banff 2013 classification:
histological evidence of of acute tissue injury( g>0, ptc>0), arteritis, acute TMA
histological evidence of recent Ab interaction with vascular endothelium( linear C4d staining inputs, g+ptc>2), increase expression of tissue gene transcripts
+ve DSA ( HLA or non HLA)
Features of chronic AMR according Banff 2013 classification:
histological evidence of chronic tissue injury ( TG, severe pic basement membrane multilayering & new onset intimal fibrosis)
histological evidence of Ab interaction with vascular endothelium ( linear C4d staining inputs, g+ptc>2, & increase expression of tissue gene transcript)
+ve DSA ( HLA & non HLA).
There are several factors increase the risk of graft loss including:
chronicity scor >8
DSA >25000 MFI
S. crat >3 mg/dl
urinary PCR > 1g/g
Banff 2011 report recognize to AMR subtypes:
type 1: usually occur in presensitized recipients during early post transplant period
type 2 : occurrence associated with de novo DSA usually in late post transplant period, commonly among non adherent recipients.
Subclinical AMR: defined as histological evidence of acute AMR with normal serum creatinine detected by protocol biopsy. It is associated with poor graft survival at 8 years (56%) when compared with subclinical cellular rejection (88%) & no rejection (90%).
previously C4d +ve was considered as marker of Ab dependent injury, but about 55% of AMR was C4d negative with strong evidence of microcirculatory inflammation. So C4d negative rejection mean microvascular inflammation associated with presence of DSA.
Non HLA AMR:
Non HLA Abs are either autoantibodies or Ab against polymorphic AG which is differ between donor & recipients. It can cause endothelial injury with out involvement of integren. Angiotensin type 1 receptor, & endothelia type A receptor Abs are marker of endothelial injury of non HLA Abs.
TG:
Histological feature of chronic AMR due to repeated attacks of endothelial injury & repair. It can lead to graft loss in 40%-70% of patients. Proteinuria > 2.5 g/day in TG associated with poor outcome. EM is the best test used to diagnose TG.
30% of patients on waiting list are sensitized & about 15% had high degree go sensitization. Desensitization therapy include:
High dose of IVIG which can act through : inhibition of T cell proliferation, cytokine synthesis, complement activation & anti-idiotypic blocker Abs.
IVIG + rituximab: rituxmab will cause B cell lysis through complement dependent cytotoxicity & Ab mediated cellular cytotoxicity.
PLEX +IVIG+rituximab
Immunoadsorption for rapid cross match conversion: more specific & more effective clearance than PLEX with out side effects of FFP & albumin as a substitution. It can remove Abs rapidly ( few hours).
Treatment of AMR:
PLEX: standard AMR treatment, remove Ab rapidly
IVIG used in combination with PLEX & rituximab
Rituximab
Bortezomib : rescue therapy added to PLEX + IVIG+ rituximab
Complement inhibitorsL eculizumab used as treatment for severe AMR not responding to standard treatment
Treatment of chronic AMR: because of the nature of chronic AMR ( saw progression) so potent IS may be of little effect. Redfield et al show that steroid/ IVIG had an improvement in graft out come.
Prevention of AMR:
avoid transplant for highly sensitized recipients
using of sensitive DSA screening to stratify immunological risk
enrolled sensitized patients into paired kidney exchange program.
participation of Eurotransplant Acceptable Mismatch Program
combining kidney paired exchange program with desensitization protocol.
post transplant DSA monitoring, protocol biopsy, & class II epitope match.
Wael Jebur
3 years ago
AMR is the main cause of chronic allograft failure.DSAs were strongly strong linked to the allograft outcome,this article is reviewing the evidences of its importance,elaborating on the different angles of its involvement in progress of acute and chronic allograft rejection.
It’s formed when there is HLA antigens mismatch due to previous transplantation, blood transfusion and pegnancy.
It might be formed pre_transplantation due to the reasons mentioned up. Or it’s formed post transplantation as De novo DSAs. It can be associated with hyperacute rejection and having positive flow cytometry assay cross match and complement dependent lymphocytotoxicity CDC is an absolute containdication for transplantation .
Several factors outline the risk of AMR, including type of DSAs, herefore, IgG 1 and IgG 3 are associated with higher risk of acute rejection. IgG 4 is associated with chronic AMR.
C1q assay is to test for potential complement fixing of the DSAs, while C1q positive DSAs are associated a risk of acute AMR,C1q negative DSAs are associated with higher risk of chronic AMR.
Similarly phenotype of DSAs are important in a way DSAs against HLA class I are associated with complement fixing and higher risk of acute AMR, on the other hand DSAs against HLA class II ARE NON COMPLEMENT fixing and associated with chronic AMR by natural killer Cells dependent reaction.
Acute AMR: either early days to weeks after transplantation, or acute late 3 months after transplantation.
Was diagnosed according to Banff classification,3 features are required to diagnose Acute AMR:
1_Histologic evidence of acute tissue injury
a:Glomerulitis or peritubular capillaritis.
b_Intimal ortransmural arteritis
c_Acute thrombotic microangiopathyTMA of no other obvious cause.
d_Acute tubular injury o no other cause.
2_Histologic evidenceof current/recent antibody interaction with vascular endothelial defined by
One of the following:
a_Linear C4d staining in the peritubular capillaries .
b_At least moderate microvascular inflammation (g+ptc of more than 2)
C_Increased expression of tissue gene transcripts,indicative of endothelial injury.
3_Detection of DSAs(HLA or non HLA) in the serum.
Chronic AMR:
IT happened months or years after transplantation.
Acute AMR is the main risk factor for chronic AMR.
3 features should be there in order to diagnose Chronic AMR:
1_histologic evidence of chronic tissue injury. Defind by the presence of one of the following:
a_Transplant glomerulopathy in the absence of chronic TMA.
b_Severe peritubular capillary basement membrane multilayered shown by electrone microscopy.
c_Intemal fibrosis with no other etiology.
2_Histologic evidence of antibody interaction with vascular endothelial,defined by presence of one of the following:
a_Linear C4d in peritubular capillaries.
B_microvascular inflammation.
C_increased expression of tissue gene transcripts ,indicative of endothelial injury.
3-DSAs(HLA or non HLA) ln serum.
Risk factor for deterioration of allograft function after the diagnosis of chronic AMR. Redfeild et al
1_chronisity score more than 8
2_DSA more than 2500 MFI.
3_Serum creatinine of more than 3
4_Protein /creatinine ratio of more than 1 g/g.
In general ,chronic AMR is associated with poor graft survival after diagnosis.
In DeKAF study found high frequency of Antibody _mediated injury (as indicated by C4d and circulating DSAs)
Similarly ,microvascular changes where recognized by Banff 2013 classification as highly suspicious of antibody injury.
Non HLA antibodies in the form of angiotensine type 1 receptor,and endothelial type a receptors were implicated as markers of endothelial injury.
Desensitization of patients with anti HLA antibodies:
1_High dose intravenous Immunoglobulin.:immunomodulatory agent with several mechanisms.
2-Combination of IVIG and Rituximab.
Rituximab monoclonal antibody against CD20 antigen induce B cells lysis.but has no effect on plasma cells as they don’t have CD 20 Antigen. Vo et al concluded the combination is effective in desensitization .
3_plasmaphersis,IVIG and Rituximab: Lefaucheur etc al concluded that this combination is significantly superior to other regimens for desensitization..
Treatment of AMR
IVIG,RITUXIMAB,BORTIZUMIB and ECULIZUMAB plus PLEX.
LEVEL OF EVIDENCE IN THIS STUDY WAS II.
Abdul Rahim Khan
3 years ago
The Antibody Mediated Rejection
AMR is an important cause of graft failure. it is characterized by high DSA, presence of neutrophils in peritubular capillaries . C4d are attached to endothelial cells. The process of graft rejection starts by activation of plasma cells and B cells against HLA and non HLA antigen leading to activation of compliment pathway leading too inflammatory process in graft leading to graft loss.
Diagnostic Criteria
A- Tissue injury is defined by the presence of one or more of the following
1- Glomerulitis or peritubular capilliritis
2-Intimal or transmural arteritis
3- TMA Acute thrombotic microangiopathy
B- Interaction of antibody with vascular endothelium
C- Presence of DSA in serum against HLA and Non HLA
Chronic Antibody mediated Rejection
It has similar features but also characterized by Transplant glomerulopathy without TMA, multi layering of capillary basement membrane identified by Electron microscopy. also there is intimal fibrosis without other cause. Urine protein / creatinine ratio>1 g/g, Chronicity score >8, DSA >MFI 2500, raised creatinine more than 3 mg/ml.
Phenotypes of Antibody mediated Rejection
These are of two type
Type 1 : early development of DSA in pre sensitized patient
Type 11: due to Denovo DSA which can due to improper immunosuppression or non adherence
Paradigm in antibody mediated rejection
Subclinical AMR- Mainly identified by protocol biopsies. It is associated with poor graft outcome.
C4d positive and C4d negative Rejection-
C4d is poor prognostic indicator in AMR and has low sensitivity. C4d negative AMR is characterized by microvascular inury in the presence of DSA
Antibody mediated Vascular Rejection
Both T cell mediated rejection and AMR show endarteritis on histology
Non HLA AMR
These are an evolving field in transplant immunology. There are two types. Antibodies directed against polymorphic antigens and autoantibodies.
Transplant glomerulopathy
Histology shows doubling of glomerular basement membrane which is due to Recurrent endothelial injury and repair. Outcome is poor.
Antibody removal in highly sensitized patients
Options include
High dose Immunoglobulins
Intravenous Immunoglobulins and Rituximab
Plasmaphresis , Intravenous Immunoglobulins and Rituximab
Immunoadsorption for rapid cross match conversion.
Treatment of AMR
1– Plasmaphresis– Mainstay of treatment and involves preformed antibodies . Bettr outcome when combined with IVIG
2- IV immunoglobulins– better outcome along with plasmaphresis.
3-Rituximab- better outcome along with IVIG and PLEX
4-Proteosome Inhibitor-it is used in combinition with IVIG,PLEX or rituximab.
5– Compliment inhibition.-Anti C5 monoclonal antibody ecluzumab and C1 estrase inhibitor. Its costly treatment and more data is required to assess outcome
Prevention of Antibody mediated rejection.
–Better to avoid transplant in highly sensitized patients- Consider enroling in paired exchange program and adopt desensitiation protocol
– Monitor denovo DSA using class 11 HLA epitope. Perform protocol biopsies to detect AMR at early stage
– Patient education and community based nephrologists may help and financial assessment Pretransplant to avoid non adherence.
Level of evidence 11B
Sahar elkharraz
3 years ago
This article review diagnostic criteria and treatment of AMR.
AMR remains a problematic event in kidney transplant which may lead to decrease of graft survival and graft loss.
AMR is humoral immune response results from presence of HLA and non HLA Ab which react to endothelium lead to activation of complement and formation of C4d which are deposits in peritubular capillary lead to endothelial injury.
AMR can be hyperacute happen within hours after vascular anastomoses.
Early acute rejection: happens within days.
Late acute rejection: happen within months.
Chronic acute rejection: from months to years.
Incidence of AMR recently declined by new immunological technology and using desensitisation protocol.
Current diagnostic Criteria of AMR:
1. Single antigen bead to detect HLA antibody
2. CDC
3. Electron microscopy help in diagnosis of AMR by morphological changes of graft.
4. Banff classification of allograft pathology.
– [ ] Diagnosis of AMR is still histological and according to Banff classification 2013 which are held in Brazil depend on presence or absence of C4d staining and presence of micro vascular inflammation and intimal arteries.
– [ ] Acute AMR: Stage I
a/ glomerulitis (g>0) or peritubular capillarities (ptc>0)
b/ intimal or transmural arteritis (v>0)
c/ acute TMA
d/ acute tubular injury.
– [ ] Stage II:
a/ linear C4d staining in ptc
b/ moderate micro vascular inflammation ( g, ptc >2)
c/ Increase expression of tissue gene transcription indicates endothelial injury.
3: detection of DSA in serum
– [ ] Diagnosis of chronic AMR is overlapping with acute AMR.
Chronic tissue injury diagnosing by histological evidence.
a/ presence of transplant glomerulopathy ( cg>0 in absence of chronic TMA.
b/ severe peritubular capillary basement membrane identifying by electron microscopy
c/ New onset arterial intimal fibrosis.
Redfield et al conducted his study by 123 patients and his conclusion chronic AMR is associated with poor graft survival after diagnosis.
criteria of diagnosis is chronicity score >8
DSA >2,500 MFI
S.Cr > 3 mg/d
Urine protein/ creatinine ratio > 1g
Moderate micro circulatory charge are classified according to banff ( g1> 25%
g2 26 to 50%
g3> 50% depend on involvement of glomeruli by leukocytes infiltration and endothelial enlargement which lead to complete occulsion of glomeruli.
– [ ] Phenotypes of AMR according to banff 2011.
Phenotype I: (early post transplant period) occur in pre sensitised patients
Phenotype II occur in late post transplant and it’s due to circulating de novo DSA and it’s maybe related to non adherence to immunosuppressive agents or inadequate doses.
Protocol for biopsy help to identify sub clinical AMR even in normal creatinine level and prevent risk of graft loss.
There’s no difference in graft survival outcome between C4d positive or negative according to banff classification but C4d positive have risk of early post transplant AMR in comparison to negative C4d.
Risk of graft loss more in AMR rather than T cell mediated rejection.
Presence of circulating non HLA Ab mediated rejection are associated with graft loss.
there’s 2 markers of non HLA Ab which are not involved in banff classification but associated with endothelial injury is Angiotensin type 1receptor and endothelial type A receptor Ab.
– [ ] Transplant glomerulopathy manifested by glomerular basement membrane duplication or splitting and associated with poor prognosis because irreversible damage.
Antibody removal for highly sensitised patients:
1/3 of patients awaiting deceased donor kidney transplant have high degree of circulating HLA Ab.
To reduce sensitisation should use desensitisation immunomodulating agents :
1. High dose of IV g; it’s mechanism inhibition of T cell proliferation and inhibition of cytokines synthesis, inhibition of complement activation and blocking actions of alloantibodies
2. Iv Rituximab monoclonal Ab against CD20 antigen and block B cell activation
3. Plasma exchanges and immunoadsorption both mechanisms same in removal of antibodies but immunoadsorption less side effects because no use Fresh frozen plasma and no use of Albumin.
4. Hyperacute rejection nowadays are completely eliminated by desensitisation protocol.
5. Bortezomib is Proteasome inhibitors
6. Eculizumab is complement inhibitors (anti C5 monoclonal antibody).
Treatment of chronic antibodies mediated rejection by pulse therapy of steroid and intravenous immunoglobulin and further trials on immunosuppressive agents to eliminate graft loss.
– [ ] Prevention of graft loss:
by technique for detection of C1q fixing DSA which are indicator of sensitised patients and risk of graft loss
1. to avoid rejection better avoid transplant in incompetent cross matches
2. If no compatible donor available should use desensitisation protocol but it’s very costly and short term coarse also may complicated with highly fatal infectious disease.
3. Extensive monitoring of de novo DSA
4. Using class II HLA epitope matching
5. Shift patients who are having incompatible donor to Parried kidney exchanges program.
6. Protocol of biopsy.
Q2 Evidence 2 cohort study
ABMR is one of the laeding causes of graft loss after kidney transplantion,
in the last two decades increaseing recognition of molecular and histological changes gave us better understanding of this process and potential therapuetic options .
what is current diagnostic criteria of ABMR?
1-ACUTE ANTIBODEY MEDIADTED REJECTION,
since inovation of single antigen beads which give us an idea about DSA pre and post kidney transplant this helped the transplant physicians a lot undersatnding the behavior and monitoring of DSA levels and classifing the patient with high risk transplantion which needs more meticulous observations after transplantion.
BANF classification and its updates had made a favourable change understanding AR episodes and,improving sensitivity and diagnosis of allograft rejection .
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
Intimal or transmural arteritis (v >0)
Acutethromboticmicroangiopathy(TMA)ofnoother obvious cause
Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium, defined by at least one of
the following:
Linear C4d staining in the peritubular capillaries
At least moderate microvascular inflammation (g þ
ptc >2)
Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
BANF CRITERIA FOR CHRONIC ANTIBODY MEDIATED REJECTION
. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
Transplantglomerulopathy(cg>0)intheabsenceof
chronic TMA
Severe peritubular capillary basement membrane
multilayering identified by electron microscopy
New-onset arterial intimal fibrosis with no other
known etiology
2. Histologicevidenceofantibodyinteractionwithvascular
endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Two phenotypes was idinetified by BANF for acute antibody mediated rejection
type 1, which occures in presentized patients and occurs early in pretransplant peroid
type 2 , which occurs late post transplant period due to denovos DSA mainly due to non adherence of immunosuppresion or inadequate immunosuppresion.
PARADIGMS OF ANTIBODY MEDIATED REJECTION
A-SUBCLINCIAL AMR,
poorest outcome , diagnosed by protocol biobsies
B-C4D POSITIVE AND C4D NEGATIVE
C4D is found in PTC indiactiing AMR, which has poosr outcome .
up to 55% of patient who has AMR doesnt has C4D positive called C4D negative AMR=(glomerulitis, peritibular capillraitis ,tma)with positive DSA.
C-ANTIBODY MEDIATED VASCULAR INJURY
Endarteritis is histological features of both TCMR and AMR but more common in AMR.
D-NON HLA ANTIBODY MEDIATED REJECTION
alloantibodies directed aganist polymorphic antigens that is different between the recipent and the donor
non HLA antibodies like (AT1 receptor)
what is meant by transplant glomerulopathy?
glomeural basment membrane duplication, double contouriing, splitting .which is considerd as a late stage of ABMR.
HOW CAN ABMR BE TREATED?
1-IV IGG commonly used for AMR tretment inhibiting t cell proliferation, inhbiting cytokine synthesis, inhbiting complement activation .
2-IV IGG WITH RITUXIMAB, which induce b cell lysis and prevent b cell matuartion and formation of antibodies, this combination was effective than iv igg alone .
3-PLEX WITH IV IGG AND RITUXIMAB,The combination of the three agents is considered better than the IVIG alone.
4-Proteasome Inhibitor. used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging result.
5-Complement Inhibition. eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition still need more studies and keep in mind the cost aspect.
HOW TO AVOID ABMR?
avoiding transplanting highly sensitzed patients
advising patient for paired exchange programm whom has cross match positive or diffrent blood groups .
monitoring of DSA after transplantion if present befor kidney transplant
counsling the patient about the importance of adherence to their mediaction.
What is the level of evidence provided by this article?
level 2 evidence , rivew article
Mohamed Saad
3 years ago
Antibody-Mediated Rejection INTRODUCTION
Antibody mediated rejection (AMR) is considered one of the most common cause of allograft failure , early it is defined by presence of neutrophils in peritubular capillaries , serological markers of de novo donor -specific antibody DSA and c4d attached o endothelial cells which identified as antibody activity.
Allograft rejection is a complex process which started by activation of immunological cells(B-cells, plasma cells )against HLA or Non-HLA antigens then complement system become activated and many inflammatory cells and markers aggregated with in the graft and lead to inflammatory process inside it (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis) all theses reaction if not treated , ended by graft loss.
Understating of the immunological mechanisms and innovation in immunosuppressive drugs and techniques of antibodies detection lead to change in the graft outcome. CURRENT DIAGNOSTIC CRITERIA
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis or peritubular capillaritis .
b. Intimal or transmural arteritis .
c. Acute thrombotic microangiopathy (TMA) .
2. Histologic evidence of current/recent antibody interaction with vascular endothelium.
3. Detection of DSAs (HLA or non-HLA) in the serum. Chronic Antibody-Mediated Rejection
Which depends on same criteria except presence of chronic histological changes as transplant glomerulopathy in the absence of chronic TMA , Severe peritubular capillary basement membrane multilayering identified by electron microscopy or New-onset arterial intimal fibrosis with no other known etiology.
Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g were associated with an increased risk of allograft loss. Phenotypes of Antibody-Mediated Rejection Type I:pre-sensitized patient with DSA which developed early. Type II:patient with de novo DSA which developed later mainly due to non-adherence or inadequate immunosuppressive drugs. PARADIGMS IN ANTIBODY-MEDIATED REJECTION -Subclinical Antibody-Mediated Rejection
Which appeared mainly with protocol biopsy and till now no strong evident guidelines for treatment and its associated with poor graft survival. C4d-Positive and C4d-Negative Rejection
C4d a poor marker for the diagnosis of AMR due to complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility.
C4d negative AMR with histological tissue injury and positive DSA. Antibody-Mediated Vascular Rejection
Endarteritis is histological features of both TCMR and AMR but more common in AMR. Non-HLA Antibody-Mediated Rejection
Two categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies. Transplant Glomerulopathy
Is histological descriptive term which mainly characterized by doubling of GBM which mainly due to recurrent endothelial injury and repair associated with chronic AMR with poor graft survival. ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS High-Dose Intravenous Immunoglobulin
One of the most common agents used in desensitized patients which acting on several mechanism . Intravenous Immunoglobulin and Rituximab
Rituximab is anti-CD 20 and prevent plasma cell to produce antibodies and with IVIG combination they give good result as per studies. Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
The combination of the three agents is considered better than the IVIG alone as per Lefaucheur et al study but still need more clinical trials and to keep cost aspect in mind. Immunoadsorption for Rapid Cross-match Conversion
IA more specific and effective than PEX and less side effects especially without plasma or albumin substitution. TREATMENT OF ANTIBODY-MEDIATED REJECTION
1-Plasmapheresis.
Which is considered the cornerstone in all protocols of AMR treatment depend on removal of performed antibodies and the good results came mainly when using with IVIG.
2-Intravenous Immunoglobulin.
When using with PEX give good result.
3-Rituximab.
Used in combination with PEX and IVIG, alone shown no effect.
4-Proteasome Inhibitor.
used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging result.
5-Complement Inhibition.
eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition still need more studies and keep in mind the cost aspect. PREVENTION OF ANTIBODY-MEDIATED REJECTION
1-several strategies to prevent AMR.
Avoiding transplantation for highly sensitized patients.
Better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening.
Enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Euro transplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols.
2 Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
3-Education for patients and community nephrologists is advised, as well as appropriate financial evaluations prior to transplantation to avoid drugs non-adherence.
Level of evidence II B
Mohamad Habli
3 years ago
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
AMR causes a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis).
Significant progress has been made since the recognition of the role of DSAs, such as new techniques to detect antibodies, the use of desensitization protocols, and the introduction of new agents that interfere with complement-mediated allograft injury.
Diagnostic methods
Single-antigen bead testing, which is used to detect antiHLA antibodies, is the final step in the current techniques used to identify antibodies that can injure the allograft.
Electron microscopy is routinely used for the biopsies of transplant recipients because early changes cannot always be detected with light microscopy.
ABMR is diagnosed based on the presence of the following components:
1-Histologic evidence of acute tissue injury related to ABMR (peritubular capillaritis-ptc and/or glomerulitis-g, Intimal or transmural arteritis-v, TMA, ATN)
2-Evidence of circulating DSAs
3-Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or at least moderate microvascular inflammation (g + ptc >2)
Phenotypes of Antibody-Mediated Rejection based on the presentation:
Phenotype 1 which occurs acutely early in the post transplant period in previously sensitized patient .
Phenotype 2 usually occurs in the late post transplant period with progressive decline in kidney function due to the development of de novo DSAs.
Subclinical Antibody-Mediated Rejection
It is histology based definition detected during protocol biopsies when patients with normal creatinine having antibody mediated injury. It has the poorest graft survival at 8 years post transplant (56%) compared with the subclinical T cell–mediated rejection (88%) and no-rejection (90%) .
C4d-based definition of Rejection
C4d staining is the surrogate marker for complement dependent antibody mediated injury; but C4d negative rejection entity has been recently recognized. C4d positivity could vary from lab to other depending on the staining method and techniques.
There are no clinical parameters which can help in differentiating between C4d-negative and C4d-positive rejection.
Key points:
C4d-positive AMR occurs earlier post transplantation
C4d-positive AMR occurs 3 times more common than C4d negative AMR
Graft survival at 1 and 2 years is lower in C4d positive than C4d negative patients
C4d-negative AMR was associated with a 2.56-fold increased risk of allograft loss compared to AMR-free patients.
Antibody-Mediated Vascular Rejection
Vascular rejection carries poor prognosis to the allograft as the risk of graft loss was 9 times higher in antibody-mediated vascular rejection than in T cell–mediated rejection .
Non-HLA Antibody-Mediated Rejection
2 categories: Alloantibodies directed against angiotensin type 1 receptor and endothelin type A and autoantibodies have been implicated in the development of acute rejection. The effect of anti-endothelial cells AT1R antibodies have been demonstrated in few studies to cause acute rejection.
Transplant Glomerulopathy
Transplant glomerulopathy is a marker of antibody-mediated injury which is usually irreversible and causes proteinuria leading to graft loss in the majority of patients. It is manifested as glomerular basement membrane duplication, double contouring, or splitting.
Treatment of acute antibody mediated rejection:
The aim of treatment of AMR is:
-Reduce the inflammation in the allograft
-Eliminate the factors that cause inflammation
-Effectively prevent antibody formation without effecting the normal immune responses that protect patients from serious infections.
Types of treatment
-Plasmapheresis- is part of the standard therapy for rapid and efficient removal of preformed antibodies.
-Intravenous Immunoglobulin- used in combination therapy with PLEX for better inhibition of antibodies production and allograft outcomes.
-Rituximab- used for B cell depletion to prevent further differentiation into plasma cells. Graft survival better with combination of PLEX,IVIG and Rituximab.
-Proteasome Inhibitor(Bortezomib)- inhibit plasma cells production of antibodies. Results are better if used in combination with IVIG,PLEX or Rtiuximab.
-Complement Inhibition- Anti-C5 monoclonal antibody- Eculizumab and a C1 esterase inhibitor have been approved so far for refractory ABMR in complement dependent rejection.
Prevention of ABMR:
-Avoid transplantation in HLA incompatible pairs
-Match with better compatible donor through kidney allocation system or KPD if the patient has living donor
-Desensitization is indicated if there is no living donor and the patient is highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
-Desensitization is more effective when plasmapheresis, low dose IVIG and Rituximab are combined
-Post-transplant serial monitoring of DSA levels in presensitized patients, CNI level, and protocol biopsies
This is a review article with level of evidence 2
Last edited 3 years ago by Mohamad Habli
Filipe prohaska Batista
3 years ago
Please summarise this article
It is a review study that discusses the concept of antibody-mediated rejection and classifies it by time (hyperacute, acute, late acute, or chronic), clinical phenotype, and histopathologically using the Banff classification. Antibodies related to HLA or not (endothelium) increase the chance of graft rejection, even subclinical manifestations are sufficient for graft loss.
SABs and Complement Dependent Cytotoxicity are still considered the gold standard for detection of preformed antibodies, but the diagnosis of AMR is still dependent on histopathological findings.
As histopathological findings of interaction in vascular endothelium and detection of DSA in serum are indifferent when evaluating acute and chronic AMR. Tissue injury findings such as glomerulitis, acute tubular injury, and microangiopathic thrombosis for acute rejection (Phenotype 1) and findings of glomerulopathy, fibrosis, and de novo lesions suggest chronic rejection (Phenotype 2).
Although vascular rejection is considered a classic finding of rejection mediated by T lymphocytes, we cannot confuse this finding with vasculitis, which is directly related to B lymphocytes and has a higher OR 9.07 of rejection with specific treatment that should be started as early as possible.
Non-HLA-related rejection such as angiotensin 1 inhibitors and transplant glomerulopathy lesions should be considered in patients with worsening renal function.
IVIg can lead to inhibition of T lymphocyte proliferation, inhibition of cytokine synthesis, inhibition of complement activation, and blockade of alloantibodies.
Rituximab it can block the activation of B lymphocytes and, consequently, prevent the maturation of plasma cells, but it cannot inhibit the plasma cells already in activity (it is believed that the associated splenectomy, in this case, could help). Its association with IVIg is superior to its use alone.
Plasma Exchange removes circulating antibodies, but it is difficult to predict treatment time and the need for intensive care.
Bortezomib is a proteasome inhibitor, decreasing the cell’s ability to perform autolysis, cytolysis, and apoptosis. This way reverses AMR frames as well as lowers DSA levels.
Complement inhibitors (C1 Inhibitor – Berinert or C5 Inhibitor – Eculizumab) decrease the role of complement in rejection, having higher efficacy when performing splenectomy. The high cost makes it an exception handler.
The presence of C1q-fixing DSA is an independent predictor of graft loss. Pregnancy, blood transfusions, and previous transplantation are risk factors for sensitized patients at high risk of AMR. Monitoring de novo DSAs, class II HLA epitope matching, CNI level, and protocol biopsies improve graft survival.
What is the level of evidence provided by this article?
They did not describe how was the choice of the articles, but it appears to have raised cohort studies and clinical trials, so it would have level of evidence IIb.
Doaa Elwasly
3 years ago
Allograft rejection is a complex process which is due interaction of different cellular and molecular pathways leading to acute tubular injury, glomerulitis, and fibrosis.
Allograft rejection can be hyperacute, acute , late acute it can occur 3 months after transplantation, or chronic
Rejection can be classified also into cellular or AMR Diagnostic criteria
SAB testing fordetecting HLA antibodiesand is diagnostic
CDC is still the standard for Ab detection.
EM for graft biopsies to detect the rejection changes.
Banff classification enhanced the sensitivity of diagnosing AMR and indicating graft survival outcome. Acute Antibody-Mediated Rejection
According to the Banff 2013 classification those 3 features are needed for the diagnosis
1. Histologic evidence of acute tissue injury estimated by
: a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute TMA of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of recent antibody interaction with vascular endothelium, manifested by:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts
3. Detection of DSAs (HLA or non-HLA) in the serum Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification,it needs 3 criteria :
1. Histologic evidence of chronic tissue injury, manifested by
a. Transplant glomerulopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis
2. Histologic evidence of antibody interaction with vascular endothelium, presented by:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum Moderate microcirculatory changes
Introduced by Banff 2013 classification as highly suspicious for antibody injury. Vasculitis and increased number of inflammatory cells in the microcirculation indicate poor graft outcome. Phenotypes of Antibody-Mediated Rejection In the 2011 Banff stated 2 phenotypes of acute AMR .
Phenotype 1 occurred during the early post transplant period in the presensitized cases .
Phenotype 2 existed due to of de novo DSAs in the late posttransplant period and it’s main reason is nonadherence or inadequate immunosuppression. Subclinical Antibody-Mediated Rejection
Protocol biopsies revealed patients with histologic evidence of antibody-mediated injury despite stable creatinine, they have the worst graft survival at 8 years posttransplant. C4d-Positive and C4d-Negative Rejection
C4d was a marker for antibody injury on the other hand C4d-negative rejection was detected with microcirculatory inflammation so it is now a poor indicator of AMR.
Orandi et al found that rejection occurred earlier in patients with C4d positive AMR cases then C4d negative AMR cases and the former group had worse graft survival. Antibody-Mediated Vascular Rejection
Endarteritis is accompanied with cellular rejection; studies showed that vasculitis occur in both T cell– mediated rejection and AMR Non-HLA Antibody-Mediated Rejection
It has 2 categories:
-alloantibodies directed against polymorphic antigens of the donor
-antibodies that recognize self-antigens or autoantibodies.
Angiotensin type I receptor and endothelin type A receptor antibodies are markers of endothelial injury as mentioned in some studies.
Loupy et al demonstrated that patients with donor-specific anti-HLA antibodies with complement binding capacity had lower graft survival . Transplant Glomerulopathy
Presented by glomerular basement membrane duplication, double contouring, or splitting.
It is associated with proteinuria and with denovo or prexsiting DSA.
It indicates a late stage of antibody-mediated injury that is irreversible and is of poor graft survival. Antibody removal for highly sensitised patients
Desensitization is done through immunomodulating therapies to decrease levels of anti-HLA antibodies enabling tranplanation. High-Dose IVIG
It acts through inhibition of T cell proliferation, and inhibiting of cytokine synthesis, complement activation, and leads to blockade of alloantibodies.
It reduces anti-HLA antibody levels and improves transplantation rates in highly sensitized patients. IVIG and Rituximab
It leads to B cell lysis by CDC and antibody-mediated cellular cytotoxicity. It blocks B cell activation and Ab forming plasma cells .
The combination of IVIG and rituximab was an effective desensitization regimen. Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
It was concluded that the combination therapy was more effective rather than IVIG alone . Immunoadsorption for Rapid Crossmatch Conversion
Was an effective method for desensitization in deceased-donor transplantation more than plasma exchange. Treatment of antibody medicated rejection
Different treatment options are rabbit antithymocyte globulin, methylprednisolone, PLEX, IVIG, B cell–depleting agents, muromonab and maintenance therapy with CNIs, antiproliferative agents, and oral steroids.
Subclinical AMR was associated with increased risk of allograft loss. Plasmapheresis
Slatinska et al mentioned that the combination of PLEX and IVIG gave better results than PLEX on it’s own. Proteasome Inhibitor
Effectively reversed AMR , including reductions in DSA levels. Complement Inhibition
eculizumab (anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.
Wongsaroj et al noticed that TMA patients recovered fully or partially after eculizumab while all TMA-positive patients treated with IVIG, rituximab, and PLEX experienced graft failure.
It was concluded that splenectomy plus eculizumab can be effective for preserving allograft function in early severe AMR cases.
Eculizumab usage before advanced renal injury can improve allograft survival. Chronic Antibody-Mediated Rejection Treatment
Fehr et al demonstrated that steroid pulse ,rituximab then IVIG showed improved allograft function.
Biopsy-proven chronic AMR, treatment with steroids/IVIG was associated with improved graft survival. Prevention of antibody mediated rejection
-C1q-fixing DSAs are an independent predictor of allograft loss.
-Djamali et demonstrated methods to prevent AMR, as avoiding transplantation for highly sensitized patients, assessing immunologic risk by detecting sensitive donor-specific anti-HLA antibody screening, involving highly sensitized patients in a paired kidney exchange program .
-Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies
-It was concluded that DSA can be detected before allograft affection.
-nonadherence to immunosuppressive therapy can lead to rejection
the level of evidence is level 2
Riham Marzouk
3 years ago
Chronic Antibody mediated rejection remains the strongest barrier against favorable graft outcome.
In spite of advancement in the technology developed to detect HLA and non-HLA antigen, still we face a lot of cases of AMR with negative impact on graft survival.
It can be diagnosed clinically by rising serum creatinine and presence of proteinuria, and pathologically by graft biopsy by presence of transplant glomerulopathy TG proved by double contour, splitting or duplication of GBM.
Current treatment of AMR include plasmapheresis , immunoadsorption or immunomodulation, IVIg, rituximab, bortezomib which is proteasome inhibitor-based therapy, new agents like eculizumab (an anti-C5 monoclonal antibody). Acute Antibody-Mediated Rejection According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following: a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum Chronic Antibody-Mediated Rejection
acute AMR has been shown to be a major risk factor for the development of chronic AMR.
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum Phenotypes of Antibody-Mediated Rejection In the 2011 Banff report:
1-presensitized patient and occurs in the early posttransplant period.
2- emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
C4d deposition and its importance
C4d is degradation from complement cascade activation and it is binds covalently to endothelium so its presence denoting complement binding DSA, and its non-presence indicate non-complement binding DSA, so it is poor marker to diagnose AMR. Non-HLA AMR It can be:
alloantibodies directed against polymorphic antigens that differ between the recipient and donor. or
antibodies that recognize self-antigens or autoantibodies.
angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury. Desensitization protocols: 1- High-Dose Intravenous Immunoglobulin 2- Intravenous Immunoglobulin and Rituximab 3- Plasmapheresis, Intravenous Immunoglobulin, and Rituximab 4- Immunoadsorption
level of evidence II
mai shawky
3 years ago
· Q. Summary
· AMR leads to Chronic AMR rejection which is a major contribution of graft loss.
· Mechanism of AMR:
o B cell activation to antibody producing plasma cells (DSA) which can interact with endothelium and disrupt graft microcirculation (activation of cellular pathway).
o Also complement activation which is evidenced by (C4D deposition in ptc) which can recruit neutrophils, monocytes and macrophages and eventually cause graft damage.
· Source of antibodies:
o Preformed DSA in sensitized patients.
o De-novo DSA due to non -compliance to immunosuppressive therapy.
o Non –DSA developed against polymorphic epitopes or autoantibodies formed against endothelium (released self antigen after surgical trauma) as anti (angiotensin type 2 receptors and anti endothelin type A). No standardized method yet for their detection, but treatment the same as DSA.
· Phenotypes of AMR:
o Type 1= preformed DSA, occurs early post-transplant.
o Type 2= de nono DSA, occurs late post-transplant due to non adherence to maintenance immunosuppression.
· Timing of AMR:
o Hyper acute (within minutes/ on table)
o Acute (days or weeks )
o Late after 3 months and up to 1year post transplant.
o Chronic (months or years post-transplant): manifested by creeping creat and proteinuria, with poor long term outcome.
· Clinical presentation:
o Clinical (rising creat + proteinuria).
o Subclinical (detected in protocol biopsy) despite stable creat, no consensus about value of its treatment on long term outcome.
· Recent advances in diagnosis of AMR:
o Luminex SAB is best method to detect DSA in AMR and follow its titer after treatment.
o CDC cross match is best to detect preformed DSA.
o E/M is best and most sensitive for biopsy examination (early detection of AMR).
· Banff 2013:
o Incorporate serological (DSA ) and histology with immunohistochemistry to increase its sensitivity.
o In 2015, they incorporated (antibody reaction with endothelium) with histopathology and DSA in serum.
o Chronic AMR : detected by transplant glomerulopathy ,double contour of peritubular capillaries BM and intimal fibrosis+ DSA detected in serum.
· AMR according to C4d deposition in ptc:
o C4d +ve (evidence of antibody reaction with endothelium)
o C4d –ve: detected in 50 % of AMR (low sensitivity).
o AMR can be diagnosed in context of c4d –ve , in case of histopathological evidence of graft injury as (glomerulitis, peritubular capillaritis and TMA)
o C4 +ve more prone to occur earlier than c4d –ve.
o C4d positivity depends on:
§ Method used for detection (IF is more sensitive than immune-histochemisty).
§ C4d threshold.
o Use of molecular genetic endothelial markers may help in diagnosis of AMR (rather than c4d +ve)
· Any histopathological evidence of microvascular inflammation(even in single capillary) is considered marker of AMR
· Poor prognostic criteria of chronic AMR (associated with graft loss):
o Creat > 3 mg/dl
o Proteinuria (p/c ratio > 1 g/g)
o Chronicity > 8
o DSA with MFI > 2500
o
· Vascular injury vasculitis can be part of both TCMR and AMR. Evidenced by neutrophils infiltration under endothelium.
· Desensitization protocols in HLA and ABO incompatible transplantation:
o No consensus on best protocol.
o PEX is standard component of various regimens.
o PEX, IvIg ± rituximab (may be mostly utilized protocol till now).
o IvIg and rituximab.
o High dose IvIg.
o IA (single session pre and one session after transplant ): rapid removal of antibodies and avoid PEX side effects of plasma infusion.
o Desensitization protocols are very coasty and full of massive side effects as infections and malignancy, so better limited to those with high PRA > 90% and very prolonged time on waiting list.
o Best option for highly sensitized is paired kidney donation in living donor and KAS in deceased donor.
· Treatment of AMR:
o Not standardized, due to heterogeneous immunological risk of transients in various studies, induction and maintenance therapy.
o PEX followed by IVIG high dose ( 2g/kg) , with or without B cell depleting agent like rituximab or plasma cell depleting agent Bortezomib.
o Combination IVIG and PEX is preferred over monotherapy with either of them.
o In addition, modification of maintenance therapy like tacrolimus instead of ciclosporin, MMF replacing azathioprine or adding steroid in case of steroid free or minimization protocols, DSA monitoring and address the compliance with immunosuppression.
o Eculizumab (distal complement inhibition) and C1 esterase inhibitor (C1-INH), (proximal complement inhibition can be used in refractory AMR but very expensive.
· Prevention of AMR:
o Use best matched donor-recipient couples.
o Address compliance to immunosuppressive therapy especially in adolescents
o Denovo DSA monitoring monthly in highly sensitized and every 3 months early post transplant then every 6 months for early detection of AMR and timely intervention.
o Protocol biopsy to detect subclinical rejection.
Q. level of evidence: review article of cohort studies (level II)
Sherif Yusuf
3 years ago
ABMR is the commonest cause of graft loss
ABMR can be classified according to the time of detection into phenotype 1 which occur due to preformed DSA detected in the patient serum before transplantation and phenotype 2 which occur due to de novo DSA which is detected post-transplantation.
The incidence of occurrence of early ABMR with subsequent graft loss is markedly increased in the patients with preformed DSA, including those who received desensitization.
DSA either preformed or denovo attacks the endothelium of the graft leading to
• Acute ABMR
• Chronic ABMR
• Subclinical rejection
All cause subsequent reduction of graft survival
Risk factors for developing preformed DSA includes pregnancy, blood transfusion, previous transplant
The most important risk factors for developing denovo DSA are HLA mismatch and non-adherence to immunosuppressive medications
DSA can be directed to one of the following targets
• HLA antigens (HLA class I, II)
• Non- HLA antigens expressed on endothelial cells
Acute ABMR
Active ABMR occurs due to binding of circulating antibodies to donor alloantigens located on graft endothelium (HLA class I, HLA class II, ABO – antigens or non HLA antigens on endothelial cells)
Ag-Ab complexes activate classical complement pathway with final production of c5b, c3b, c3a, c5a leading to inflammation, cell damage and graft dysfunction
One of degradation products of classical pathwaty is C4b which is converted to C4d, the later binds covalently to endothelium of peritubular capillaries (PTCS) and act as a food print for complement activation and ABMR
3 components are required for the diagnosis of ABMR :
• Histologic evidence of acute tissue injury (peritubular capillaritis-ptc and/or glomerulitis-g, Intimal or transmural arteritis-v, TMA, ATN)
• Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or At least moderate microvascular inflammation (g + ptc >2)
The g score: according to percent of glomeruli involved: g1 =1%-25%, g2= 26%-50%, and g3= >50%.
• Serologic evidence of circulating DSAs
If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have ABMR, this means C4d staining can replace DSA, and C4d negative ABMR exists (ABMR without activation of complement cascade)
Patients with DSA who are C4d positive are 3 folds more common than C4d negative ones and tends to occur earlier than Cd negative ABMR
Patients with C4d positive ABMR has lower graft survival than those who are C4d negative, this means that it is a marker for severity and has prognostic implication. but C4d negative patients have higher rate of developing transplant glomerulopathy if untreated
Indications for treatment of ABMR
1- Presence of histologic features of ABMR plus either detection of circulating DSA or C4d staining even if creatinine is normal (subclinical ABMR)
2- Rapid increase of DSA with normal or near normal biopsy in in patients who received desensitization to render cross match negative
Current treatment
· Intensification of maintenance immunosuppression
· Decreasing inflammation produced by rejection: high dose steroids
· Decreasing production of antibodies (IVIG)
· Depleting B cells (rituximab)
· Removing DSA (6 sessions of plasmapharesis daily or every other day), better outcome if used early < 1 year post transplant
· 2nd line agents includes : Bortezomib and eculizumab which may have rule in treatment of acute resistant ABMR
Chronic active ABMR
Chronic ABMR is the most common cause of graft failure, tends to occur late > 6 months with or without previous history of acute ABMR
3 components are required for the diagnosis of chronic active ABMR :
• Histologic evidence of chronic tissue injury (transplant glomerulopathy-cg, multilayering of the PTC BM or chronic arteriopathy with fibrous intimal thickening) and no evidence of acute inflammation
• Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or At least moderate microvascular inflammation (g + ptc >2)
• Serologic evidence of circulating DSAs
If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have chronic active ABMR, this means C4d staining can replace DSA, and C4d negative chronic active ABMR exists
So evidence of chronic tissue injury with C4d staining in a patient with DSA and history of acute ABMR before is typical for chronic active ABMR Transplant Glomerulopathy
· TG is an irreversible histologic finding that occur in late stages of ABMR, best diagnosed using EM
· Nearly around half of high risk transplant recipients will develop TG
· Present by gradual decline of renal functions together with proteinuria
· Once occur it indicate poor graft survival Treatment of chronic active ABMR
No optimal treatment is set for chronic active ABMR, and treatment is difficult since there it is associated with irreversible tissue damage Current treatment is directed against the following:
· Intensification of maintenance immunosuppression
· Decreasing inflammation produced by rejection (high dose steroids)
· Decreasing production of antibodies (IVIG)
· Depleting B cells (rituximab)
· Removing DSA (plasmapharesis) play no rule in chronic active ABMR
· 2nd line agents includes : Bortezomib and eculizumab showed no benefit in treatment of chronic active ABMR
Prevention of ABMR:
1- Whenever possible avoid transplantation of HLA incompatible pairs
2- Always try to rely on finding compatible donor through kidney allocation system or KPD if the patient has living donor, and try to avoid desensitization
3- Desensitization is indicated if there is no living donor and the patient is highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
4- Several regimens are used for desensitization, the most effective is combination of plasmapheresis, low dose IVIG and Rituximab
5- Post-transplant monitoring including serial DSA levels, CNI level, and protocol biopsies
Dear All
I’m not impressed with your answer regarding the level of evidence of this article. Many of you copied the answer from each other. See the diagram and answer the question regarding the level of evidence
I think level of evidence is 1
Why do you think it is level 1? Do you see meta-analysis, RCT, or systematic review in this paper
Clue: Mixed methods Systematic review
Not impressed Shereen
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
Am confused about narrative reviews i don’t get it i will work on it
level 1
Not impressed
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
0
Reply
level 1B
Not impressed
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
level 1
Not impressed Shereen
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
level 5
Excellent Abullrahman
Level 5 narrative review ( comprehensive, critical and objective analysis of the current knowledge on a topic).
Allograft rejection is a complex process with the involvement of different cellular and molecular pathways that cause allograft injury.Antibody ligation to human leukocyte antigen (HLA) or blood antigens expressed on the endothelium, can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/macrophage– mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
Diagnostic criteria using Banff classification
Acute Antibody-Mediated Rejection According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
Chronic Antibody-Mediated Rejection . According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
Phenotypes of Antibody-Mediated Rejection
according to 2011 Banff report, 2 principal phenotypes of acute AMR were defined.
Phenotype 1: occurs in the presensitized patient and occurs in the early post-transplant period.
Phenotype 2: develops from the emergence of de novo DSAs in the late post-transplant period and is thought to be related primarily to non adherence or inadequate immunosuppression.
Paradigms in antibody mediated rejection
Antibody removal for highly sensitized patients
Treatment of antibody mediated rejection
The goal for the treatment of AMR is to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without compromising the normal immune responses that protect patients from serious infections.
Prevention of antibody mediated rejection
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival
review article : level 5
Antibody-Mediated Rejection
Level of evidence: Review article level V
Summary:
Background: Chronic antibody mediated injury is a serious threat to allograft outcomes and may cause graft failure. Recent advances in molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However still ABMR is the main cause for graft failure.
Methods: The reviewed the current diagnostic criteria for AMR; AMR paradigms; and desensitization, treatment, and prevention strategies.
Introduction:
Allograft rejection is a complex process that involves different cellular and molecular pathways that cause a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis). Antibody against human leukocyte antigen (HLA) or blood antigens, including non-HLA antigens expressed on the endothelium, can activate the complement system, leading to recruitment of leukocytes and facilitation of NKC or monocyte/macrophage mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
Allograft rejection can be hyperacute due to high levels of preformed antibodies, early acute occurring days to weeks after transplantation, late acute occurring 3 months after transplantation, or chronic occurring months to years after transplantation. Rejection also can be classified as per histopathological picture o TCM and ABMR.
The Banff classification for allograft rejection pathology has made a dramatic improvement in detection, standardizing, and incorporating histologic, immunohistochemical, and serologic factors that all causing improve sensitivity in the diagnosis of allograft rejection and in providing good idea regarding outcome data in terms of allograft survival.
Acute Antibody-Mediated Rejection According to the Banff 2013 classification: all the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury:One of the following a. Glomerulitis or peritubular capillaritis b. Intimal or transmural arteritis c. Acute thrombotic microangiopathy (TMA) d. Acute tubular injury.
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum.
Chronic Antibody-Mediated Rejection: According to the revised Banff 2013 classification the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis
2. Histologic evidence of antibody interaction with vascular endothelium a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum.
Antibody-Mediated Rejection phenotypes:
There are 2 principal phenotypes of acute AMR:
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
C4d-Positive and C4d-Negative Rejection: C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation.
Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies. They include angiotensin type I receptor and endothelin type A receptor antibodies
Transplant Glomerulopathy
Transplant glomerulopathy is characterized by glomerular basement membrane duplication, double contouring, or splitting.The electron microscopy provides the best tool for the early diagnosis of transplant glomerulopathy and should be incorporated into the definition of chronic glomerulopathy.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
High-Dose Intravenous Immunoglobulin
Intravenous Immunoglobulin and Rituximab
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Immunoadsorption for Rapid Crossmatch Conversion Compared to PLEX,
TREATMENT OF ANTIBODY-MEDIATED REJECTION
Plasmapheresis PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR
Intravenous Immunoglobulin
Rituximab
Proteasome Inhibitor: Bortezomib has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
Complement Inhibition:The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.Only limited data, usually single cases, are available on the efficacy of eculizumab in patients with severe AMR.
Chronic Antibody-Mediated Rejection Treatment: PREVENTION OF ANTIBODY-MEDIATED REJECTION
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are strategies used to reduce or early diagnose AMR and improve allograft survival.
In summary, a reduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure.
Antibody Mediated Rejection.
This article is a narrative review with level 5 evidence for the AMR current diagnostic criteria and paradigms. Besides, it emphasizes the AMR desensitization protocol, treatment, and prevention strategies.
AMR diagnosis criteria.
1. Evidence of chronic tissue injury in renal HPE as defined by at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known aetiology.
2. Histology evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury.
3. Detection of DSAs (HLA or non-HLA) in the serum.
In the 2011 Banff report 2 principal phenotypes of acute AMR.
Phenotype 1 occurs in the pre sensitized kidney transplant recipient and occurs in the early post-transplant period.
Phenotype 2 develops from the development of de novo DSAs in the late posttransplant period due to poor compliance or inadequate immunosuppression.
AMR Paradigms.
a) Subclinical Antibody-Mediated Rejection
-Poor graft survival.
b) C4d-Positive and C4d-Negative Rejection
-Poor marker for AMR.
c) Antibody-Mediated Vascular Rejection
-The risk of graft loss is greater in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
d) Non-HLA Antibody-Mediated Rejection
-Increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
e) Transplant Glomerulopathy
-Lead to progressive allograft failure. Poor prognosis and eventual contribute to 40%-70% allograft loss.
Desensitizing protocol.
a) Intravenous immunoglobulin (IVIG).
b) IV Rituximab. May combine with IVIG for more effective desensitization. However, larger trial needed.
c) Plasmapheresis, Intravenous Immunoglobulin, and Rituximab. High-dose IVIG is inferior to combination therapy.
d) Immunoadsorption for Rapid Crossmatch Conversion.
Treatment of AMR.
a) Plasmapheresis.
-Removes preformed antibodies.
b) Intravenous Immunoglobulin.
c) Rituximab.
d) Proteasome Inhibitor. Bortezomib. Has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with good outcome.
e) Complement Inhibition. Eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH).
Chronic Antibody-Mediated Rejection Treatment
a) Steroid and IVIG. Rigorous and potent immunosuppressive agents might not be feasible.
Prevention of AMR.
Pregnancies, blood transfusions, patient nonadherence and previous organ transplantation are major risk factors for recipient sensitization and AMR.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies.
Conclusion.
Alloimmune response remains crucial for successful long-term allograft function. Banff classification histology criteria remain useful for the diagnosis of AMR. Plasmapharesis and IVIG are still considered mainstay therapies for the treatment of AMR. Further evidence needed for newer therapy for AMR.
Summary
Introduction
Different cellular and molecular processes lead to rejection. This causes injury to the allograft, such as acute tubular injury, glomerulitis, capillarities, and fibrinoid necrosis.
There are different types of allograft rejection with respect to period of occurrence post transplant – these include :
CAMR can present with transplant glomerulopathy with basement membrane duplication, double contouring or splitting as typical histological features for identification. Clinically, proteinuria and increase in creatinine will be seen.
Diagnostic criteria
SAB or single antigen bead testing are sensitive for identification of anti HLA antibodies and consequently AMR.
Banff classification 2013 is used for differentiating features of acute and chronic AMR.
Acute AMR :
Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium, defined by at least one of
the following:
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic AMR :
Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
2. Histologicevidenceofantibodyinteractionwithvascular
endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes
Phenotype 1 :
Phenotype 2 :
Treatment
Treatment options for AMR include the following
PLEX removes preformed antibodies. Outcome is better with a combination of PLEX and IVIG versus PLEX alone.
Rituximab along with PLEX also gives good outcome, possibly better than PLEX and IVIG.
Bortezomib can be used in a regimen of PLEX, IVIG, Rituximab can work against AMR.
Prevention
Conclusion
Alloimmune response is the major barrier to successful organ transplant. AMR, whichever period it occurs in, can result in significant harm to the graft or even graft loss, if not detected early and treated sufficiently. Early detection can be done with proper followup and repeat DSA testing. Necessary precautions for prevention of rejection include identifying non-adherence, and maintaining adequate immunosuppression through the lifetime of the patient. Patient awareness regarding immunossive regimen dose, frequency, and importance is paramount to long term success of transplant and graft as well as patient survival.
Level of Evidence
This is a narrative review. Level of evidence 5.
The histology of acute and chronic AMR overlaps
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum
Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g were associated with an increased risk of allograft loss. The authors concluded that chronic AMR was associated with poor graft survival after diagnosis.
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cellmediated rejection (88%) and no-rejection (90%) groups (P<0.001)
In addition to complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility make C4d a poor marker for the diagnosis of AMR.
No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive
angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies
agreed that electron microscopy unequivocally provides the best tool for the early diagnosis of transplant glomerulopathy and should be incorporated into the definition of chronic glomerulopathy.
🏣level 5
Evidence
Summary of Antibody-mediated rejection:
Introduction:
Allograft rejection is a complex process that involves different cellular and molecular pathway which can cause a broad range of allograft injury .
Classification of allograft rejection based on the time of rejection:
1. Hyperacute (occurring minutes after the vascular anastomosis)
2. Acute (days to weeks after transplantation)
3. Late acute (occurring 3 months after transplantation)
4. Chronic (occurring months to years after transplantation)
Rejection classification based on the pathophysiological events:
1. Cellular
2. AMR
3. Both
Current diagnostic criteria:
Despite the major advances in molecular biology and gene rearrangement the diagnosis of AMR is still depend on histological finding
Acute antibody-mediated rejection:
Banff 2013 classification all of the following 3features are required for the diagnosis of a cute AMR:
1. Histological evidence of acute tissue injury defined by the presence of one or more of the following
A. Glomerulitis or peritubular capillaritis
B. Intimal or transmural arteritis
C. Acute thrombotic microangiopathy
D. Acute tubular injury
2. Histological evidence of current antibody interaction with vascular endothelium
3. Detection of DSA (HLA or non HLA) in the serum
Chronic antibody-mediated rejection:
Banff 2013 classification the diagnosis of chronic active AMR require 3 features:
1. Histological evidence of chronic tissue injury defined by the presence of at least one of the following:
A. TG
B. Multi-layering of peritubular capillary basement membrane
C. New onset arterial intimal fibrosis with no other known aetiology
2. Histological evidence of antibody interaction with vascular endothelium
3. Detection of DSAs (HLA or non HLA )in the serum
Phenotype of antibody-mediated rejection:
In Baff 2011 report 2 phenotypes of acute AMR:
1. Phenotype 1
Occurs in the pre-sensitized patients
Occur early post renal transplant period
2. Phenotype 2
Occur from de novo DSAs
Occur in late post renal transplant period
Related to non-adherence or inadequate immunosuppression
Paradigms in antibody-mediated rejection:
Subclinical antibody-mediated rejection
Protocol biopsy identified a sub-group of patients with histological evidence of antibody-mediated injury despite creatinine stable
Lack of long term follow up data has prevented the development of strong guidelines for effective therapeutic intervention
Subclinical AMR if left untreated increased the risk of allograft loss
C4d-positive and c4d-negative rejection:
Banff 2013 classification included others marker for endothelial activation and injury such as:
Increased expression of endothelial activation and injury transcripts or other gene expression markers of endothelial injury in the tissue biopsy
C4d-Negative AMR:
Microvascular injury (glomerulitis, peritubular capllaritis, TMA) in the presence of DSAs and absence of c4d deposition in PTC
Present later compare to c4d positive AMR
Less common than c4d positive AMR
Increase risk of allograft loss in c4d positive compare to c4d negative AMR
Antibody-mediated vascular rejection:
Population based study demonstrated that vasculitis belong to T-cell mediated rejection and AMR hence the risk of graft loss 9 times in AMR vascular rejection these T-cell mediated rejection without vasculitis
Non-HLA antibody-mediated rejection:
Non-HLA antibodies are 2 types
1. Alloantibodies against polymorphic antigens
2. Antibodies that recognize self-antigens or auto-antibodies
Eg:
a-angiotensin type 1 receptor
b-endothelium type A receptor antibodies
Transplant glomerulopathy:
Glomerular basement membrane
Late stage of antibody mediated injury which associated with poor graft survival
High-dose intravenous immunoglobulin:
Mechanism of IVIG:
1. Inhibition of T-cell proliferation
2. Inhibition of cytokines synthesis
3. Inhibition of complement activation
4. Ant idiotypic blockade of alloantibodies
Some of studies conclude IVIG was better in replacing anti-HLA antibody levels and improving transplantation rate in highly sensitized patients with ESRD
Intravenous immunoglobulin and Rituximab:
The researchers concluded that the combination of IVIG and Rituximab was effective as desensitization regimens
Plasmapheresis, intravenous immunoglobulin, and Rituximab
The researcher concluded that high dose IVIG is inferior to combination therapy
Immunoadsorption for rapid crossmatch conversion:
Treatment consisted of a single session of immediate pretransplant IA(protein) followed by posttransplant IA
Conclusion that IA is an effective strategy for rapid desensitization in deceased-donor transplantation
Treatment of antibody-mediated rejection:
Optimization of baseline immunosuppression (CNI+ antiproliferative agents, +steroid)
Pulse steroid
Rabbit ATG
PLEX, IVIG
B-cell depleting agents
Plasmapheresis:
Rapidly removed performed antibodies
PLEX and IVIG was superior to PLEX alone
Intravenous immunoglobulin:
Better allograft outcome in combination therapy PLEX and Rituximab
Rituximab:
Combination of Rituximab, PLEX and IVIG
Graft survival was better in this control group
Protease inhibitors:
Removing plasma cells
Bortezomib approved for the treatment of multiple myeloma
Has been used in combination with PLEX, IVIG, or Rituximab
Complement inhibition:
Eculizumab (anti C5 monoclonal antibody) and C1 esterase inhibitor (C1-INH)
Early use of eculizumab before advanced change in kidney injury are identified can improved responses and allograft survival
Chronic antibody mediated rejection treatment:
Therapy has been used for the treatment of chronic AMR data are limited
Prevention of antibody-mediated rejection:
To prevent AMR:
1. Avoid transplant for highly sensitized patients
2. Enrolling highly sensitized patients in approved. Kidney exchange programme
3. Participating in special programme such as Euro transplant Acceptable MB match programme
4. Combined kidney paired exchange programme with desensitization protocol
5. Maintain de novo DSAs using class 11 HLA epitopes matching and performing protocol biopsy
Conclusion:
Alloimmune response remains an important barrier for successful long term allograft function
Histological criteria driven by Banff classification has helped standardized the diagnosis of AMR
Treatment of AMR are PLEX and IVIG
More research is required in the field of AMR
2- level of evidence is 5
Antibody-Mediated Rejection: A Review
Allograft rejection can be
-hyperacute (occurring within minutes after the vascular anastomosis),
-acute (occurring days to weeks after transplantation), – late acute (occurring 3mmonths after transplantation), or
– chronic (occurring months to years after transplantation).
Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
Because of current improvement in immunossuppresion treatment ,It is not uncommon for rates of acute rejection to be < 15%.
CURRENT DIAGNOSTIC CRITERIA
Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the
following 3 features are required for the diagnosis of acute
AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis or peritubular capillaritis
b. Intimal or transmural arteritis
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy ) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Redfield et al conducted a study of 123 -The authors concluded that chronic AMR was associated with poor graft survival after diagnosis.
Moderate Microcirculatory Changes
Microcirculatory changes were introduced in the revised Banff 2013 classification and are recognized as highly suspicious for antibody injury. Only the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
Phenotypes of Antibody-Mediated Rejection
2 principal phenotypes of acute AMR were defined.
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.
Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
Subclinical Antibody-Mediated Rejection
Patients with subclinical AMR had the poor graft survival Post transplant compared with the subclinical T cell – mediated rejection and no-rejection. Orandi and colleagues reported that subclinical AMR, if left untreated, increased the risk of allograft loss.
C4d-Positive and C4d-Negative Rejection
In 1993, Feucht et al were the first to report the presence of C4d deposition in peritubular capillaries and the correlation with allograft loss.
C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation.
C4d-negative rejection was not different from C4d-positive rejection in any baseline characteristic. Compared to patients with C4d-negative rejection, patients with C4d-positive AMR were more likely to present earlier post transplantation and were more common. Graft survival in C4d-negative AMR patients was better in C4d-positive AMR patients . C4d-negative AMR was associated with a 2.56-fold increased risk of allograft loss compared with AMR-free matched controls.
No clinical characteristic could distin guish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection
Traditionally, endarteritis has been associated with cellular rejection; however, a population-based study demonstrated that vasculitis belongs to both T cell – mediated rejection and AMR.the result of one study, the risk of graft loss was 9.07 times higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
Non-HLA Antibody-Mediated Rejection
Patients with complement binding DSA after transplantation had a lower graft survival compared with patients with non-complement-binding DSA and patients without DSA antibodies .
These antibodies were associated with an increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
Transplant Glomerulopathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring,
or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
Transplant glomerulopathy causes progressive allograft failure with a poor prognosis and eventual allograft loss and is considered a histologic feature associated with chronic AMR that results from recurrent events of endothelial activation injury and repair.
-electron microscopy unequivocally provides the best tool for the early diagnosis of transplant glomerulopathy
High-Dose Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent.
Several mechanisms of IVIG action have been proposed, including
§ the inhibition of T cell proliferation,
§ the inhibition of cytokine synthesis,
§ The inhibition of complement activation,
§ the antiidiotypic blockade of alloantibodies.
In one study The authors concluded that IVIG was better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease.
Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventualmaturation to antibody-forming plasma cells .
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Lefaucheur et al compared the outcome of a plasmapheresis (PLEX)-, IVIG-, and rituximab-based protocol vs IVIG alone. The researchers concluded that high-dose IVIG is inferior to combination therapy.
Immunoadsorption for Rapid Crossmatch Conversion
Compared to PLEX, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
Because of current immunosuppressive medications, the rates of acute rejection and 1-year graft survival have substantially improved . The threat of hyperacute rejection has been completely eliminated.
The treatment of subclinical AMR and its potential benefits are still under investigation.
Subclinical AMR was independently associated with a increased risk of allograft loss compared to matched controls but was not different from clinical AMR.
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
In an observational study, the auther found that the combination of PLEX and IVIG was superior to PLEX alone.
One study patients receives treatment with PLEX alone,compared to received treatment with a combination of PLEX and IVIG (0.5 g/kg). One-year graft survival was significantly higher in the PLEX plus IVIG group than in the PLEX-alone group. Similarly, patient survival was higher in the PLEX plus IVIG group vs the PLEX-alone group.
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
Proteasome Inhibitor
Removing plasma cells that generate antibodies is therationale behind using a proteasome inhibitor (PI) as therapy for AMR.
has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results. This large experience with PI based AMR therapy demonstrated that it provides effective AMR reversal, including substantial reductions in DSA levels.
Complement Inhibition
The FDA has approved 2 agents, for complement inhibition
· eculizumab (an anti-C5 monoclonal antibody) and
· a C1 esterase inhibitor (C1-INH),
-Eculizumab was approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
-C1-INH was approved for use in patients with hereditary angioedema. Only limited data, usually single cases, are available on the efficacy of eculizumab in patients with severe AMR.
In a 2014 study, found that eculizumab was not effective in severe oliguric early-onset AMR. The researchers con cluded that splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR.
Chronic Antibody-Mediated Rejection Treatment
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited. Because of the slow progression of chronic AMR compared to acute AMR, subjecting patients to rigorous and potent immunosuppressive agents might not be feasible. despite the best available therapies, patients experienced poor graft survival.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
1-avoiding transplantation for highly sensitized patients,
2-better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening,
3- enrolling highly sensitized patients in a paired kidney exchange program, 4-Monitoring de novo DSAs,
5- using class II HLA epitope matching,
6- performing protocol biopsies .
level 5
Please summarise this article :
* The first description of acute AMR identified neutrophils in peritubular capillaries and de novo donor-specific antibodies (DSAs).
* C4d, a degradation product of the complement pathway that binds covalently to the endothelium, was identified as marker of endothelial injury and hence of antibody activity.
* B cells and plasma cells produce DSAs that interact with the endothelium, which activates the cellular pathways responsible for the development of microcirculatory changes and tissue injury.
* Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
* CURRENT DIAGNOSTIC CRITERIA :
– Single-antigen bead testing .
– Complement-dependent cyto- toxicity .
– Electron microscopy is routinely used for the biopsies of transplant recipients.
* Acute Antibody-Mediated Rejection :
– 1. Histologic evidence of acute tissue injury .
– 2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium.
– 3. Detection of DSAs (HLA or non-HLA) in the serum.
* Chronic Antibody-Mediated Rejection:
– – 1. Histologic evidence of acute tissue injury .
– 2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium.
– 3. Detection of DSAs (HLA or non-HLA) in the serum.
* Phenotypes of Antibody-Mediated Rejection:
– Phenotype 1 occurs in the presensi- tized patient and occurs in the early posttransplant period.
– Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to non-adherence or inadequate immuno- suppression.
* PARADIGMS IN ANTIBODY-MEDIATED REJECTION Subclinical Antibody-Mediated Rejection:
– Patients with subclin- ical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell– mediated rejection (88%) and no-rejection (90%) groups (P<0.001).Orandi and colleagues reported that subclin- ical AMR, if left untreated, increased the risk of allograft loss.
– C4d-negative AMR, defined by microvascu- lar injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
* Non-HLA Antibody-Mediated Rejection:
– angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies.
* Transplant Glomerulopathy:
– It is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. The prevalence of transplant glomerulopathy is 5%-20% in most series, increasing to 55% in high-risk cohorts.
* Intravenous Immunoglobulin and Rituximab:
– The researchers concluded that the combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
– IA is an effective strategy for rapid desensitization in deceased-donor transplantation.
– The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune respons- es that protect patients from serious infections.
* Treatment of ANTIBODY- Mediated rejection:
– Plasmapheresis.
– IVIG .
– Protesome inhibitors .
– complement Inhibition .
* PREVENTION OF ANTIBODY-MEDIATED REJECTION:
Djamali et al proposed several strategies to prevent AMR, including avoiding transplantation for highly sensitized patients, better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desen- sitization protocols.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
REFERENCES
1. Terasaki PI. A personal perspective: 100-year history of the humoral theory of transplantation. Transplantation. 2012 April 27;93(8):751-756. doi: 10.1097/TP.0b013e3182483713.
2. Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014 Feb;14(2):255-271. doi: 10.1111/ajt.12589.
3. Mauiyyedi S, Pelle PD, Saidman S, et al. Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol. 2001 Mar;12(3):574-582.
4. Farkash EA, Colvin RB. Diagnostic challenges in chronic antibody-mediated rejection. Nat Rev Nephrol. 2012 Mar 27; 8(5):255-257. doi: 10.1038/nrneph.2012.61.
5. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant. 2010 Feb;15(1):42-48. doi: 10.1097/MOT.0b013e3283352a50.
It is a narrative review and level of evidence 5
Diagnoses of acute AMR:
-Evidence of acute tissue injury at the histology level defined by the presence of one or more of the following:
*Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
*Intimal or transmural arteritis (v >0)
*Acute thrombotic microangiopathy(TMA) with no obvious cause
*Acute tubular injury with no obvious cause
-Evidence of current or recent antibody reaction with vascular endothelium, defined by at least one of
the following:
* C4d staining (in linear pattern) in the peri tubular capillaries
*At least moderate microvascular inflammation
*Increased expression of tissue gene transcripts
-Presence of DSAs in the serum either HLA or non-HLA.
Diagnosis of Chronic AMR :
As per revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
– Evidence of chronic tissue injury, defined by the presence of at least one of the following:
*Transplant glomerulopathy without chronic TMA
* Multi layering in peritubular capillary basement membrane by electron microscopy
*Arterial intimal fibrosis of new onset without known etiology
– Evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
* Linear C4d staining in the peritubular capillaries
* Moderate microvascular inflammation
* Increased expression of tissue gene transcripts indicative of endothelial injury
-Presence of DSAs in the serum either HLA or non-HLA.
Treatment of AMR:
-Plasmapheresis: to removes the antibodies.
– IVIG.
– Rituximab.
– Proteasome Inhibitor. Bortezomib.
– Complement Inhibition. Eculizumab
Antibody-Mediated Rejection: A Review
Allograft rejection is a complex process that involves the interplay of different cellular and molecular pathways that cause a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis). Antibody ligation to human leukocyte antigen (HLA) or blood antigens, including non-HLA antigens expressed on the endothelium, can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/macrophage– mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
With the introduction of T cell–depleting drugs, calcineurin inhibitors (CNIs), and antiproliferative agents, the field of transplantation has experienced exceptional improvement in allograft survival. Other progress was recognition of the role of DSAs, such as new techniques to detect antibodies, the use of desensitization protocols, and the introduction of new agents that interfere with complement-mediated allograft injury.
1 – CURRENT DIAGNOSTIC CRITERIA:
The Banff classification for allograft pathology has made considerable progress during the last 2 decades in capturing, standardizing, and incorporating histologic, immunohistochemical, and serologic factors believed to improve sensitivity in the diagnosis of allograft rejection and in providing outcome data in terms of allograft survival.
The 12th Banff Conference on allograft pathology was held in Brazil in August 2013. Different working groups presented their findings to reach consensus on the diagnosis of AMR: – presence and absence of a C4d stain;
– role of microcirculatory inflammation,
including thresholds for glomerulitis;
– the role of intimal arteritis;
– comparisons of different methodologies for evaluating interstitial fibrosis;
– role of implantation biopsies in terms of allograft outcomes.
Despite the major advances in molecular biology and gene rearrangement, the diagnosis of AMR is still dependent on histologic findings
1.A – Moderate Microcirculatory Changes
The Banff renal pathologists involved with the evaluation of kidney biopsies established the presence of glomerulitis and graded this finding based on the complete occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement
1.B – Phenotype of Antibody-mediated rejection
The 2011 Banff report, 2 principal phenotypes of acute AMR were defined.13 Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
2 – PARADIGMS ANTIBODY-MEDIATED REJECTION
2.A – Subclinical Antibody-Mediated Rejection
Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell– mediated rejection (88%) and no-rejection (90%) groups (P<0.001). If left untreated, increased the risk of allograft loss.
2.B – C4d positive and C4d negative rejection
C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation
2.c – Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies.23,24 Non-HLA antibodies use different pathways to cause endothelial injuries that do not involve the presence of integrins, as with HLA antibodies
2.d- Transplant Glomerulypathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. Transplant glomerulopathy causes progressive allograft failure with a poor prognosis and eventual allograft loss in 40%-70% of patients and is considered a histologic feature associated with chronic AMR that results from recurrent events of endothelial activation injury and repair.
Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome (graft loss of 92% vs 33%, P< 0.005) and is strongly associated with preexisting or de novo DSAs.
3 – ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Approximately one-third of patients awaiting a deceased donor kidney transplant have circulating anti-HLA antibodies, and almost 15% have a high degree of sensitization to potential kidneys. Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
3.A – High-Dose Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
3.B – Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complemente dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen. The researchers concluded that the combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
3.C – Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
Assay compared the outcome of a plasmapheresis (PLEX)-, IVIG-, and rituximab-based protocol vs IVIG alone. The researchers concluded that high-dose IVIG is inferior to combination therapy
3.D – Immunoadsorption for Rapid Crossmatch Conversion
Compared to PLEX, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. Three or more plasma exchanges can be processed during a single session. Some authors have proposed that this technique may provide rapid and selective antibody depletion in a few hours. At 5 years, overall graft survival, death-censored graft survival, and patient survival were 63%, 76%, and 87%, respectively, without any differences among crossmatch-positive, crossmatch-negative/DSA-positive, and crossmatch-negative/DSA-negative recipientes.
4 – TREATMENT OF ANTIBODY-MEDIATED REJECTION
4.A – Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. Pascual et al evaluated the role of PLEX and tacrolimus (TAC)-mycophenolate rescue therapy for AMR. Slatinska et al found that the combination of PLEX and IVIG was superior to PLEX alone.
4.B – Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
4.C – Rituximab
4.D – Proteasome Inhibitor
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor (PI) as therapy for AMR. Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
4.E – Complement Inhibition
The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition. Wongsaroj et al reported on the efficacy and safety of eculizumab in treating patients with severe AMR episodes unresponsive to standard treatment with IVIG plus rituximab with or without PLEX.
4.F – Chronic Antibody-Mediated Rejection Treatment
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited
5 – PREVENTION OF ANTIBODY-MEDIATED REJECTION
Choosing donors with lower sensitization to recipients, as well as avoiding reduced immunosuppression, appear to be the actions with the best result to avoid rejection.
This article is a narrative review – evidence level 5.
What is the level of evidence provided by this article?
Level 5 narrative review
Antibody-Mediated Rejection: A Review
before ABMR was adisaster unknown ghost that led to graft loss,The first description of acute AMR identified neutrophils in peritubular capillaries and de novo donor-specific antibodies (DSAs). C4d, a degradation productof the complement pathway that binds covalently to the endothelium, was identified as marker of endothelial injury and hence of antibody activity.
CURRENT DIAGNOSTIC CRITERIA.
single-antigen bead testing (SAB)used to detect anti-HLA antibodies,current technique of choice used to identify antibodies that can injure the allograft .
graft biopsy could be done by electron microscopy .
cdc nowdays is not the technique of choice.
Acute Antibody-Mediated Rejection
Banff 2013 classification
all of the following 3 features are required for the diagnosis of acute AMR
A. Histologic evidence of acute tissue injury as Glomerulitis or peritubular capillaritis Intimal or transmural arteritis ,tubular injury with out obvious cause.
B. Histologic evidence of current/recent antibody interaction with vascular endothelium
need only one of the following C4d staining in the peritubular capillaries,moderate microvascular inflammation,endothelial injury.
C. positive DSA.
Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification, the diagnosis ofchronic, active AMR requires 3 features:
A. evidence of chronic tissue injury in the form of Transplant glomerulopathy in the absence of chronic TMA , Severe peritubular capillary basement membrane
multilayering identified by electron microscopy, arterial intimal fibrosis with out obvious cause.
B. Histologic evidence of antibody interaction with vascular endothelium requires one of the following C4d staining in the peritubular capillaries,moderate microvascular inflammation,endothelial injury.
C.positive DSA.
Antibody removal for highly sensitized patients
High dose Intravenous immunoglobulin (IVIG) immunomodulatory agent Inhibits complement activation, T cell proliferation, cytokine release.
It was found to be better than placebo with efficacy of 52%(9/17) in reducing anti-HLA antibodies in sensitized patients.
IVIG and Rituximab
Rituximab is an ati-CD20 monoclonal antibody Causes B cell lysis and blocks B cell activation. Does not affect already formed plasma cells which lack CD20.
Has been found to be effective in desensitization a regimen when combined with IVIG.
PPS, IVIG, and Rituximab this combination lead to graft survival at 36 months of 91.7% in vs 50% with IVIG alone.
Immunoadsorption for Rapid Crossmatch Conversion appears to be better than plasmapheresis with faster clearance immunoglobulins.
What is the level of evidence provided by this article?
narrative review level 5
Summarise this article:
Allograft rejection can be hype acute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation).
Complement-dependent cytotoxicity is still considered the gold standard for the detection of preformed antibodies. Electron microscopy is routinely used for the biopsies of transplant recipients because early changes cannot always be detected with light microscope .
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.
the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
2 principal phenotypes of acute AMR were defined .Phenotype 1 occurs in the presensitized patient . Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group.
The risk of graft loss was 9.07 times higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
Patients with complement binding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graft survival (54%) compared with patients with non-complement-binding donor-specific anti HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%).
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting30 and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome (graft loss of 92% vs 33%) and is strongly associated with preexisting or de novo DSAs.
treatment of highly sensitizing patients, high-dose Intravenous immunoglobulin, intravenous immunoglobulin and rituximab, plasmapheresis, intravenous immunoglobulin, and rituximab, combination therapy is superior to other.
by immunoabsorption, three or more plasma exchanges can be processed during a single session, this technique may provide rapid and selective antibody depletion in a few hours.
treatment of acute Ab mediated rejection
-Plasmapharesis .
-IVIg.
-Rituximab
-Bortezomib.
-eculizumab.
-in chronic antibody-mediated rejection treatment the previously mentioned therapies have been used for the treatment of chronic AMR although data are limited.
-The 5-year graft survival for patients with no DSAs, non–C1q-binding DSAs, and C1q-binding DSAs was 94%, 93%, and 54%, respectively.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
What is the level of evidence provided by this article?
Honestly in the first I think it is Level 2 but after read of diagram of Professor Ahmed Halawa it is LEVEL 5.
This article is a narrative review with the level 5 of evidence.
Introduction: the development of antibodies against HLA and non-HLA antibodies and their binding to HLA antigens and non-HLA antigens on the endothelium is essential in the allograft rejection that lead to complement system activation and subsequent recruitment of leukocytes, initiation of NK cells and macrophage mediated cytotoxicity. Ultimately interplay of different cellular and molecular pathways lead to endothelial damage and increased coagulation, and consequently allograft rejection. Allograft rejection can be hyperacute, early acute, late acute and chronic. It also can be cellular and, or Antibody mediated. With the significant progression in the field of recognition of the roles of DSAs, new techniques of detection of DSAs, development of new drugs and desensitization protocols result in decline in the rate of acute rejection less than 15%.
Current diagnostic criteria
These days single antigen bead testing is the final step in detection of DSA, monitoring of transplant recipients and also utilize as a tool for diagnosis of AMR. Electron microscopy integrate the light microscopy findings of transplant recipient’s kidney biopsy findings for diagnosis of rejection. The Banff classification by incorporating histologic, immunological and serologic factors for pathologic diagnosis of allograft rejection has been in progress in recent decades.
Acute ABMR
In accord with Banff 2013 classification all of these three features are required for the diagnosis of acute AMR: histologic evidence of acute tissue injury, histologic evidence of current or recent antibody interaction with endothelium, detection of DSA in the serum.
Chronic AMR
There are overlaps between histologic evidence of acute and chronic AMR. And acute AMR is a risk factor for chronic AMR. For diagnosis of chronic, active AMR 3 features are required including histologic evidence of chronic tissue injury, histologic evidence of antibody interaction with endothelium, detection of DSA in the serum.
In one study, chronicity scores>8, DSA>2500 MFI, ser Cr> 3 mg/dl, and urine Pr/Cr ratio more than 1 gr/gr were correlated with higher risk for graft loss.
Moderate microcirculatory changes
It is recognized as a highly suspicious for antibody mediated injury and defined in the presence of vasculitis and high number of inflammatory cells in the microcirculation which is associated with poor outcome.
Phenotypes of AMR
Two principle phenotypes of AMR are phenotype 1 is related to preexisting DSA and occurs in early post transplantation, phenotype 2 is related to de novo DSA that occurs later and is associated with non-adherence and low level of immunosuppression.
Subclinical AMR
It is defined as histologic evidence of AMR and normal serum Cr. It is associated with poorer graft survival compared with subclinical TCM rejection and no rejection and if it is not treated appropriately, will lead to increased rate of rejection.
C4d-positive and C4d negative rejection
C4d positivity in the absence of evidence of allograft injury was reported, and on the other hand, up to 55% of patients with acute AMR can be C4d-negative. Thus, other markers of endothelial injury such as injury transcripts incorporate in Banff classification. C4d-negative AMR has been defined as microvascular injury in the presence of DSAs. In one study, comparison between C4d-positive and C4-d negative DSA demonstrated that similar baseline and clinical characteristics, similar DSAs and poorer graft survival in the C4d positive group.
Antibody mediated vascular rejection
Endarteritis is associated with both AMR and TCM rejection, but in correlation with AMR is related to significant increased risk of graft loss.
Non-HLA AMR
Non-HLA antibodies are either alloantibodies directed against polymorphic antigens such as angiotensin type 1 receptor and endothelin type A receptors antibodies or autoantibodies. Presence of complement fixing anti HLA DSAs is associated with poorer graft survival compared with non-complement binding DSAs.
Transplant glomerulopathy
Transplant glomerulopathy that is characterized by duplication and splitting of GBM is considered the histologic finding of late stage of AMR, with prevalence of 5-20%, and correlated with graft loss. It is associated with heavy proteinuria and electron microscopy is the best tool for diagnosis. Risk stratification based on serum Cr, proteinuria, and chronic inflammatory scores may provide guidance for prognosis and treatment.
Antibody removal for highly sensitized patients
One third of patients in waiting list for deceased donor have circulating DSAs, and 15% are highly sensitized. Thus, different immunomodulatory strategies are utilized for decreasing the level of these antibodies consist of IVIG, rituximab, plasmapheresis, and immunoadsorption. IVIg can plat its immunomodulatory role by different mechanism including inhibition of T cell proliferation, cytokine synthesis, and complement activation, and blockade of alloantibodies.
Rituximab, induce CD20+ B cell lysis and block B cell activation but does not affect on plasma cells. It is reported that combination of Rituximab and IVIG can be effective as desensitization protocol. The combination of IVIG, Rituximab, and plasmapheresis may be better than IVIG as desensitization protocol. Immunoadsorption provide more specific and more effective clearance of circulating alloantibodies and lead to rapid and selective antibody removal on a few hours. As a result, IA can be an effective strategy for rapid desensitization.
Treatment of AMR
Protocol biopsy and DSA monitoring has been considered for follow up of kidney transplant recipients. If subclinical AMR leave untreated it may progress to transplant glomerulopathy. There is uncertainty about the treatment of subclinical AMR, and it is required large randomized clinical trials. Untreated subclinical AMR may be associated with more than 2-3 fold increased risk of allograft loss. Plasmapheresis is a part of standard treatment of AMR, but the results about its efficacy is conflicting. Combination of PLEX and IVIG is more effective than PLEX alone or IVIG alone in treatment of AMR. Rituximab in addition to IVIG and PLEX has been associated with good graft survival in AMR (>90%). Another option with encouraging result for treatment of AMR is bortezomib (by removing plasma cells) in combination with IVIG, PLEX, and/or rituximab. Inhibition of complement system by eculizumab in severe and unresponsive AMR has been reported in few case reports, that was especially effective in cases with TMA. One study suggested splenectomy in combination with eculizumab can be effective in treatment of acute early AMR.
Chronic AMR
Administration of mentioned medication for treatment of chronic AMR because of its slow rate of progression is not widely accepted. Although , the studies are conflicting.
Prevention of AMR
Presence of C1q-fixing DSAs is considered as an independent predictor of graft loss. Some strategies were proposed for prevention of AMR, such as avoiding transplantation in highly sensitized patients, utilizing sensitive anti-HLA DSA screening test, enrolling highly sensitized patients in paired donation programs alone or in combination with desensitization protocols and monitoring of de novo DSAs, anti-class II HLA, and protocol biopsy for early diagnosis of AMR. Even low level of DSAs and suboptimization of immunosuppressive drugs are associated with poor graft survival.
Identification of molecular and histologic changes allowed AMR therapeutic intervention
AMR is a major enemy threating allograft function
(DSAs).
DSA come from both B cell and plasma cell, injure the endothelium and microcirculatory changes after activation of cellular pathways.
CURRENT DIAGNOSTIC CRITERIA
Current diagnostic criteria :
Biopsy: light microscopy with immunohistochemistry for C4d , C1q (Banff classification)and EM to examine early detection not detected by light microscopy
Detection of DSA : CDC ,single antigen bead
Acute Antibody-Mediated Rejection
Acute ABMR diagnosed according to the Banff 2013 classification with all of the 3 features
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
While chronic ABMR diagnosed with at least one of the following:
1. histologic features of tissue injury
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotype of ABMR:
Type 1: with the persistence of preformed DSA, occur early
Type 2: de novo DSA, later on
Paradigm of ABMR
1. Subclinical ABMR:
Diagnosed with protocol biopsy and associated with poorer outcome in means in graft survival 56% vs 90% in patients without it
Intravenous Immunoglobulin
Not alone with RTX or plasmapharesis
Rituximab
Manty studies showed acceptable graft survival with ppx and IVIG either in 500mg/m2 or 375/m2/w
Proteasome Inhibitor
To remove plasma cell producing and memorizing DSAs
In a dose (1.3 mg/m2/dose 3-4 doses) with IVIG and rtx showed promising results in histological reversal of the rejection.
Complement Inhibition
Two monoclonal abs are approved now eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH),
Scarce data are available for their use in reversal of AMR (not in early oliguric sever AMR) and ttt of TMA
Chronic Antibody-Mediated Rejection Treatment
The aggressive IS used in management of acute ABMR may not be feasible in chronic AMR being slowly progressive.
Data supporting the use of RTX, IVIG are limited and of low evidence(case series)
PREVENTION OF ANTIBODY-MEDIATED REJECTION
Prediction:
1- C1q-fixing DSAs Prescence predict allograft loss
level 5 evidence
Antibody-Mediated Rejection: A Review
This is a narrative review with class 5 evidence
ABMR can be either hyperacute, acute, late acute or chronic based on timing of rejection and cellular and/ or AMR with reference to the phenotype. DSA has an important role rejection
AMR diagnosis:
Banff classification for AMR includes Acute AMR and Chronic AMR whereby 3 features are required for the diagnosis.
Graft survival has been shown to be inferior in patients with AMR as compared to those without rejection. Patients with chronic AMR have poor graft prognosis with approximately 80% graft loss in 1.9 years post-diagnosis.
AMR phenotypes:
Patients with subclinical AMR has worst graft survival as compared to those with subclinical T cell mediated rejection or no rejection, and hence should be treated. C4d negative AMR is also quite common, up to 55%, is due to complement-independent pathways and has 2.5 times increased risk of graft loss than those without AMR. C4d positive AMR presents earlier, has worse allograft outcomes, and has clinical features like C4d negative AMR. Complement binding DSAs are associated with increased risk of AMR and graft loss, more severe graft injury, more C4d deposition, more micro-circulatory inflammation, and worse graft survival.
Vasculitis in AMR can be seen in up to 21% patients and is associated with 9 times increased graft loss than vasculitis in T cell mediated rejection. Non-HLA antibodies like anti angiotensin type 1 receptor and anti-endothelin type A receptor antibodies also have role in AMR. Transplant glomerulopathy, presenting as double contouring on electron microscopy, usually causes proteinuria and is seen in late stage of AMR indicating irreversible damage leading to graft loss.
AMR prevention pre-transplant:
involves either including the patients in a paired transplant program or desensitization (removal of antibodies to get a negative crossmatch) in a highly sensitized patient.
Various protocols utilized include
AMR treatment:
involves
Subclinical AMR, if not treated, leads to poor graft outcomes.
The treatment modalities used in AMR include:
AMR prevention post-transplant:
Under-immunosuppression, due to non-adherence or drug minimization/withdrawal, should be avoided.
Introduction ;
AMR is complex process that result in micro-vascular inflammation, compliment activation, recruitment of macrophages/monocytes and endothelial damages[5]
Willicombe et al showed that AMR was associate with inferior allogratf survival compared to non-rejection[7]. This paper reviewed the current diagnostic criteria for AMR, AMR paradigms, de-sensitization, treatment & preventive strategies
Current diagnostic criteria ; Base on Banff 2013, all 3 required for diagnosis of AMR
2.Evidence of recent/current antibody interaction with vascular endothelium; at least one of the following
3. Presence of DSA in the serum(HLA & non-HLA)
Chronic Antibody-Mediated Rejection ; Acute AMR is the major risk factors for
Chronic active AMR. The histology overlaps, based on Banff 2013 Chronic active AMR requires 3 features ;
1.Evidence chronic tissue injury, at least one of the following
2.Evidence of antibody interaction with vascular endothelium; at least one of the fellowing
3.DSA
Phenotype of AMR ;
1.Phenotype 1 ;
2.Phenotype 2;
Paradigms in AMR ;
1.Sub-clinical AMR ;
2.C4d positive Rejection ;
3.C4d negative Rejection ;
Summary ;
3.The presence of complement-independent pathway for AMR
Solutions ; due to problems of C4d , Banff 2013 introduced gene expression markers e.g.endothelial transcript into the diagnosis of AMR to compensate for C4d[8]
Antibody-Mediated Vascular rejection ;
Non-HLA AMR ; Two main groups[23,24]
1.Allo-antibodies ; to antigen other than HLA
2.Auto-antibodies ; against self-antigen
Mechanism of injury does not involve integrins as in HLA-Abs
Examples ; angiotensin type I receptor antibodies[25-27]
Complement -binding DSA & non-complement binding DSA ;
Complement fixing DSA is associated with lower 5 year graft survival rate compared with non-complement binding DSA & those without DSA. This may due to more severe phenotype of allograft injury, more C4d deposition , & aggressive microvascular inflammation[28]
Transplant glomerulopathy ;
1.Glomerular basement membrane duplication
2.Double contouring or splitting
Prognostic index/score[35] ; based on Cr, protenuria, chronicity on Bx ;
Anti-body removal for highly sensitized patients ;
2.IVIG & Rituximab :
Combination of IVIG + Rituximab was effect desensitization protocol butv more studies are needed in this area[43]
3.IVIG + Rituximab + plasmpheresis(pp) ;
4.Immuno-adsorption for rapid cross-match conversion ;
Treatment of Antibody-Mediated Rejected ; Goals of treatments are 1. Decrease inflammation in the allograft 2. Remove factors associated with inflammation 3. Prevent antibody formation without interference with normal immune mechanisms that protect the host against infection
Chronic AMR treatment ;
Prevention of AMR ; Dijamali et al starateges[2]
Other measures ;
Conclusion ;
this is a narative review so the level is 5
Ferrari, Rossella. (2015). Writing narrative style literature reviews. Medical Writing. 24. 230-235. 10.1179/2047480615Z.000000000329.
This is a review of AMR current diagnostic criteria, paradigms and treatment.
For diagnosing acute/ Chronic active Antibody-Mediated Rejection( Banff 2013), 3 features are required. 2 features are common in both acute and chronic active AMR
1-histologic evidence of current/recent antibody interaction with vascular endothelium(at least one of linear peritubular C4d staining , moderate microvascular inflammation (g þ ptc >2) or Increased expression of tissue gene transcripts )
2- detection of DSAs.
The third feature is histologic evidence of tissue injury. In acute it is defined by one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
in the chronic active the chronic tissue injury is defined by one or more of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
Hence the diagnosis of AMR is mainly dependent on histologic findings.
The principal phenotypes of acute AMR were : Phenotype 1 ( presensitized patient in the early posttransplant period) and Phenotype 2 (de novo DSAs in the late posttransplant period related primarily to nonadherence or inadequate immunosuppression).Clinical manifestations of AMR include proteinuria and a rise in serum creatinine.
Current treatment of AMR include antibody removal with plasmapheresis , immunoadsorption , immunomodulation with intravenous immunoglobulin , and lymphocytes depleting agents. Strategies include combinations of these modalities with different success rate.
Antibody mediatedrejection
the development of antibodies plays a critical-
role.
and antibodies are considered a major cause of allograft failure.
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
CURRENT DIAGNOSTIC CRITERIA
Single-antigen bead testing, which is used to detect antiHLA antibodies, is the final step in the current techniques used to identify antibodies that can injure the allograft
Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
2. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.
According to the revised Banff 2013 classification
the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Moderate Microcirculatory Changes
the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
The Banff renal pathologists involved with the evaluation of kidney biopsies established the presence of glomerulitis and graded this finding based on the complete occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement.
Phenotypes of Antibody-Mediated Rejection
Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION Subclinical Antibody-Mediated Rejection
Protocol biopsies have identified a subgroup of patients with histologic evidence of antibody-mediated injury despite stable creatinine.
Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cellmediated rejection (88%) and no-rejection (90%) groups (P<0.001).
C4d-Positive and C4d-Negative Rejection
C4d was considered a marker for antibody injury; however, we now know that up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation.
C4d a poor marker for the diagnosis of AMR
C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
C4d-negative rejection was not different from C4d-positive rejection in any baseline characteristic. Compared to patients with C4d-negative rejection, patients with C4d-positive AMR were more likely to present earlier posttransplantation (median of 14 days vs 46 days for C4d-negative rejections
No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection
demonstrated that vasculitis belongs to both T cellmediated rejection and AMR.
Non-HLA Antibody-Mediated Rejection
into 2 primary categories:
alloantibodies directed against polymorphic antigens that differ between the recipient and donor
and antibodies that recognize self-antigens or autoantibodies.
Patients with complementbinding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graft survival (54%) compared with patients with non-complement-binding donor-specific antiHLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P2.5 g/d is associated with a worse outcome
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
High-Dose Intravenous Immunoglobulin
Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
Intravenous Immunoglobulin and Rituximab
It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen.
combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
high-dose IVIG is inferior to combination therapy.
Immunoadsorption for Rapid Crossmatch Conversion
IA is an effective strategy for rapid desensitization in deceased-donor transplantation
immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin.
Three or more plasma exchanges can be processed during a single session.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune responses that protect patients from serious infections.
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR
Currently, strategies for the treatment of non-HLA antibodies are based on the same principle used for AMR, which mainly involves extracorporeal techniques to remove antibodies, including PLEX or IA
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
Rituximab
In a pilot study of 7 AMR patients treated using PLEX and IVIG at 100 mg/kg/d for 3 days, then 3 times per week for 2-4 weeks, then rituximab 500 mg/m2 for 1 dose if AMR was ongoing at week 4
Proteasome Inhibitor
Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
bortezomib (1.3 mg/m2/dose 3 4 doses) preceded by a single rituximab dose and PLEX prior to each bortezomib dose.
Complement Inhibition
the early use of eculizumab before advanced changes in kidney injury are identified can improve responses and allograft survival.
Chronic Antibody-Mediated Rejection Treatment
series conducted by Fehr et al of 4 adult patients who received steroid pulse and rituximab (375 mg/m2) followed by IVIG (0.4 g/kg/d for 4 days) showed improved kidney allograft function.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
it is well recognized that pregnancies, blood transfusions, and previous organ transplantation are major risk factors for recipient sensitization and AMR.
The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss
However, the C1q binding assay currently is neither widely available nor validated
donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols.
Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
Patients received IVIG monthly for 4 months with additional infusions at 12 and 24 months or the equivalent volume of placebo. IVIG significantly reduced PRA levels, and more patients in the IVIG group were transplanted (35% vs 17%).
In summary, a reduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure. Education for patients and community nephrologists is advised, as well as appropriate financial evaluations prior to transplantation. Lack of financial support is a major barrier for adherence to the long-term use of immunosuppressive medications. Community physicians tend to lower the dose of CNIs and/or antiproliferative agents based on the longevity of the allograft without considering potential late rejection.
2- level 5
According to the Banff 2013 categorization, all three of the following characteristics must be present for the diagnosis of acute AMR to be established:
1. The presence of one or more histologic features of acute tissue damage on histological examination.
a) At least one histologic demonstration of current or recent antibody interaction with the vascular endothelium
3) Detection of DSAs in the blood (HLA or non-HLA).
Evidence of acute tissue damage on histologic examination: a. Glomerulitis (g > 0) or peritubular capillaritis (ptc > 0)
V > 0 indicates intimal or transmural arteritis.
In the absence of any other clear reason, acute thrombotic microangiopathy (TMA) occurs.
tubular harm that occurs suddenly with no apparent reason (d).
Recent/current antibody contact with the vascular endothelium as shown by histologic findings:
a. C4d staining in the peritubular capillaries with a linear pattern
(g ptc >2) Microvascular inflammation is present in at least moderate amounts.
c. Increased expression of gene transcripts in the tissue that are suggestive of endothelial injury
Identification of Chronic AMR; According to the updated Banff 2013 categorization, three characteristics are required for the identification of chronic, active AMR:
a histologic characteristic indicating chronic tissue damage, or the presence of at least one such feature
A histologic finding indicating an antibody interaction with the vascular endothelium is required in this case.
3) Detection of DSAs in the blood (HLA or non-HLA).
Chronic tissue damage manifests itself histologically as: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA; and b. Transplant glomerulopathy in the presence of chronic TMA.
By using electron microscopy, it was discovered that there was severe peritubular capillary basement membrane multilayering.
c. New-onset arterial intimal fibrosis with no known underlying cause.
The following are examples of histologic evidence of antibody interactions with vascular endothelium: a. Linear C4d staining in the peritubular capillaries; and b. Linear C4d staining in the peritubular capillaries.
(g ptc >2) Microvascular inflammation is present in at least moderate amounts.
c. Increased expression of gene transcripts in the tissue that are suggestive of endothelial injury.
Desensitization to HLA antibodies is achieved by the use of immunomodulating agents.
treatments aimed at lowering levels of anti-HLA antibodies in order to improve kidney function
Transplantation is an option that is viable.
Immunoglobulin administered intravenously at a high dose
An agent that has immunomodulatory properties.
IVIG’s mechanisms of action
T cell growth is one of the things that is inhibited.
Inhibition of cytokine synthesis is the term used.
Complement activation is prevented from occurring.
Alloantibodies are blocked by anti-idiotypic antibodies.
Intravenous Immunoglobulin and Rituximab Rituximab is a kind of immunoglobulin that is given intravenously.
A chimeric monoclonal antibody directed against the CD20 antigen promotes B cell lysis via the activation of the CD20 receptor.
Complement-dependent cytotoxicity and antibody-mediated cellular cytotoxicity are two types of cellular cytotoxicity.
The investigators came to the conclusion that the combination of IVIG and rituximab was effective.
as a desensitization strategy that is successful
Plasmapheresis, intravenous immunoglobulin, and Rituximab are all treatments for leukaemia.
Immunoadsorption for Crossmatch Conversion in a Short Time:
IA is a successful technique for achieving fast desensitization in deceased-donor patients.
transplantation.
The following is the treatment for ANTIBODY-MEDIATED REJECTION:
Plasmapheresis:
PLEX is a fast-acting antibody remover that is considered a typical element of immunotherapy.
Therapy is included in the majority of AMR treatment regimens that have been devised.
When it is effective
in combination with IVIG
The one-year graft survival rate in the PLEX + IVIG group was considerably greater than in the control group.
in comparison to the PLEX alone group (90.9 per cent vs 46.2 per cent, P14.044).
Immunoglobulin administered intravenously:
IVIG is anticipated to be ineffective as a monotherapy for AMR due to its low effectiveness. Allograft performance is improved.
Combination treatment with PLEX and rituximab has shown promising results in several studies.
Inhibitor of the proteasome:
Bortezomib, which is now licensed for the treatment of multiple myeloma, has been approved for the treatment of other cancers as well.
Rescue treatment for AMR is utilized in conjunction with other drugs such as PLEX, IVIG, or rituximab.
as well as some favourable outcomes
Inhibition of the Complement System:
On the effectiveness of Eculizumab, very few data are available, most of which are from single instances.
in individuals suffering from severe AMR
Treatment for Chronic Antibody-Mediated Rejection (CARM):
Chronic pain has been successfully treated using the methods listed above for many years.
AMR, despite the fact that data is scarce.
ASSISTANCE IN PREVENTING ANTIBODY-MEDIATED REJECTION
AMR prevention strategies include the following:
In the case of severely sensitive individuals, transplantation should be avoided.
Using sensitive donor-specific anti-HLA antibodies, we can better stratify immunologic risk.
-LEVEL of evidence 5
Antibody-Mediated Rejection: A Review
Introduction
Allograft injury can cause tubulitis, glomerulitis, fibrinoid necrosis and capillaritis.
Antibodies can be produce against HLA-molecules, non-HLA antigens on endothelial cells or against blood antigens
Antibodies cause damage by activating complement, recruitment of leukocytes leading to natural killer cell or macrophage mediated injury
Pathology; Endothelial injury, loss of vascular integrity and coagulation.
Hyperacute rejection: Occurs within minutes of releasing anastomotic clamps.
Acute; Days to weeks, Late acute: 3 months after transplantation.
Chronic rejection: Months to years
Diagnosis of Acute AMR
3 features required
1. Histological evidence of tissue injury defined by any of; glomerulitis, peritubular capillaritis, intimal or transmural arteritis, TMA of no other cause, tubular injury of no other cause.
2. Histological Evidence of current or recent antibody interaction with vascular endothelium e.g C4d staining of ptc,
3. Detection of DSA in serum
Chronic AMR
3 features
1. Histological evidence of chronic tissue injury any of; Transplant glomerulopathy without chronic TMA, severe capillary basement multilayering, new onset intimal fibrosis.
2. Similar to acute AMR for 2&3.
Phenotypes of Antibody-Mediated Rejection
Phenotype 1- occurs due to preformed DSA, in the early transplant period.
Phenotype 2- occurs due to de novo DSA, in the late transplant period.
Paradigms in AMR
1.Subclinical Antibody-Mediated Rejection; Identified on protocol biopsies, patients have stable creatinine with histological evidence of AMR.
2. Non-HLA AMR- could be due antibodies against polymorphic antigens differing between donor and transplant or due to autoantibodies.
3. Transplant glomerulopathy; double contour, GBM duplication or splitting.
A feature of chronic AMR, occurs with proteinuria of more than 2.5 g/day
Requires electron microscopy to diagnose
Antibody removal for highly sensitized patients
High dose Intravenous immunoglobulin (IVIG)
Works as an immunomodulatory agent
Inhibits complement activation, T cell proliferation, cytokine release.
It was found to be better than placebo with efficacy of 52%(9/17) in reducing anti-HLA antibodies in sensitized patients.
IVIG and Rituximab
Rituximab is an ati-CD20 monoclonal antibody
Causes B cell lysis and blocks B cell activation.
Does not affect already formed plasma cells which lack CD20.
Has been found to be effective in desensitization a regimen when combined with IVIG.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
This combination lead to graft survival at 36 months of 91.7% in vs 50% with IVIG alone.
Immunoadsorption for Rapid Crossmatch Conversion
Appears to be better than plasmapheresis with faster clearance immunoglobulins.
Treatment of antibody-mediated rejection
Plasmapheresis
Removes preformed antibodies.
Has been found to be beneficial in randomized controlled trials.
Intravenous Immunoglobulin
Useful in combination with other modalities.
Rituximab
Main concern is infections.
Proteosome inhibitors
Removes plasma cells that produce antibodies.
Bortezomib has been used as rescue therapy for AMR in combination with IVIG, PLEX and rituximab.
Complement Inhibition
Eculizumab a C5a inhibitor and C1-INH
Mixed results with use of Eculizumab in AMR.
Chronic Antibody-Mediated Rejection Treatment
Similar agents have used in the treatment of chronic AMR.
Data is limited due to the slow progression of chronic AMR
This is a review article.
It is not an ideal to consider it as level of evidence. It has discussed a few studies on the different treatment aspects.
I would rank it between level IV and V.
I. Antibody-Mediated Rejection: A Review
Please summarise this article
Introduction
AMR is a well recognized cause of allograft failure.
Complex interactions between cellular & molecular processes cause a range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, & fibrinoid necrosis).
Complement system is activated when antibody binds to HLA-or ABO-antigens, & non-HLA antigens expressed on the endothelium. This leads to recruitment of leukocytes & facilitation of NK cell–mediated or macrophage–mediated cytotoxicity, that leads to endothelial damage, loss of vascular integrity, & increased coagulation.
Allograft rejection classified as:
– Hyper-acute (within minutes after transplant)
– Acute (after days to weeks)
– Late acute (3 months after transplant)
– Chronic (months to years).
Pathophysiologically rejection is classified as cellular &/or AMR.
AMR occurs in 10% & graft survival is inferior to those with no rejection (Willicombe et al).
Graft survival is improving with new advances in immunology & use of new drugs.
This article reviews the current diagnostic criteria for AMR, its treatment, & prevention modalities.
Current diagnostic criteria
Although CDC is still present in many centers, SAB is now widely used to detect anti-HLA antibodies, monitor recipients & as a diagnostic tool for AMR.
LM cannot detect early changes in many biopsies & EM is therefore being increasingly used.
The Banff classification believed improved sensitivity survival.in the diagnosis & data about allograft vV&
Acute antibody-mediated rejection (banff 2013)
All of the following are required for the diagnosis:
(1). Histologic evidence of acute tissue injury defined by 1 or more of the following:
a. Glomerulitis (g >0) or PTC (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute TMA of no other cause
d. Acute tubular injury of no other cause
(2). Histologic evidence of antibody/vascular endothelium interaction, defined by one of the following:
a. Linear C4d staining in the PTCs
b. At least moderate MVI (g+ptc >2)
c. Increased tissue gene transcripts
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic antibody-mediated rejection (Banff 2013)
Diagnosis requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by at least 1 of the following:
a. TG (cg >0) in the absence of chronic TMA
b. Severe PTC BM multilayering (by EM)
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by at least 1 of the following:
a. Linear C4d staining in the PTCs
b. At least moderate MVI (g+ ptc >2)
c. Increased expression of tissue gene transcripts
3. Detection of DSAs (HLA or non-HLA) in the serum
Increased risk of allograft loss was associated with:
– Chronicity scores >8
– DSA >2,500 MFI
– S. creatinine >3 mg/Dl
– Urine PCR >1 g/g
Phenotypes of AMR (2011 Banff report):
– Phenotype 1: early posttransplant in presensitized patients.
– Phenotype 2 due to de novo DSAs: occurs late posttransplant; related to nonadherence or inadequate IS.
Subclinical antibody-mediated rejection
– Diagnosed by protocol biopsy.
– Evidence of AMR despite stable creatinine.
– No strong guidelines of therapeutic interventions due to lack of long-term follow-up.
– Poorest graft survival at 8 years compared with the subclinical TCMR & no-rejection groups
– Risk of allograft loss if left untreated (Orandi et al)
C4d-positive & C4d-negative Rejection
– C4d is split product of C4 activation
– No known biologic action
– Variable frequency depending on methods of detection, positivity threshold & prevalence of highly sensitized patients.
– Isolated C4d positivity without allograft injury has been reported.
– C4d is a poor marker for the diagnosis of AMR due to:
@ Low sensitivity (50%-60%)
@ 55% can have a C4d-ve rejection
@ Presence of complement-independent pathways
@ Poor reproducibility
– Owing to its low sensitivity, Banff 2013 included increased expression of endothelial activation & injury transcripts in the tissue biopsy.
– C4d-negative AMR are reported both in on cause & protocol biopsies.
– Orandi et al compared C4d-ve with C4d+ve in terms of the risk of allograft loss:
– Similar baseline characteristics.
– C4d+ve AMR presented earlier.
– C4d +ve AMR 3 times more common.
– Better graft survival at 1 & 2 years in C4d-ve AMR.
– C4d-ve AMR has increased risk of graft loss compared to no-AMR.
– Anti-HLA DSA class was not different between the 2 groups
Antibody-Mediated Vascular Rejection
Seen in both TCMR & AMR.
Non-HLA Antibody-Mediated Rejection
– Classified into:
– Alloantibodies (recognize polymorphic antigens that differ between the recipient & donor)
– Autoantibodies (recognize self-antigens)
– Not well defined by available tests
– Not included in the revised Banff 2013 classification.
– AT1R & ET type A receptor antibodies are implicated as markers of endothelial injury.
Role of complement-binding anti-HLA antibodies in kidney allograft failure (Loupy et al):
– Lower 5-year graft survival compared with non-complement-binding DSAs & non-DSA.
– Increased risk of allograft loss
– Increased rate of AMR
– More severe graft injury phenotype with increased microcirculatory inflammation
– C4d deposition.
Transplant Glomerulopathy
– GBM duplication, double contouring, or splitting
– A late stage of irreversible antibody-mediated injury
– Indicator of poor graft survival.
– Prevalence: 5%-20%; 55% in high-risk cohorts (T cell CDC-XM).
– Proteinuria >2.5 g/d is associated with a worse outcome.
– Strongly associated with preexisting or de novo DSAs.
– EM is the best tool for early diagnosis(Banff 2013 meeting)
– A prognostic index may guide prognosis & treatment (Patri et al).
Desensitization to HLA antibodies:
A. Immunomodulating agents- high-dose IVIG:
– Inhibit T cell proliferation
– Inhibit cytokine synthesis
– Inhibit complement activation
– Anti-idiotypic blockade of alloantibodies
– Better than placebo in highly sensitized (Jordan et al)
B. IVIG & Rituximab:
– Rituximab induces B cell lysis via CDC & antibody-mediated cellular cytotoxicity.
– Plasma cells not affected (no expression of CD20 antigen).
– Combination of IVIG & rituximab was fo
C. Plasmapheresis, IVIG, & Rituximab vs IVIG alone:
– High-dose IVIG was inferior to this combination(Lefaucheur et al).
D. IA for Rapid XM Compared to PLEX:
– More specific & effective removal of circulating Igs without S/Es of FFP or albumin.
– Rapid (few hours) & selective antibody depletion.
– Effective for rapid desensitization in deceased-donor transplantation(Bartel et al).
Studies looking into the effect of treatment in patients with DSA-associated AMR:
1. No change in DSA levels or histopathology with monthly high dose IVIG, & pulse steroids (Wiebe et al).
2. Archdeacon et al described 13 case series & controlled trials using different treatment modalities:
– AMR is less common than acute TCM
– Incidence of AMR exceeds 25% in highly
sensitized patients , & more severe
injuries leading to late allograft failure.
3. Orandi et al compared 219 patients with
AMR to matched controls:
– Subclinical AMR was associated with
increased risk of allograft loss but was
not different from clinical AMR.
– Treated subclinical AMR patients had no
difference in graft loss compared to
matched controls
4. Plasmapheresis rapidly removes preformed antibodies:
– An RCT by Bonomini et al found it to be beneficial.
– Two controlled trials by Blake et al & Allen et al found no benefit.
– Kirubakaran et al found potential harm with PLEX.
– PLEX significantly decreased DSAs to pretransplant levels in 4 of 5 patients, & improved renal function in all patients (Pascual et al)
– Slatinska et al: combination of PLEX & IVIG was superior to PLEX alone in terms of 1 year graft & patient survival.
5. Rituximab:
– Faguer et al, reported a 75% graft survival at 10-month with 50% infectious complications.
– Mulley et al found 100% graft survival at 21-month using PLEX, IVIG & rituximab.
– Kaposztas et al retrospectively studied 54 AMR patients compared with historic control: Graft survival was better treatment group.
6. Proteasome Inhibitor (e.g. Bortezomib):
Woodle & colleagues: Used as rescue therapy in combination with PLEX, IVIG, or rituximab demonstrated effective AMR reversal.
7. Complement Inhibition
– Wongsaroj et al: 7 TMA patients showed full or partial recovery vs 100% graft failure in TMA patients treated with IVIG, rituximab, & PLEX.
– Orandi et al found that eculizumab was not effective in severe oliguric early-onset AMR.
– The authors reported different rescue therapies in 24 patients with AMR including splenectomy (n=14), eculizumab (n=5), or splenectomy + eculizumab (n=5), in addition to PLEX: Splenectomy + eculizumab may be effective for rescuing & preserving allograft function in early severe AMR.
– Eculizumab, if used early, can improve responses & allograft survival (Yelken et al).
Chronic antibody-mediated rejection treatment
Slow progressive nature might not allow the use of potent & aggressive immunosuppressives.
Fehr et al, in a series of 4 patients who received steroid pulse, rituximab & IVIG, showed improved allograft function.
Redfield et al retrospectively reviewed 123 patients with biopsy-proven chronic AMR, treated with steroids/IVIG, & reported improved graft survival.
Prevention of antibody-mediated rejection
Stratification & prediction of allograft outcomes are not well charachterized.
Loupy et al differentiated DSAs by C1q binding(as a measure of the ability to fix complement).
The 5-year graft survival was least for C1q-binding DSAs (54%) compared to no-DSAs (94%) & non–C1q-binding DSAs (93%).
C1q binding assay is not widely available & not validated.
Djamali et al proposed several strategies to prevent AMR:
– Avoid transplanting highly sensitized patients
– Better immunological risk stratification.
– Use of sensitive DSA screening methods.
– PKE program
– Participation in special programs such as the Eurotransplant Acceptable Mismatch Program
– Combining PKE programs with desensitization protocols.
– Monitoring de novo DSAs, using class II HLA epitope
matching.
– Performing protocol biopsies
Conclusion
Alloimmune response is a barrier for successful long-term allograft function.
Banff classification criteria has helped standardize
the diagnosis of AMR.
Treatment of AMR with current therapies has produced a variety of results
PLEX & IVIG are the main therapies for the treatment of AMR.
RCTs are needed to find surrogate markers & improve the efficacy of therapy.
What is the level of evidence provided by this article?
Level V: A narrative review; a summary of literature in a way which is not explicitly systematic
Summary //
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
The understanding of renal allograft rejection has paralleled new discoveries in human immu- nology and the development of new drugs and biologic products. It is not uncommon for rates of acute rejection to be 0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c.Acutethromboticmicroangiopathy(TMA)ofnoother obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium, defined by at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.10 According to the revised Banff 2013 classification,8 the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplantglomerulopathy(cg>0)intheabsenceof
chronic TMA
b. Severe peritubular capillary basement membrane
multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other
known etiology
2.Histologicevidenceofantibodyinteractionwithvascular
endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes of Antibody-Mediated Rejection
Phenotype 1 occurs in the presensi- tized patient and occurs in the early posttransplant period.
Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immuno- suppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECT
Subclinical Antibody-Mediated Rejection
C4d-Positive and C4d-Negative Rejection
Antibody-Mediated Vascular Rejection
Non-HLA Antibody-Mediated Rejection
Transplant Glomerulopathy
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
Desensitization to HLA antibodies involves treatment with immunomodulating therapies de- signed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option
1-High-Dose Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies.
2-Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement- dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen.
3-Plasmapheresis, Intravenous Immunoglobulin, and Rituximab.
5-Immunoadsorption for Rapid Crossmatch Conversion
TREATMENT OF ANTIBODY-mediated rejection:
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and Rituximab
Rituximab
Proteasome Inhibitor
Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combina- tion with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
Complement Inhibition
The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.
Chronic Antibody-Mediated Rejection Treatment
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited.
Level of evidence 5 / narrative study
Dear THOSE WHO THINK IT IS LEVEL I/II EVIDENCE
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
Rejection involves different cellular and molecular pathways causing allograft injury which may e hyperacute, acute, late acute or chronic and classified into cellular and/or AMR.
Current diagnostic criteria:
According to Banff 2013 classification
Acute antibody mediated rejection:
3 features are required:
Histologic evidence of acute tissue injury.
Histologic evidence of current/recent antibody interaction with vascular endothelium Detection of DSAs (HLA or non-HLA) in serum.
Chronic antibody mediated rejection:
3 features are required:
Histologic evidence of chronic tissue injury.
Histologic evidence of antibody interaction with vascular endothelium
Detection of DSAs (HLA or non-HLA) in serum
Chronic AMR is associated with poor graft survival.
Moderate microcirculatory changes:
They are considered highly suspicious for antibody injury.
Vasculitis and high rate of inflammatory cells in microcirculation were associated with poor outcome.
Presence of glomerulitis is determined by occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement
Phenotypes of AMR:
Phenotype 1: occur in pre-sensitized patient and early post transplant.
Phenotype 2: occur due to emergence of de novo DSA in late post transplant period and is related to non-adherence or inadequate immunosuppression.
Paradigms in AMR:
Subclinical AMR:
Presence of histologic evidence of AMR in protocol biopsy with stable graft function
No guidelines available for treatment, A study showed that untreated subclinical rejection increases the risk of graft loss.
C4d positive and C4d negative rejection:
They are similar in baseline characteristics and can’t be differentiated clinically
Now, C4d is not considered mandatory for diagnosing AMR due to presence of independent complement pathway and its low sensitivity.
C4d positive group have poorer graft outcome.
Antibody mediated vascular rejection:
It is associated with higher risk of graft loss than TCMR without vasculitis.
Non-HLA antibody mediated rejection:
Non-HLA antibodies are either alloantibodies against polymorphic antigens different between donor and recipient or antibodies recognizing self antigens (autoantibodies).
they are associated with high risk of graft loss, increased rate of AMR and more severe graft injury.
Transplant glomerulopathy:
Manifest as basement membrane duplication, double contouring or splitting, electron microscopy provides best tool for diagnosis.
Considered irreversible, indicates poor graft survival.
Frequently causes proteinuria and is associated with chronic AMR.
Antibody removal for highly sensitized patients:
Desensitization involves treatment with immunomodulating therapy to decrease level of anti-HLA antibodies to allow transplantation.
High dose IVIG
IVIG and rituximab
Plasmapheresis, IVIG and rituximab
Immunoadsorption for rapid crossmatch conversion:
It provides more specific and effective clearance of circulating immunoglobulins without side effects of plasmapheresis
Effective strategy for rapid desensitization in deceased donor transplant
Treatment of AMR:
Treatment of subclinical rejection and its benefits are still under investigation, also the effect of treatment on DSA associated AMR is understudied.
Plasmapheresis:
Considered standard part of therapy in most protocols, It rapidly removes preformed antibodies.
IVIG
Rituximab:
A study showed that patients with AMR treated with plasmapheresis, IVIG then rituximab had 100% graft survival at 21-months follow up.
Proteasome inhibitor
Complement inhibition
Eculizumab and C1 esterase inhibitor are approved for complement inhibition but limited data are available on efficacy in severe AMR
Treatment of chronic AMR:
Potent immunosuppression agents may be not feasible due to its slow progression compared to acute AMR.
Treatment with steroids and IVIG was associated with improved graft survival.
Further studies are needed to improve graft survival in chronic AMR.
Prevention of AMR:
Avoiding transplantation of highly sensitized patients or enrolling them in special programs, using sensitive DSA screening for better risk stratification, kidney paired donation and desensitization protocols
Monitoring de novo DSA and performing protocol biopsy for early detection and treatment of AMR to improve graft survival.
Avoiding reduction of immunosuppression (intended or due to non adherence)
Ensuring presence of financial support prior to transplantation.
Level of evidence: 5
Excellent Heba
Its systematic review, level 1
Summary:
Antibody-Mediated Rejection:
Definitions & histological changes:
Allograft rejection can be classified according to onset to hyperacute, acute, late acute or chronic. Also, Rejection can be classified according to the pathophysiologic event: cellular and/or AMR.
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR
.
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. At least moderate microvascular inflammation (g þ ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-HLA) in the serum.
Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g were associated with an increased risk of allograft loss.
Moderate Microcirculatory Changes are highly suspicious for antibody injury and have been associated with poor outcomes.
Phenotypes of Antibody-Mediated Rejection In the 2011 Banff report, 2 principal phenotypes of acute AMR were defined. Phenotype 1 occurs in the pre-sensitized patient and occurs in the early post-transplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late post-transplant period and is thought to be related primarily to non-adherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
· Subclinical AMR: Patients with Subclinical AMR had the poorest graft survival at 8 years post-transplant compared with the subclinical T cell– mediated rejection and no-rejection groups.
· C4d-Positive and C4d-Negative Rejection: C4d was considered a marker for antibody injury; however, up to 55% of patients can have a C4d-negative rejection with obvious evidence of microcirculatory inflammation. No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group, also patients with C4d-positive AMR were more likely to present earlier post-transplantation.
· Antibody-Mediated Vascular Rejection: The risk of graft loss was higher in antibody-mediated vascular rejection than in T cell–mediated rejection without Vasculitis.
· Non-HLA Antibody-Mediated Rejection: Angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies. Patients with complement binding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graft survival compared with patients with non-complement-binding donor-specific anti HLA antibodies. These antibodies were associated with an increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
Transplant Glomerulopathy
Transplant glomerulopathy causes progressive allograft failure with a poor prognosis and eventual allograft loss in 40%-70% of patients and is considered a histologic feature associated with chronic AMR that result from recurrent events of endothelial activation injury and repair.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
· High-Dose Intravenous Immunoglobulin used as immunomodulatory agent.
· Intravenous Immunoglobulin and Rituximab
· Plasmapheresis, Intravenous Immunoglobulin, and Rituximab : Combination therapy is superior to a high-dose IVIG alone.
· Immunoadsorption for Rapid Crossmatch Conversion IA was shown in one study as an effective strategy for rapid desensitization in deceased-donor transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
The treatment of subclinical AMR and its potential benefits are still under investigation. Treated subclinical AMR patients had no difference in graft loss compared to matched controls, but untreated subclinical AMR patients had a 3.34-fold higher risk of graft loss compared to matched controls.
Treatment of antibody-mediated rejection includes:
· Plasmapheresis PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. However, the results of the different analyses are conflicting results.
· Intravenous Immunoglobulin The efficacy of IVIG as monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
· Currently, strategies for the treatment of non-HLA antibodies are based on the same principle used for AMR.
· Proteasome Inhibitor as Bortezomib, demonstrate effective AMR reversal, including substantial reductions in DSA levels.
· Eculizumab (an anti-C5 monoclonal antibody)
For Chronic Antibody-Mediated Rejection the previously mentioned therapies have been used for the treatment of chronic AMR although data are limited.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
Several strategies are proposed to prevent AMR, including:
· Avoiding transplantation for highly sensitized patients,
· Better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening,
· Enrolling highly sensitized patients in a paired kidney exchange program,
· Monitoring de novo DSAs,
· Performing protocol biopsies.
· Patient’s education regarding adherence to medications.
· Appropriate financial evaluations and support prior to transplantation.
· Education to Community physicians who tend to lower the dose of CNIs and/or anti-proliferative agents based on the longevity of the allograft without considering potential late rejection.
Not impressed Shereen
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
NTRODUCTION:
AMR or humoral rejection—after renal transplantation was a devastating event that
inevitably led to allograft loss. In recent years, an increased recognition of
molecular and histologic changes has provided a better understanding of this
process as well as potential therapeutic interventions. In the continuum of allograft
rejection, the development of antibodies plays a critical role, and antibodies are
considered a major cause of allograft failure.
Allograft rejection is a complex process that involves the interplay of different
cellular and molecular pathways that cause a broad range of allograft injuries:
Allograft rejection can be:
Hperacute (occurring within minutes after the vascular anastomosis).
Acute (occurring days to weeks after transplantation).
Late acute (occurring 3 months after transplantation).
Chronic (occurring months to years after transplantation).
Rejection can also be classified according to the pathophysiologic event:
Cellular and/or AMR.
CURRENT DIAGNOSTIC CRITERIA:
Single-antigen bead testing.
CDC.
EM.
Acute Antibody-Mediated Rejection:
According to the Banff 2013 classification:
All of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more
of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (PTC >0)
b. Intimal or transmural arteritis (v >0).
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause.
2. Histologic evidence of current/recent antibody interaction with vascular
endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries .
b. At least moderate microvascular inflammation (g þ PTC >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury.
3. Detection of DSAs (HLA or non-HLA) in the serum.
CAMR:
According to the revised Banff 2013 classification, the diagnosis of chronic, active
AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least
one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA .
b. Severe peritubular capillary basement membrane Multilayering identified by
electron microscopy.
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by
the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries .
B. At least moderate microvascular inflammation (g þ PTC >2)
c. Increased expression of tissue gene transcripts indicative of endothelial
injury.
3. Detection of DSAs (HLA or non-HLA) in the serum.
Phenotypes of Antibody-Mediated Rejection:
Recognized In Banff 2013:
Phenotype 1: occurs in the presensitized patient and occurs in the early post
transplant period.
Phenotype 2 develops from the emergence of de novo DSAs in the late post
transplant period and is thought to be related primarily to nonadherence or
inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION;
Subclinical Antibody-Mediated Rejection:
Patients with histologic evidence of antibody-mediated injury despite stable
creatinine. Patients with subclinical AMR had the poorest graft survival at 8 years
post transplant (56%) compared with the subclinical T cell– mediated rejection
(88%) and no-rejection (90%) groups.
C4d-Positive and C4d-Negative Rejection;
C4d was considered a marker for antibody injury; however, we now know that up to
55% of patients can have a C4d-negative rejection with obvious evidence of
microcirculatory inflammation.18 At least 3 well-designed studies have
demonstrated a sensitivity of only 50%- 60%.
C4d a poor marker for the diagnosis of AMR.
Compared to patients with C4d-negative rejection, patients with C4d-positive AMR
were more likely to present earlier post transplantation.
C4d-negative AMR was associated with a 2.56-fold increased risk of allograft loss
compared with AMR-free matched controls.
No clinical characteristic could distinguish C4d-negative from C4d-positive
rejection, and the allograft outcome was worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection:
Vasculitis belongs to both T cell– mediated rejection and AMR.
Transplant Glomerulopathy:
It is a manifested as glomerular basement membrane duplication, double
contouring, or splitting and is considered to be a late stage of antibody-mediated
injury that is usually irreversible and an indicator of poor graft survival.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS:
Desensitization to HLA antibodies involves treatment with immunomodulating
therapies designed to reduce levels of anti-HLA antibodies to make kidney
transplantation a feasible option.
High-Dose Intravenous Immunoglobulin
Immunomodulatory agent.
Mechanisms of IVIG.
Including the inhibition of T cell proliferation.
The inhibition of cytokine synthesis
.
Inhibition of complement activation.
Antiidiotypic blockade of alloantibodies.
Intravenous Immunoglobulin and Rituximab Rituximab:
A chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via
complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity.
The researchers concluded that the combination of IVIG and rituximab was
effective as a desensitization regimen.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab:
Immunoadsorption for Rapid Crossmatch Conversion:
IA is an effective strategy for rapid desensitization in deceased-donor
transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION:
Plasmapheresis:
PLEX rapidly removes preformed antibodies and is considered a standard part of
therapy in most protocols developed for the treatment of AMR.Effective when
combined with IVIG.
One-year graft survival was significantly higher in the PLEX plus IVIG group than in
the PLEX-alone group (90.9% vs 46.2%, P¼0.044).
Intravenous Immunoglobulin:
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft
outcomes have been reported in combination therapy with PLEX and rituximab.
Proteasome Inhibitor:
Bortezomib, currently approved for the treatment of multiple myeloma, has been
used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR
with some encouraging results.
Complement Inhibition:
Only limited data, usually single cases, are available on the efficacy of Eculizumab
in patients with severe AMR.
Chronic Antibody-Mediated Rejection Treatment:
The previously mentioned therapies have been used for the treatment of chronic
AMR although data are limited.
PREVENTION OF ANTIBODY-MEDIATED REJECTION:
Strategies to prevent AMR:
Avoiding transplantation for highly sensitized patients.
Better stratifying immunologic risk by using sensitive donor-specific anti-HLA
antibody screening.
Enrolling highly sensitized patients in a paired kidney exchange program.
Participating in special programs such as the Eurotransplant Acceptable Mismatch
Program.
Combining kidney paired exchange programs with desensitization protocols.
Monitoring de novo DSAs, using class II HLA epitope matching.
Performing protocol biopsies are also strategies used to reduce or early diagnose
AMR and improve allograft survival.
Level of evidence v.
Excellent
Diagnosis of acute AMR;
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. The presence of one or more Histologic feature of acute tissue injury .
2. At least one Histologic evidence of current/recent antibody interaction with vascular endothelium.
3. Detection of DSAs (HLA or non-HLA) in the serum.
Histologic evidence of acute tissue injury :
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other
obvious cause
d. Acute tubular injury of no other obvious cause
Histologic evidence of current/recent antibody interaction with vascular endothelium:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury.
Diagnosis of Chronic AMR;
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. the presence of at least one Histologic feature of chronic tissue injury.
2. the presence of at least one Histologic evidence of antibody interaction with vascular endothelium .
3. Detection of DSAs (HLA or non-HLA) in the serum.
Histologic features of chronic tissue injury are;
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multi layering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology.
Histologic evidence of antibody interactions with vascular endothelium are;
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury.
Phenotypes of Antibody-Mediated Rejection;
1-Phenotype 1 occurs in the pre sensitized patient and occurs in the early post transplant period.
2-Phenotype 2 develops from the emergence of de novo DSAs in the late post transplant period and is thought to be related primarily to non adherence or inadequate immunosuppression.
Types of AMR;
1-Subclinical Antibody-Mediated Rejection
2-C4d-Positive and C4d-Negative Rejection
3-Antibody-Mediated Vascular Rejection
4-Non-HLA Antibody-Mediated Rejection
5- Transplant Glomerulopathy;
PREVENTION OF ANTIBODY-MEDIATED REJECTION
1- better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening.
2-The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss.
3- enrolling highly sensitized patients in a paired kidney exchange program .
4- combining kidney paired exchange programs with desensitization protocols.
5-Monitoring de novo DSAs, using class II HLA epitope matching .
6- performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
Antibodies removal for highly sensitized patients
The following protocols are used in desensitization;
1- High-Dose Intravenous Immunoglobulin .
2- Intravenous Immunoglobulin and Rituximab .
3-Plasmapheresis, Intravenous Immunoglobulin, and Rituximab .
4-Immunoadsorption for Rapid Crossmatch Conversion .
Treatment of AMR ;
The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune responses that protect patients from serious infections.
Treatment of subclinical AMR;
Treated subclinical AMR patients had no difference in graft loss compared to matched controls , but untreated subclinical AMR patients had a higher risk of graft loss compared to matched controls.
Treatment Chronic AMR;
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited. Because of the slow progression of chronic AMR compared to acute AMR, subjecting patients to rigorous and potent immunosuppressive agents might not be feasible.
Medication used in the desensitization and treatment of AMR ;
1- Intravenous Immunoglobulin;
Intravenous immunoglobulin (IVIG) is considered an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the antiidiotypic blockade of alloantibodies. The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
2- Rituximab ;
A chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complementdependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20. The combination of IVIG and rituximab was effective as a desensitization regimen .
3-Bortezomib;
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor (PI) as therapy for AMR. Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging results.
4-Complement Inhibition;
Eculizumab was approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.Only limited data, usually single cases, are available on the efficacy of eculizumab in patients with severe AMR.Wongsaroj et al reported on the efficacy and safety of eculizumab in treating patients with severe AMR episodes unresponsive to standard treatment with IVIG plus rituximab with or without PLEX. Splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR. The early use of eculizumab before advanced changes in kidney injury are identified can improve responses and allograft survival.
5- Plasmapheresis;
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. Currently, strategies for the treatment of non-HLA antibodies are based on the same principle used for AMR, which mainly involves extracorporeal techniques to remove antibodies, including PLEX or IA.
6-Immunoadsorption for Rapid Crossmatch Conversion;
Compared to PLEX, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. IA is an effective strategy for rapid desensitization in deceased-donor transplantation.
What is the level of evidence provided by this article?
The level of evidence is 5( a narrative review).
.
.
Antibody-Mediated Rejection: A Review
Graft rejection can be either hyperacute, acute, late acute or chronic on the basis of timing of rejection and cellular and/or antibody mediated rejection (AMR) with reference to the phenotype. Donor specific antibodies (DSA) have an important role in AMR.
AMR diagnosis:
AMR diagnosis has evolved over years. Currently, kidney biopsy (with histopathological examination and C4d staining) and single antigen bead testing, to detect DSA are the two important components essential for diagnosing AMR.
Banff classification for AMR includes Acute AMR and Chronic AMR whereby 3 features are required for the diagnosis. Detection of DSA (HLA or non-HLA) in the serum with histological evidence of antibody interaction with the vascular endothelium (linear C4d staining in peritubular capillaries, at least moderate microvascular inflammation or increased expression of tissue gene transcripts pointing towards endothelial injury) are common features in acute and chronic AMR. In acute AMR, histological evidence of acute tissue injury must be there in form of either glomerulitis or peritubular capillaritis, intimal or transmural arteritis, acute thrombotic microangiopathy (TMA) or acute tubular injury of no other cause. In chronic AMR, evidence of chronic tissue injury like transplant glomerulopathy, severe peritubular capillary basement membrane multilayering on electron microscopy or new-onset arterial intima fibrosis is seen.
Graft survival has been shown to be inferior in patients with AMR as compared to those without rejection. Patients with chronic AMR have poor graft prognosis with approximately 80% graft loss in 1.9 years post-diagnosis.
AMR phenotypes:
There are two phenotypes of AMR: phenotype 1, occurring early due to pre-formed DSAs and phenotype 2, presenting late, due to de novo DSAs formed usually due to non-adherence or under-immunosuppression.
Patients with subclinical AMR has worst graft survival as compared to those with subclinical T cell mediated rejection or no rejection, and hence should be treated. C4d negative AMR is also quite common, upto 55%, is due to complement-independent pathways and has 2.5 times increased risk of graft loss than those without AMR. C4d positive AMR presents earlier, has worse allograft outcomes and has clinical features similar to C4d negative AMR. Complement binding DSAs are associated with increased risk of AMR and graft loss, more severe graft injury, more C4d deposition, more micro-circulatory inflammation and worse graft survival.
Vascultis in AMR can be seen in upto 21% patients and is associated with 9 times increased graft loss than vascultis in T cell mediated rejection. Non-HLA antibodies like anti angiotensin type 1 receptor and anti endothelin type A receptor antibodies also have role in AMR. Transplant glomerulopathy, presenting as double-contouring on electron microscopy, usually causes proteinuria and is seen in late stage of AMR indicating irreversible damage leading to graft loss.
AMR prevention pre-transplant:
AMR prevention involves either including the patients in a paired transplant program or desensitization (removal of antibodies to get a negative crossmatch) in a highly sensitized patient. Various protocols utilized include
1) High dose intravenous immunoglobulin (IVIG), by antiidiotypic blockade of alloantibodies and by inhibiting T cell proliferation, cytokine synthesis and complement activation, helps in reducing anti-HLA antibody levels thereby increasing chances of transplantation.
2) IVIG and rituximab has also been shown to improve chances of transplantation in highly sensitized patients.
3) Plasmapheresis, IVIG and rituximab combination has been shown to be superior to IVIG alone.
4) Immunoadsorption, with its fast and selective removal of antibodies, helps in rapid desensitization and early transplant.
AMR treatment:
AMR treatment involves reducing inflammation in the graft, removing factors causing inflammation and prevention of further antibody formation. Subclinical AMR, if not treated, leads to poor graft outcomes. The treatment modalities used in AMR include:
1) Plasmapheresis: removes antibodies rapidly, but studies have shown mixed results with plasmapheresis alone. Plasmapheresis with IVIG is superior to plasmapheresis alone.
2) IVIG: monotherapy not useful, better results when used in association with plasmapheresis and rituximab.
3) Rituximab:
4) Proteasome inhibitor bortezomib: Useful if used in conjunction with plasmapheresis, IVIG and rituximab.
5) Complement inhibitor Eculizumab and C1 esterase inhibitor: Splenectomy with Eculizumab have been shown to be helpful in early severe, refractory AMR.
AMR prevention post-transplant:
It involves protocol biopsies and post-transplant DSA monitoring for early detection and treatment. Under-immunosuppression, due to non-adherence or drug minimization/withdrawal, should be avoided.
Level 5: Narrative review
Excellent
Antibody-Mediated rejection: A Review
Level Narrative review
antibody-mediated rejection was a destructive event that cause allograft loss. recently with the evolving knowledge in molecular and histologic changes accompanying this event, therapeutic interventions as well, evolving. antibodies are the major cause of allograft failure. These (DSAs) are produced by B-cells and plasma cells, interact with (HLA) or blood antigens that include non-HLA antigens expressed on the endothelium, leading to activation of the complement system, leading to cell-mediated cytotoxicity that result in endothelial damage and increase coagulation. The allograft injuries include; acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis.
Rejection classification by time:
1- Hyperacute rejection occurring within minutes after vascular anastomosis nowadays it becomes very rare
2- Acute rejection occurs days to weeks after transplantation
3- Late acute occurring 3 months after transplantation
4- Chronic occurring months to years after transplantation
Rejection classification by pathophysiologic event:
1- Cellular
2- AMR
3- Mixed
With the recognition of the role of DSAs, new techniques to detect them, the use of desensitization protocols, and the induction of new drugs, significant progress has been made in an improvement of graft survival.
This article gives describes the classification of AMR and gives the spotlight on the available treatment options
The phenotypes of AMR are:
a- Phenotype 1: due to pre-sensitized recipient, occurs in the early post-transplant period.
b- Phenotype 2: due to emerging de novo DSAs and occurs in the late post-transplant period likely due to non-adherence or low immunosuppression.
CURRENT DIAGNOSTIC CRITERIA
Identification of DSAs is the cornerstone step in the prevention of AMR
§ Complement dependent cytotoxicity is still considered the gold standard method for the detection of preformed antibodies.
§ Single-antigen bead test now used to monitor transplant recipients and used as a diagnosed tool for AMR.
§ Electron microscopy is routinely used to examine allograft biopsy to detect early changes.
For diagnosis of allograft pathology; Banff classification has been used, which depend on histologic, immunohistochemical, and serologic factors to increase the sensitivity of the diagnosis and provide outcome data in term of allograft survival.
Despite the major advances in molecular biology and gene rearrangement, the diagnosis of AMR is still dependent on histologic findings (Glomerulitis, intimal arteritis, interstitial fibrosis).
A- Acute AMR: its diagnosis according to Banff 2013 needs the presence of all of the following features:
§ Histologic evidence of acute tissue injury is defined by the presence of one or more of the following:
a- Glomerulitis (g>0) or peritubular capillaritis (ptc> 0)
b- Intimal or transmural arteritis (v>0)
c- C- Acute thrombotic microangiopathy (TMA) of no other obvious cause
d- Acute tubular injury of no other obvious cause
§ Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of
the following:
a- Linear C4d staining in the peritubular capillaries
b- At least moderate microvascular inflammation (g + ptc>2)
c- An increased expression of tissue gene transcripts indicative of endothelial injury (What does mean??//)
§ Detection of DSAs (HA or non-HLA).
B- Chronic AMR: The diagnosis of chronic active AMR requires 3 features: According to revised Banff 2013 to which vascular changes had been added (vasculitis)
1- Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a- Transplant glomerulopathy (cg>0) in the absence of chronic TMA
b- Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c- New-onset arterial intimal fibrosis with no other known aetiology
2- Histological evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a- Linear C4d staining in the peritubular capillaries
b- At least moderate microvascular inflammation (g + ptc >2)
c- An increased expression of tissue gene transcripts indicative of endothelial injury
3- Detection of DSAs (HLA or nono-HLA) in the serum
The histology of acute and chronic AMR overlaps significantly, and acute AMR is a major risk factor for chronic AMR
The g score was determined based on the per cent of involved glomeruli (occlusion of at least one glomerular capillary by infiltrated leucocytes or endothelial cell enlargement)
g 1 ——1% – 25% of the glomeruli are involved
g 2 —–26% – 50%
g 3 > 50%
Types of AMR:
A- Subclinical AMR:
Protocol biopsy has identified histological evidence of AMR in spite of normal serum creatinine in the subgroup of patients, which carry a high risk of graft loss if left untreated
B- C4d-Positive and C4d-Negative Rejection
§ C4d is a split product of C4 activation. C4d has no known biological action. It is a marker of antibody injury. The frequency of its positivity varies between centres due to differences in the method used to detect it, the prevalence of highly sensitized patients, and the threshold for C4d positivity (low sensitive marker)
§ It is a poor marker for diagnosis of AMR, because its absence does not exclude AMR. up to 55% of patients can have C4d negative rejection.
§ Positive C4d without evidence of allograft injury has been reported. C4d positive AMR presents earlier and has poorer graft outcome as compared to C4d negative one, although both have the same baseline characteristics.
Therefore, Banff classification 13 has incorporated increased expression of injury transcripts or other gene expression markers of endothelial injury on biopsy.
C- Antibody-mediated vascular injury
§ Vasculitis belongs to both T cell-mediated rejection and AMR.
§ The risk of graft loss is higher in antibody-mediated vascular rejection than in T-cell mediated rejection without vasculitis
D- Non-HLA Antibody-Mediated Rejection: it is of two primary types
1- Alloantibodies directed against polymorphic antigens that differ between the recipient and donor
2- Antibodies that recognize self-antigens or autoantibodies
§ Examples of non-HLA antigens are angiotensin type 1 receptor and endothelin type A receptor antibodies.
§ These antibodies currently are not well characterized by the available assays.
§ Complement binding antibodies are more dangerous than non-complement binding.
E- Transplant Glomerulopathy
§ Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting. Electron microscopy should be incorporated into the definition of chronic glomerulopathy according to Banff 2013
§ considered to be a late stage of antibody-mediated injury that is usually irreversible
§ it is of poor graft survival, ultimately lead to graft loss
§ frequent cause of proteinuria.
§ strongly associated with preexisting or de
novo DSAs.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
1- High-Dose Intravenous Immunoglobulin
Mechanism of action includes inhibition of T cell proliferation, inhibition of cytokine synthesis, inhibition of complement activation, and anti-idiotypic blockade of alloantibodies.
IVIG was better than placebo in reducing anti-HLA antibody levels and improving the transplantation rate in highly sensitized patients.
2- Intravenous Immunoglobulin and Rituximab
It induces B cell lysis via complement-dependent cytotoxicity and antibody-mediated cellular cytotoxicity. Also, block B cell activation and maturation to plasma cells that produce antibodies. But it has no effect on pre-existing plasma cells (these cells do not express CD 20)
3- Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
This combination is better than IVIG alone
4- Immunoadsorption for Rapid Crossmatch Conversion
IA allows more specific and effective clearance of the DSAs compared to PLEX
It gives rapid desensitization in deceased-donor transplantation
TREATMENT OF ANTIBODY-MEDIATED REJECTION
1- Plasmapheresis
It removes preformed antibodies and is considered part of any protocol for the treatment of AMR.
2- Intravenous Immunoglobulin
Monotherapy with IVIG is of limited efficacy in AMR therapy. Combination therapy with PLEX and rituximab carry better graft outcome
3- Rituximab
A combination of PLEX and IVIG carries a better outcome
4- Proteasome Inhibitor (PI) ,, Bortezomib,,
Acts by removing plasma cells (the cells producing antibodies)
Treatment protocols that include Bortezomib provide effective AMR reversal, including substantial reductions in DSA levels.
5- Complement Inhibition
v Eculizumab (an anti-C5 monoclonal antibody) FDA approved treatment for PNH and Atypical HUS
v C1 esterase inhibitor (C1-INH) approved for hereditary angioedema
There is limited data about its use. Some reports early use of eculizumab before progressive changes in kidney injury are identified can improve responses and allograft survival.
Chronic Antibody-Mediated Rejection Treatment
Limited data about its treatment
PREVENTION OF ANTIBODY-MEDIATED REJECTION
Possible strategies are:
· avoiding transplantation for highly sensitized patients,
· better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening,
· enrolling highly sensitized patients in a paired kidney exchange program,
· participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols.
· Monitoring de novo DSAs, using class II HLA epitope.
· performing protocol biopsies
· appropriate immunosuppression dose and avoid unnecessary reduction
· education of the patient with emphasis about drug adherence
What is the level of evidence
The level of evidence is 4 (like a narrative review)
In this article, the author reviewed the AMR in detail
summary:
contrary to past, now we have understood more about molecular basis of AMR. this resulted in less frequent rejection or graft loss compared to the era before this understanding wich also was poor in respect to late novel immune suppressions like Tacrolimus. recognition of cd4 despoistion which is degradation of complement pathway as endothelial injury marker helped in early detection of AMR before even elevation of creatinine level. Rejection is a complexinreplay of multiple pathways. rejection can be hyper acute, acute, late accute or chronic. while chronic occursa months to years post transplantation, late acute is usually seen 3 months after transplantation. even if treated, AMR cases have low survival rates compared ton no rejection cases (wellcomb etal).
current diagnostic criteria:
SAB is now used as diagnostic tool for AMR. CDC is still a gold standard fo preformed DSA’s. electron microscopy is preferrable to light microscopy (not all centres have).
since BANFF2003 criteria the acute cellular rejection was differentiated from AMR. Histologic features still the backbone of diagnosis
Acute AMR/Chronic AMR:
both should have histologic evidence of defines by linear staining of cd4 in pericapillar tubules , at least moderate microvascular inlamamtion (g+>2) in addition to detection of DSAs (either HLA on non-HLA). The main difference is that we have histologic acute tissue injury (golemrulitis, inteimal or transmural arterits and unexplained TMA) in acute AMR while in chronic AMR we have transplant glomerulopathy with chronic TMA, newonset arterial intima fibrosis and severe severe multilayering of peritubular capillary basement membranes defined by electron microscopy)
Phenotypes of AMR:
two phenotypes where defined in BANFF 2011: type one is seen in presensitized patients while phenotype 2 occurs in case of de novo DSA.
…
protocol biopsies defines AMR cases even with stable creatinine level
although cd4 positivity was defined in 1993 as marker of ABM rejection, up to %55 may have negative cd4.
although endarteritis was considered as feature of cellular ejection, it was found with AMR.
NON-HLA AMR:
complement fixing antibodies cause more graft loss compared to non-fixing. non-HLA antibodies alike angiotensin type 1 receptor and endothelin type A may have potential endothelial injury as shown in case reports.
Transplant Glomerulopathy:
TG a late stage of AMR is defined as doubling of glomerular basement membrane. is considered late stage may present with proteinurea and have worse prognosis leading to earlier graft loss
Antibody removal for highly sensetized patients:
High dose IVIG
IVIG isan immune modulator that is thought te have role in T cell iprofileration and cytokine nhibition as well.
IVIG and Rituximab:
was found helpful but still we need confirmation trials
plasmapheresis, IVIG and Rituximab:
was found better than IVIG alone
Immunoadsorption for rapid crossmach conversion:
Immunoadsorption has the advantage of removal of antibodies without need for plasma or albumin load. and maybe more effective in terms of circulating antibody removal
AMR treatment:
plasmapheresis helps in removal of preformed antibodies
IVIG is better when combined with PLEX and Rituximab
Bortezomib (proteasome inhibitor) was shown to be helpfull
Thanks Mahmud
It is level 5. This is better than your colleagues who said level 1
level of evidence is 5 as it is a Review
the summary of the article
Introduction
In the past AMR was a catastrophic event in kidney post-transplant which eventually leads to graft loss. However, the recent years after advancement of the diagnostic and therapeutic tools, AMR becomes a possible treatable condition but still has its negative impact on the graft survival so the prevention of it still has the priority in kidney transplant era.
The first description of acute AMR identified neutrophils in peritubular capillaries and de novo donor-specific antibodies (DSAs). Almost concomitantly, C4d, a degradation product
of the complement pathway that binds covalently to the endothelium, was identified as marker of endothelial injury and hence of antibody activity. the correlation between DSAs and diffuse C4d deposition (>50%) as diagnostic markers for AMR. A recent research has indicated that B cells and plasma cells produce DSAs that interact with the endothelium, which activates the
cellular pathways responsible for the development of microcirculatory changes and tissue injury.
Current Diagnostic Criteria
– Complement-dependent cytotoxicity is still considered the gold standard for the
detection of preformed antibodies
– Electron microscopy is routinely used for the biopsies of transplant recipients because early changes cannot always be detected with light microscopy.
– The Banff classification for allograft pathology
– Single-antigen bead testing, which is used to detect anti-HLA antibodies, is the final step in the current techniques used to identify antibodies that can injure the allograft
Acute Antibody-Mediated Rejection
According to the Banff 2013 classification,8 all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g> 2, ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
The histology of acute and chronic AMR overlaps significantly, and acute AMR has been shown to be a major risk factor for the development of chronic AMR.10 According to the revised Banff 2013 classification,8 the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular
endothelium, defined by the presence of at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes of Antibody-Mediated Rejection
– Phenotype 1 occurs in the pre-sensitized patient and occurs in the early posttransplant period.
– Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression
Can AMR diagnosed although C4d deposition is negative?
Yes
Up to 55% of patients can have a C4d-negative rejection with obvious evidence of
microcirculatory inflammation.
Why? Because, in addition to complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility make C4d a poor marker for the diagnosis of AMR.
Antibody-Mediated Vascular Rejection
Traditionally, endarteritis has been associated with cellular rejection; however, a population-based study demonstrated that vasculitis belongs to both T cell– mediated rejection and AMR.
Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are:
– alloantibodies directed against polymorphic antigens that differ between the recipient and donor
– autoantibodies antibodies that recognize self-antigens
Although they are not well characterized by current available tests or included in the revised Banff 2013 classification, angiotensin type I receptor and endothelin type A receptor antibodies
have been implicated as markers of potential endothelial injury in case reports and clinical studies. New specific assays to identify these antibodies would facilitate the understanding and diagnosis of allograft dysfunction and would likely identify molecular pathways for effective
treatment.
Transplant Glomerulopathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
It is considered a histologic feature associated with chronic AMR that results from recurrent events of endothelial activation injury and repair.
Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome.
It is strongly associated with preexisting or de novo DSAs
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
A) High-Dose Intravenous Immunoglobulin
It is an immunomodulatory agent. Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the anti-idiotypic blockade of alloantibodies.
B) Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen.
The researchers concluded that the combination of IVIG and rituximab was effective as a desensitization regimen, but they acknowledged the need for larger trials to evaluate the efficacy of this intervention.
C) Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
This combination has more potent effect
D) Immunoadsorption (IA) for Rapid Crossmatch Conversion
Compared to plasmapheresis, immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin. this technique may provide rapid and selective antibody depletion in a few hours.
Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by
posttransplant IA. IA is an effective strategy for rapid desensitization in deceased-donor transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
Protocol biopsies and DSA monitoring at predetermined intervals are gaining wide acceptance, primarily at centers that perform HLA- and ABO-incompatible transplants. The treatment of subclinical AMR and its potential benefits are still under investigation.
1- Plasmapheresis (PLEX)
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. The combination of PLEX and IVIG was superior to PLEX alone.
2- Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab
3- Rituximab
4- Proteasome Inhibitor
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor (PI) as therapy for AMR. Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for
AMR with some encouraging results
5- Complement Inhibition
The FDA has approved 2 agents, eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.
the efficacy and safety of eculizumab in treating patients with severe AMR episodes unresponsive to standard treatment with IVIG plus rituximab with or without PLEX.
CHRONIC ANTIBODY-MEDIATED REJECTION TREATMENT
The previously mentioned therapies have been used for the treatment of chronic AMR although data are limited
PREVENTION OF ANTIBODY-MEDIATED REJECTION
– Avoiding transplantation for highly sensitized patients
– better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening
– enrolling highly sensitized patients in a paired kidney exchange program
– Monitoring de novo DSAs, using class II HLA epitope matching,
– and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and
improve allograft survival
– ensure adherence to Is medications
Excellent
# Please summarise this article
# Allograft rejection is a complex process that involves the interplay of different cellular and molecular pathways that
cause allograft injuries.
# Allograft rejection can be
– hyperacute: occurring within minutes after the vascular anastomosis .
– acute: occurring days to weeks after transplantation .
– late acute: occurring 3
months after transplantation .
– chronic: occurring months to years after transplantation .
# Rejection can also be
classified according to the pathophysiologic event: cellular or AMR.
# Diagnostic criteria
– Single antigen bead testing
to detect antiHLA antibodies, a diagnostic tool for AMR.
– Complement dependent cytotoxicity
is gold standard for the detection of preformed antibodies.
– Electron microscopy used for the biopsies
– The Banff classification for allograft pathology has improve sensitivity in the diagnosis of rejection and the outcome of allograft survival
# Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of
the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
# Chronic Antibody Mediated Rejection
* Acute AMR has been shown to be a major risk factor for the development of chronic AMR.
* According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
# Moderate Microcirculatory Changes
– Introduced in the revised Banff 2013 classification as highly suspicious for antibody injury.
– Only the presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcome.
# Phenotypes of Antibody-Mediated Rejection
In the 2011 Banff defined, 2 phenotypes of acute AMR.
* Phenotype 1: occurs in the early posttransplant period in presensitized patient
* Phenotype 2: occurs in the late posttransplant period due to de novo DSA and is thought to be related to non adherence or inadequate immuno- suppression.
# PARADIGMS IN ANTIBODY-MEDIATED REJECTION
*Subclinical Antibody Mediated Rejection
– Protocol biopsies identified patients
with histologic evidence of antibody mediated injury despite stable creatinine.
– Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant .
# C4d-Positive and C4d-Negative Rejection
– The frequency of C4d positivity varies
from center to center because of the methodology used, prevalence of highly sensitized patients, and the threshold for C4d positivity.
– C4d was considered a marker for antibody injury also many patients have a C4d-negative rejection with microcirculatory inflammation.
– The low sensitivity make C4d a poor marker for the diagnosis of AMR,
for this reasons Banff 2013 classification increased expression of endothelial activation and injury transcripts or gene expression markers of endothelial injury in the biopsies.
– C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the
presence of DSAs.
– patients with C4d positive AMR were more likely to present earlier posttransplantation than C4d negative patient.
# Antibody Mediated Vascular Rejection
Endarteritis has been associated with
cellular rejection, however, study
demonstrated that vasculitis belongs to both T cell mediated rejection and AMR.
# Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified
into 2 categories:
* Alloantibodies directed against
polymorphic antigens that differ between the recipient and donor
* Antibodies that recognize self antigens or autoantibodies.
– Angiotensin type I receptor and endothelin type A receptor antibodies
have been implicated as markers of potential endothelial injury
– Patients with complement binding DSA after transplantation had a lower 5-year graft survival compared with patients with non complement binding DSA and patients without DSA
# Transplant Glomerulopathy
* Manifested as glomerular basement membrane duplication, double contouring, or splitting.
* Glomerulopathy causes proteinuria.
associated with a worse outcome
and is strongly associated with preexisting or de novo DSAs.
* late stage of antibody mediated injury that is usually irreversible and an
indicator of poor graft survival.
# ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
* Desensitization to HLA antibodies
involves treatment with immunomodulating therapies to reduce levels of anti-HLA antibodies to make
kidney transplantation a feasible option.
#High Dose Intravenous Immunoglobulin
(IVIG) is considered an immunomodulatory agent. It cause inhibition of T cell proliferation, cytokine synthesis, complement activation, and the antiidiotypic blockade of alloantibodies.
* IVIG reducing anti HLA antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease.
# Intravenous Immunoglobulin and – Rituximab
– Rituximab a chimeric monoclonal antibody against the
CD20
– Induces B cell lysis via complement dependent cytotoxicity and antibody mediated cellular cytotoxicity.
– It blocks B cell activation and maturation to antibody forming plasma cells
– It does not affect existing plasma cells
– Combination of IVIG and rituximab was effective as a desensitization regimen
# Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
* Study conducting that combination of plasmapheresis , IVIG, and rituximab superior to high dose IVIG alone.
# Immunoadsorption for Rapid Crossmatch Conversion
* Compared to PLEX, immunoadsorption (IA) allows more specific and effective clearance of circulating immunoglobulins without the side effects associated with fresh frozen plasma or albumin.
* They concluded that it is an effective strategy for rapid desensitization in deceased donor transplantation.
# TREATMENT OF ANTIBODY-MEDIATED
REJECTION
* Different treatment modalities including – rabbit antithymocyte globulin -methylprednisolone
– Plasmapheresis (PLEX )
rapidly removes preformed antibodies and isconsidered a standard part of therapy in most protocols
*combination of PLEX and IVIG superior to PLEX alone.
– Intravenous Immunoglobulin
* The efficacy of IVIG as a mono-
therapy for AMR is likely limited.
* Better allograft outcomes if used in-
combination therapy with PLEX and rituximab.
– Rituximab
– Proteasome Inhibitor
* Removing plasma cells that generate antibodies .
– Bortezomib has been used in combination with PLEX, IVIG, or rituximab for AMR
– Complement Inhibition
* Eculizumab ( anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH),for complement inhibition.
* Eculizumab was used in treating
patients with severe AMR episodes unresponsive to IVIG plus rituximab with or without PLEX.
* patients had AMR with TMA recovered fully or partially after eculizumab compared with graft failure in TMA positive patients treated with IVIG, rituximab and PLEX
* Eculizumab was found not effective in severe oliguric early onset AMR.
* The researchers concluded that splenectomy plus eculizumab may provide an effective intervention for preserving allograft function for patients with early severe AMR.
* The early use of eculizumab before advanced changes in kidney injury are identified can improve responses and
allograft survival.
– B cell depleting agents, muromonab
and maintenance therapy with CNIs, antiproliferative agents,and oral steroid
* Subclinical AMR was independently associated with a risk of allograft loss .
# Chronic Antibody Mediated Rejection Treatment
* Patients who received steroid pulse and rituximab followed by IVIG showed improved kidney allograft function.
* Biopsy proven chronic AMR
treatment with steroids/IVIG was associated with improved graft survival.
#PREVENTION OF ANTIBODY MEDIATED
REJECTION
* The presence of C1q fixing DSAs has emerged as an independent predictor of allograft loss.
* They recognized that pregnancies, blood transfusions, and previous organ transplantation are major risk factors for recipient sensitization and AMR.
* To prevent AMR avoiding transplantation for highly sensitized
patients, better stratifying immunologic risk by using sensitive DSA screening, enrolling highly sensitized patients in a paired kidney exchange program.
* Monitoring de novo DSAs, using class II HLA epitope matching and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
* Reduction of immunosuppression whether physician driven or because of patient nonadherence, is a well recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure.
# What is the level of evidence provided by this article?
level of evidence is I
(
Not impressed
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
☆ Antibody-Mediated Rejection:
This reviews the current diagnostic criteria for antibody mediated rejection (AMR); AMR paradigms; and desensitization, treatment, and prevention strategies.
INTRODUCTION:
*Allograft rejection:
Is a complex process that involves the interplay of different cellular and molecular pathways that cause a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis).
Types:
_______
1. Hyperacute (occurring within minutes after the vascular anastomosis)
2. Acute (occurring days to weeks after transplantation)
3. Late acute (occurring 3 months after transplantation)
4. Chronic (occurring months to years after transplantation).
☆Classified according to the pathophysiologic event:
1. Cellular
2. AMR
3. Cellular + AMR
CURRENT DIAGNOSTIC CRITERIA for AMR:
____________________________________________
1) Single-antigen bead testing (used to detect antiHLA antibodies) is currently used to:
i. Monitor transplant recipients
ii. Diagnose AMR.
2) Complement-dependent cytotoxicity is still considered the gold standard for the
detection of preformed antibodies.
3) Electron microscopy for the biopsies.
▪︎Banff has differentiated acute cellular rejection from AMR since 2003.
▪︎ In the 12th Banff Conference(2013) different findings were presented to reach consensus on the diagnosis of AMR in the presence and absence of a C4d stain
▪︎The diagnosis of AMR is dependent on histological findings.
*Acute and chronic Antibody-Mediated Rejection:
____________
▪︎Can be diagnosed according to the Banff 2013 classification
▪︎Their histology overlaps.
▪︎Acute AMR has been shown to be a major risk factor for the development of chronic AMR.
▪︎Moderate Microcirculatory Changes is highly suspicious for antibody injury.
▪︎The presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
▪︎The biopsies according to Banff is graded into g1, g2, and g3.
Phenotypes of Acute AMR ( 2011 Banff report):
__________
1) Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.
2) Phenotype 2 develops from the emergence of de novo DSAs in the late post transplant period and is thought to be related primarily to non-adherence or inadequate immunosuppression.
☆PARADIGMS IN ANTIBODY-MEDIATED REJECTION
*Subclinical AMR:
____________________
▪︎Histologic evidence of antibody mediated injury despite stable creatinine.
▪︎These patients had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell– mediated rejection (88%) and no-rejection (90%) groups
▪︎ If left untreated, increased the risk of allograft loss.
*C4d-Positive and C4d-Negative Rejection:
_____________________________________________
▪︎C4d deposition in peritubular capillaries correlates with allograft loss.
▪︎ C4d is split product of C4 activation and has no known biologic action
▪︎C4d positivity without other evidence of allograft injury has been reported.
▪︎ C4d-negative rejection with obvious evidence of microcirculatory inflammation can occur in 55% of patients.
▪︎C4d is a poor marker for the diagnosis of AMR due complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility.
▪︎Because of the low sensitivity of C4d, the Banff 2013 classification incorporates increased expression of endothelial activation and injury transcripts or other gene expression markers of endothelial injury in the tissue biopsy.
▪︎C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies
performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
▪︎ No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome is worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection
__________________________________________
▪︎Vasculitis belongs to both T cell–mediated rejection and AMR.
▪︎The risk of graft loss is higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis
Non-HLA Antibody-Mediated Rejection
__________________________________________
▪︎Are classified into 2 primary categories:
1) Alloantibodies directed against polymorphic antigens that differ between the recipient and donor.
2) Antibodies that recognize self-antigens or autoantibodies.
▪︎Non-HLA antibodies use different pathways to cause endothelial injuries that do not involve the presence of integrins, as with HLA antibodies.
▪︎Angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury.
Transplant Glomerulopathy:
_______________________________
▪︎There is glomerular basement membrane duplication, double contouring, or splitting
▪︎Is considered to be a late stage of AMR that is usually irreversible and an indicator of poor graft survival.
▪︎A frequent cause of proteinuria and is strongly associated with preexisting or de
novo DSAs
▪︎ Diagnosis: by electron microscopy.
▪︎Prognostic index based on the risk factors for allograft failure within 5 years of diagnosis. (The factors considered in the score included serum creatinine, level of proteinuria, and chronic inflammation score at biopsy based on the Banff classification.
▪︎The risk stratification may provide guidance for prognosis and treatment.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS:
___________________________
These includes:
1) High-Dose Intravenous Immunoglobulin
2) Intravenous Immunoglobulin and Rituximab.
3) Plasmapheresis, Intravenous Immunoglobulin, and Rituximab: Superior to high-dose IVIG.
4) Immunoadsorption: This is an effective strategy for rapid desensitization in deceased-donor transplantation.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
______________
These include:
1) Plasmapheresis: rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
2) Intravenous Immunoglobulin: The efficacy is better in combination therapy with PLEX and rituximab.
3) Rituximab
4) Proteasome Inhibitor to remove plasma cells: Bortezomib in combination with PLEX, IVIG, or rituximab.
5) Complement Inhibition: Eculizumab and a C1 esterase inhibitor (C1-INH). The early use of eculizumab before advanced changes in kidney injury are identified can improve responses and allograft survival. Splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR.
TREATMENT OF CHRONIC AMR:
__________________
▪︎ Steroid pulse and rituximab (375 mg/m2) followed
by IVIG (0.4 g/kg/d for 4 days)
▪︎Steroids/IVIG was associated with improved graft survival despite the limitations of the review.11
▪︎ Further studies are needed
PREVENTION OF AMR:
_________________________
▪︎Avoiding transplantation for highly sensitized patients.
▪︎Stratifying immunologic risk by using sensitive DSA screening
▪︎Enrolling highly sensitized patients in a paired kidney exchange program
▪︎ Monitoring de novo DSAs
▪︎Using class II HLA epitope matching
▪︎Performing protocol biopsies to early diagnose AMR (DSAs are present before the detection of allograft dysfunction).
▪︎Avoiding reduction of immunosuppression, whether physician driven or because of patient nonadherence.
●Level of evidence: Level II
Not impressed
It is level 5
It is a narrative review not a systematic review. Looks you have not read it properly
-Antibody-mediated rejection (AMR) is considered a major cause of allograft failure.
-C4d, a degradation product of the complement pathway that binds covalently to the endothelium, was identified as a marker of endothelial injury and hence of antibody activity.
-Antibody for HLA or blood antigens, including non-HLA antigens expressed on
the endothelium can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/ macrophage– mediated cytotoxicity, leading to endothelial damage, loss
of vascular integrity, and increased coagulation.
-Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation).
-Rejection can also be classified according to the pathophysiologic event: cellular
and/or AMR.
– One study showed allograft survival was inferior in the AMR group compared with the nonrejection group .
CURRENT DIAGNOSTIC CRITERIA
-Single-antigen bead testing, is currently used to monitor transplant recipients and used as a diagnostic tool for AMR.
-Complement-dependent cytotoxicity is still considered the gold standard for the
detection of preformed antibodies.
-The Banff classification improves sensitivity in the diagnosis of allograft rejection and in providing outcome data in terms of allograft survival.
-Acute Antibody-Mediated Rejection
According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury is defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction
with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g +ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification,8 the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g +ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
– The presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
Phenotypes of Antibody-Mediated Rejection
– Phenotype 1 occurs in the presensitized patient and occurs in the early posttransplant period.
-Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
Subclinical Antibody-Mediated Rejection
-Protocol biopsies have identified a subgroup of patients with histologic evidence of antibody-mediated injury despite stable creatinine.
C4d-Positive and C4d-Negative Rejection
– C4d has no known biologic action, and it is a split product of C4 activation. C4d
positivity without other evidence of allograft injury has been reported.
-55% of patients can have a C4d-negative rejection with obvious evidence of
microcirculatory inflammation.
-C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies
performed because of graft dysfunction and in protocol biopsies of grafts with stable function.
-No clinical characteristic could distinguish C4d-negative from C4d-positive rejection, and the allograft outcome was worse in the C4d-positive group.
Antibody-Mediated Vascular Rejection
-Vasculitis belongs to both T cell– mediated rejection and AMR.
Non-HLA Antibody-Mediated Rejection
– Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and
donor and antibodies that recognize self-antigens or autoantibodies.
Transplant Glomerulopathy
– Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splittingand is considered to be a late stage of
antibody-mediated injury that is usually irreversible and an indicator of poor graft survival.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
-Desensitization to HLA antibodies involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies to make kidney transplantation a feasible option.
1.High-Dose Intravenous Immunoglobulin
2.Intravenous Immunoglobulin and Rituximab
3.Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
4.Immunoadsorption for Rapid Crossmatch Conversion
TREATMENT OF ANTIBODY-MEDIATED REJECTION
-The treatment of subclinical AMR and its potential benefits are still under investigation.
1.Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR.
2.Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
3.Rituximab
4.Proteasome Inhibitor
-Bortezomib, currently approved for the treatment of multiple myeloma, has been used in combination with PLEX, IVIG, or rituximab as a rescue therapy for
AMR with some encouraging results.
5.Complement Inhibition
-Eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition
Chronic Antibody-Mediated Rejection Treatment
-Biopsy-proven chronic AMR, treatment with steroids/IVIG was associated with improved graft survival despite the limitations of the review.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
-The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss.
-Pregnancies, blood transfusions, and previous organ transplantation are major
risk factors for recipient sensitization and AMR.
-Strategies to prevent AMR, including :
-avoiding transplantation for highly sensitized patients, better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, and
combining kidney paired exchange programs with desensitization protocols.
-Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and
improve allograft survival.
-Areduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft
failure.
-Level of evidence 2
level of evidence 1
Assignment I
Antibody mediated rejection A review
In the past, AMR was inevitably leading to allograft loss. Mauiyyedi et al described the correlation between DSAs and diffuse C4d deposition (>50%) as diagnostic markers for AMR. Recently, its evidenced that B cells and Plasma cells activate cellular pathways when interacting with the endothelium developing microcirculatory changes and tissue injury.
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
The development of t cell-depleting drugs, calcineurin inhibitors and anti-proliferative drugs has
significantly improved graft survival and decrease the risk of acute rejection to less than 15%
with the introduction of T cell–depleting drugs, calcineurin inhibitors (CNIs), and
antiproliferative agents, the field of transplantation has experienced exceptional improvement in
allograft survival, which was considered impossible in the
Diagnostic criteria of AMR
Despite the major advances in molecular biology and gene rearrangement, the diagnosis of AMR is still dependent on histologic findings.
Acute Antibody-Mediated Rejection
Banff 2013 diagnstic criteria, all of the following are needed:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other
obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g + ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
Acute AMR is a risk factor for chronic AMR, Banff 2013 diagnostic criteria, all of the following
are needed:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g + ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Redfield et al concluded that chronic AMR was associated with poor graft survival after diagnosis, poor prognostic features included: Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g
Moderate Microcirculatory Changes
Microcirculatory changes that are highly suspicious for antibody injury and poor graft outcome, includes: vasculitis and the high rate of inflammatory cells in the microcirculation
The g score was determined based on the percent of involved glomeruli: 1%-25%, 26%-50%, and >50% equate to g scores of g1, g2, and g3, respectively. Glomerulitis was graded depending on the finding of complete occlusion of one or more glomerular capillary by leukocytes infiltration and endothelial enlargement.
Phenotypes of Antibody-Mediated Rejection
Phenotype 1 occurs in the pre-sensitized patient and occurs in the early posttransplant period. Phenotype 2 develops from the emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
Subclinical Antibody-Mediated Rejection
A subgroup of patients has histologic evidence of AMR despite of normal creatinine level. Patients with subclinical AMR had the poorest graft survival at 8 years posttransplant (56%) compared with the subclinical T cell–mediated rejection (88%) and no-rejection (90%) groups.
C4d-Positive and C4d-Negative Rejection
C4d has no known biologic action, and it is a split product of C4 activation. C4d positivity varies from center to center because of the methodology used to detect C4d, the prevalence of highly sensitized patients, and the threshold for C4d positivity. C4d positivity is a poor marker for the diagnosis of AMR.
C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs has been reported both in biopsies performed because of graft dysfunction and in protocol biopsies of grafts with stable function C4d negative AMR present later than C4d positive AMR (No clinical characteristic could distinguish C4d-negative from C4d-positive rejection,) and 2.5X increased risk of graft loss compared to AMR negative patients.
Antibody-Mediated Vascular Rejection
Vasculitis is not exclusive for AMR, it occurs with TCMR also. Antibody-mediated vascular rejection has 9 times more risk of graft loss than in T cell–mediated rejection without vasculitis
Non-HLA Antibody-Mediated Rejection
Non-HLA antibodies are classified into 2 primary categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies. Non-HLA Abs include angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury in case reports and clinical studies.
complement-binding capacity of anti-HLA antibodies played a role in kidney allograft failure, patients with complement binding DSAs have increased risk of allograft lost at 5 years follow up compared to non-compliment binding DSAs and no DSAs at all. Also, they were associated with an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
Transplant Glomerulopathy
Transplant glomerulopathy is manifested as glomerular basement membrane duplication, double contouring, or splitting and is considered to be a late stage of antibody-mediated injury that is usually irreversible and an indicator of poor graft survival. Transplant glomerulopathy is a frequent cause of proteinuria. Proteinuria >2.5 g/d is associated with a worse outcome (graft loss of 92% vs 33%,P<0.005) and is strongly associated with preexisting or de novo DSAs.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED
PATIENTS
Approximately one-third of patients awaiting a deceased donor kidney transplant have circulating anti-HLA antibodies, and almost 15% have a high degree of sensitization to potential kidneys. Desensitization reduces levels of anti-HLA antibodies to make kidney transplantation a feasible option. Options include: High dose IVIG, IVIG and Rituximab, Plasmapheresis with Intravenous Immunoglobulin and Rituximab, Immunoadsorption for Rapid Crossmatch Conversion
High-Dose Intravenous Immunoglobulin
Several mechanisms of IVIG action have been proposed, including the inhibition of T cell proliferation, the inhibition of cytokine synthesis, the inhibition of complement activation, and the ant idiotypic blockade of alloantibodies IVIG was better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease
Intravenous Immunoglobulin and Rituximab
Rituximab, a chimeric monoclonal antibody against the CD20 antigen, induces B cell lysis via complement dependent cytotoxicity and antibody-mediated cellular cytotoxicity. It blocks B cell activation and eventual maturation to antibody-forming plasma cells but does not affect existing plasma cells as they do not express the CD20 antigen. the combination of IVIG and rituximab was effective as a desensitization regimen, but needs larger trials to evaluate the efficacy of this intervention.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
The triple therapy has a better outcome than high dose IVIG on graft survival but larger studies are needed.
Immunoadsorption for Rapid Crossmatch Conversion
immunoadsorption (IA) allows not only a more specific but also a more effective clearance of circulating immunoglobulins without the side effects associated with the substitution of fresh frozen plasma or albumin compared to plasmapheresis. Immunoadsorption is an effective strategy for rapid desensitization in deceased-donor transplantation
TREATMENT OF ANTIBODY-MEDIATED REJECTION
The obvious goal for the treatment of AMR should be to reduce the inflammation in the allograft, eliminate the factors that cause inflammation, and effectively prevent antibody formation without jeopardizing the normal immune responses that protect patients from serious infections.
Only a few studies to date have reported on the effect of treatment in patients with DSA associated AMR. Wiebe et al reported no impact on DSA levels or histopathology from optimization of baseline immunosuppression, monthly high dose IVIG, and pulse steroids
Plasmapheresis
PLEX rapidly removes preformed antibodies and is considered a standard part of therapy in most protocols developed for the treatment of AMR. The data is debatable with some studies show benefits of PLEX, others no benefits and others considered PLEX as harmful!
Intravenous Immunoglobulin
The efficacy of IVIG as a monotherapy for AMR is likely limited. Better allograft outcomes have been reported in combination therapy with PLEX and rituximab.
Rituximab
Rituximab solely for AMR has inferior results than combination of Rituximab, IVIG and PLEX.
Proteasome Inhibitor
Removing plasma cells that generate antibodies is the rationale behind using a proteasome inhibitor. experience with PI-based AMR therapy demonstrated that it provides effective AMR reversal, including substantial reductions in DSA levels
Complement Inhibition
Eclizumab treatment for patients with TMA has superior results than IVIG, Rituximab and PLEX combination. Splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function for patients with early severe AMR
Chronic Antibody-Mediated Rejection Treatment
The previous treatment modalities are harmful to apply for long periods on patients with chronic AMR.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
few tools are available that can be used to stratify and predict allograft outcomes or patients at risk for allograft failures.
The presence of C1q-fixing DSAs has emerged as an independent predictor of allograft loss pregnancies, blood transfusions, and previous organ transplantation are major risk factors for recipient sensitization and AMR.
Proposed strategies to prevent AMR, include: avoiding transplantation for highly sensitized patients, better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening, enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Eurotransplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols, Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies a reduction of immunosuppression, whether physician driven or because of patient nonadherence, is a well-recognized risk factor for DSA formation and subclinical rejection and hence should be avoided to prevent allograft failure.
Finally, there is no straightforward algorithm to treat AMR, treatments modalities need larger well controlled studies and may need to be individualized for each patient apart!
The level of evidence is II (a review article)
It is a review article, level 2 evidence ,
INTRODUCTION
Allograft rejection is a complex process
Antibody ligation to human leukocyte antigen (HLA) or blood antigens, including non-HLA antigens expressed on the endothelium,can activate the complement system, leading to recruitment of leukocytes and facilitation of natural killer cell–mediated or monocyte/macrophage– mediated cytotoxicity, leading to endothelial damage, loss of vascular integrity, and increased coagulation.
CURRENT DIAGNOSTIC CRITERIA
*Acute Antibody-Mediated Rejection
According to the Banff 2013 classification all of the following 3 features are required for the diagnosis of acute AMR:
1 Histologic evidence of acute tissue injury with one or more of the following:
Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
Intimal or transmural arteritis (v >0)
Acute thrombotic microangiopathy (TMA) of no other obvious cause
Acute tubular injury of no other obvious cause
2 Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
Linear C4d staining in the peritubular capillaries
At least moderate microvascular inflammation (g þ ptc >2)
Increased expression of tissue gene transcripts indicative of endothelial injury
3 Detection of DSAs (HLA or non-HLA) in the serum.
*Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1 Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
Transplant glomerulopathy (cg >0) in the absence of chronic TMA
Severe peritubular capillary basement membrane multilayering identified by electron microscopy
New-onset arterial intimal fibrosis with no other known etiology
2 Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
Linear C4d staining in the peritubular capillaries
At least moderate microvascular inflammation (g þ ptc >2)
Increased expression of tissue gene transcripts indicative of endothelial injury
3 Detection of DSAs (HLA or non-HLA) in the serum
chronic AMR was associated with poor graft survival after diagnosis.
●Moderate Microcirculatory Changes
presence of vasculitis and the high rate of inflammatory cells in the microcirculation have been associated with poor outcomes.
Presence of glomerulitis is established in biopsy when there is complete occlusion of at least one glomerular capillary by leucocyte infiltration and endothelial cell enlargement.
2 principal phenotypes of acute AMR were defined.
*Phenotype 1 occurs in the presensi-tized patient in the early posttransplant period. *Phenotype 2 due to de novo DSAs in the late posttransplant period primarily to nonadherence or inadequate immuno-suppression.
Paradigm in antibody mediated rejection
●Subclinical Antibody-Mediated Rejection
protocol biopsies was done in some Patients with stable creatinine showed evidence of AMR they had the poorest graft survival at 8 years compared with the subclinical TCR or no rejection ,subclinical AMR, if left untreated, increased the risk of allograft loss.
●C4d-Positive and C4d-Negative Rejection
the Banff 2013 classification incorporates increased expression of endothelial activation and injury transcripts or other gene expression markers of endothelial injury in the tissue biopsy. C4d-negative AMR, defined by microvascular injury (glomerulitis, peritubular capillaritis, TMA) in the presence of DSAs .
patients with C4d-positive AMR were more likely to present earlier in posttransplantation ,C4d-negative AMR patients had better survival thsn c4d positive receipts.
●Antibody-Mediated Vascular Rejection
vasculitis belongs to both T cell– mediated rejection and AMR.
graft loss was higher in antibody-mediated vascular rejection than in T cell–mediated rejection without vasculitis.
●Non-HLA Antibody-Mediated Rejection
Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had a lower 5-year graf survival. These antibodies were associated with an increased risk of allograft loss, an increased rate of AMR, and a more severe graft injury phenotype with increased microcirculatory inflammation and more C4d deposition.
●Transplant Glomerulopathy
It is manifested as glomerular basement membrane duplication, double contouring, or splitting it is a late stage of antibody-mediated injury that is usually irreversible lead to poor graft survival.
Transplant glomerulopathy is a frequent cause of proteinuria and is strongly associated with preexisting or de novo DSAs.
▪︎ ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
*High-Dose Intravenous Immunoglobulin
IVIG reducing anti-HLA antibody and improving transplantation rates in highly sensitized patients
*Intravenous Immunoglobulin and Rituximab
combination of IVIG and rituximab was effective as a desensitization regimen but more studies are needed
*Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
combination of the three agents is considered better than the IVIG alone.
*Proteasome Inhibitor.
used in combination with PL EX, IVIG, or rituximab as therapy for AMR with good results.
*Complement Inhibition.
still need more studies
Prevention of AMR
Proper matching for receiptnt and
Doner
avoiding transplanting highly sensitized receptient
Encourge paired exchange for proper matching and better allocationof graft
monitoring of DSA after transplantion and protocol biopsy.
I think level of evidence is 1
Please summarise this article
1- AMR results in transplant glomerulopathy, manifested by basement membrane duplication or splitting.
2- the clinical manifestations of AMR include proteinuria and increased S. creatinine.
3- treatment modalities include the following :
a- plasmapharesis.
b- immunoadsorption.
c- immunomodulation with IVIG.
d- T-cell or B-cell depleting agents.
e- Rituximab.
f- Bortezomab : – proteosome inhibitor, of low significant benefits as documented in most recent studies.
g- Eculizomab.
1- AMR is an area of active research.
2- allo-immune reaction remains a significant barrier for successful long-term graft function despite advanced techniques in allo-antibody detection.
3- new therapies are promising but high-powered studies are still awaited for confirming efficacy
What is the level of evidence provided by this article?
Level of evidence 1
AMR considered as dangerous complication of solid organ transplantation leading to graft loss. Now after better understanding of causes & pathogenesis of rejection with improvement in IS used for treatment, there was an improvement in graft survival.
DSA is the most important factor in development of AMR. Acute rejection can be classified according to the time of occurrence (hyper acute, acute, late acute, & chronic) or according to the histopathological events ( cellular, & humoral)
The incidence of AR decline dramatically (<15%) after development of T cell depleting agent, CNI, & anti proliferative.
Banff classification can differentiate between ACR & AMR.
Features of AMR according Banff 2013 classification:
Features of chronic AMR according Banff 2013 classification:
There are several factors increase the risk of graft loss including:
Banff 2011 report recognize to AMR subtypes:
Subclinical AMR: defined as histological evidence of acute AMR with normal serum creatinine detected by protocol biopsy. It is associated with poor graft survival at 8 years (56%) when compared with subclinical cellular rejection (88%) & no rejection (90%).
previously C4d +ve was considered as marker of Ab dependent injury, but about 55% of AMR was C4d negative with strong evidence of microcirculatory inflammation. So C4d negative rejection mean microvascular inflammation associated with presence of DSA.
Non HLA AMR:
Non HLA Abs are either autoantibodies or Ab against polymorphic AG which is differ between donor & recipients. It can cause endothelial injury with out involvement of integren. Angiotensin type 1 receptor, & endothelia type A receptor Abs are marker of endothelial injury of non HLA Abs.
TG:
Histological feature of chronic AMR due to repeated attacks of endothelial injury & repair. It can lead to graft loss in 40%-70% of patients. Proteinuria > 2.5 g/day in TG associated with poor outcome. EM is the best test used to diagnose TG.
30% of patients on waiting list are sensitized & about 15% had high degree go sensitization. Desensitization therapy include:
Treatment of AMR:
Treatment of chronic AMR: because of the nature of chronic AMR ( saw progression) so potent IS may be of little effect. Redfield et al show that steroid/ IVIG had an improvement in graft out come.
Prevention of AMR:
AMR is the main cause of chronic allograft failure.DSAs were strongly strong linked to the allograft outcome,this article is reviewing the evidences of its importance,elaborating on the different angles of its involvement in progress of acute and chronic allograft rejection.
It’s formed when there is HLA antigens mismatch due to previous transplantation, blood transfusion and pegnancy.
It might be formed pre_transplantation due to the reasons mentioned up. Or it’s formed post transplantation as De novo DSAs. It can be associated with hyperacute rejection and having positive flow cytometry assay cross match and complement dependent lymphocytotoxicity CDC is an absolute containdication for transplantation .
Several factors outline the risk of AMR, including type of DSAs, herefore, IgG 1 and IgG 3 are associated with higher risk of acute rejection. IgG 4 is associated with chronic AMR.
C1q assay is to test for potential complement fixing of the DSAs, while C1q positive DSAs are associated a risk of acute AMR,C1q negative DSAs are associated with higher risk of chronic AMR.
Similarly phenotype of DSAs are important in a way DSAs against HLA class I are associated with complement fixing and higher risk of acute AMR, on the other hand DSAs against HLA class II ARE NON COMPLEMENT fixing and associated with chronic AMR by natural killer Cells dependent reaction.
Acute AMR: either early days to weeks after transplantation, or acute late 3 months after transplantation.
Was diagnosed according to Banff classification,3 features are required to diagnose Acute AMR:
1_Histologic evidence of acute tissue injury
a:Glomerulitis or peritubular capillaritis.
b_Intimal ortransmural arteritis
c_Acute thrombotic microangiopathyTMA of no other obvious cause.
d_Acute tubular injury o no other cause.
2_Histologic evidenceof current/recent antibody interaction with vascular endothelial defined by
One of the following:
a_Linear C4d staining in the peritubular capillaries .
b_At least moderate microvascular inflammation (g+ptc of more than 2)
C_Increased expression of tissue gene transcripts,indicative of endothelial injury.
3_Detection of DSAs(HLA or non HLA) in the serum.
Chronic AMR:
IT happened months or years after transplantation.
Acute AMR is the main risk factor for chronic AMR.
3 features should be there in order to diagnose Chronic AMR:
1_histologic evidence of chronic tissue injury. Defind by the presence of one of the following:
a_Transplant glomerulopathy in the absence of chronic TMA.
b_Severe peritubular capillary basement membrane multilayered shown by electrone microscopy.
c_Intemal fibrosis with no other etiology.
2_Histologic evidence of antibody interaction with vascular endothelial,defined by presence of one of the following:
a_Linear C4d in peritubular capillaries.
B_microvascular inflammation.
C_increased expression of tissue gene transcripts ,indicative of endothelial injury.
3-DSAs(HLA or non HLA) ln serum.
Risk factor for deterioration of allograft function after the diagnosis of chronic AMR. Redfeild et al
1_chronisity score more than 8
2_DSA more than 2500 MFI.
3_Serum creatinine of more than 3
4_Protein /creatinine ratio of more than 1 g/g.
In general ,chronic AMR is associated with poor graft survival after diagnosis.
In DeKAF study found high frequency of Antibody _mediated injury (as indicated by C4d and circulating DSAs)
Similarly ,microvascular changes where recognized by Banff 2013 classification as highly suspicious of antibody injury.
Non HLA antibodies in the form of angiotensine type 1 receptor,and endothelial type a receptors were implicated as markers of endothelial injury.
Desensitization of patients with anti HLA antibodies:
1_High dose intravenous Immunoglobulin.:immunomodulatory agent with several mechanisms.
2-Combination of IVIG and Rituximab.
Rituximab monoclonal antibody against CD20 antigen induce B cells lysis.but has no effect on plasma cells as they don’t have CD 20 Antigen. Vo et al concluded the combination is effective in desensitization .
3_plasmaphersis,IVIG and Rituximab: Lefaucheur etc al concluded that this combination is significantly superior to other regimens for desensitization..
Treatment of AMR
IVIG,RITUXIMAB,BORTIZUMIB and ECULIZUMAB plus PLEX.
LEVEL OF EVIDENCE IN THIS STUDY WAS II.
The Antibody Mediated Rejection
AMR is an important cause of graft failure. it is characterized by high DSA, presence of neutrophils in peritubular capillaries . C4d are attached to endothelial cells. The process of graft rejection starts by activation of plasma cells and B cells against HLA and non HLA antigen leading to activation of compliment pathway leading too inflammatory process in graft leading to graft loss.
Diagnostic Criteria
A- Tissue injury is defined by the presence of one or more of the following
1- Glomerulitis or peritubular capilliritis
2-Intimal or transmural arteritis
3- TMA Acute thrombotic microangiopathy
B- Interaction of antibody with vascular endothelium
C- Presence of DSA in serum against HLA and Non HLA
Chronic Antibody mediated Rejection
It has similar features but also characterized by Transplant glomerulopathy without TMA, multi layering of capillary basement membrane identified by Electron microscopy. also there is intimal fibrosis without other cause. Urine protein / creatinine ratio>1 g/g, Chronicity score >8, DSA >MFI 2500, raised creatinine more than 3 mg/ml.
Phenotypes of Antibody mediated Rejection
These are of two type
Type 1 : early development of DSA in pre sensitized patient
Type 11: due to Denovo DSA which can due to improper immunosuppression or non adherence
Paradigm in antibody mediated rejection
Subclinical AMR- Mainly identified by protocol biopsies. It is associated with poor graft outcome.
C4d positive and C4d negative Rejection-
C4d is poor prognostic indicator in AMR and has low sensitivity. C4d negative AMR is characterized by microvascular inury in the presence of DSA
Antibody mediated Vascular Rejection
Both T cell mediated rejection and AMR show endarteritis on histology
Non HLA AMR
These are an evolving field in transplant immunology. There are two types. Antibodies directed against polymorphic antigens and autoantibodies.
Transplant glomerulopathy
Histology shows doubling of glomerular basement membrane which is due to Recurrent endothelial injury and repair. Outcome is poor.
Antibody removal in highly sensitized patients
Options include
High dose Immunoglobulins
Intravenous Immunoglobulins and Rituximab
Plasmaphresis , Intravenous Immunoglobulins and Rituximab
Immunoadsorption for rapid cross match conversion.
Treatment of AMR
1– Plasmaphresis– Mainstay of treatment and involves preformed antibodies . Bettr outcome when combined with IVIG
2- IV immunoglobulins– better outcome along with plasmaphresis.
3-Rituximab- better outcome along with IVIG and PLEX
4-Proteosome Inhibitor-it is used in combinition with IVIG,PLEX or rituximab.
5– Compliment inhibition.-Anti C5 monoclonal antibody ecluzumab and C1 estrase inhibitor. Its costly treatment and more data is required to assess outcome
Prevention of Antibody mediated rejection.
–Better to avoid transplant in highly sensitized patients- Consider enroling in paired exchange program and adopt desensitiation protocol
– Monitor denovo DSA using class 11 HLA epitope. Perform protocol biopsies to detect AMR at early stage
– Patient education and community based nephrologists may help and financial assessment Pretransplant to avoid non adherence.
Level of evidence 11B
This article review diagnostic criteria and treatment of AMR.
AMR remains a problematic event in kidney transplant which may lead to decrease of graft survival and graft loss.
AMR is humoral immune response results from presence of HLA and non HLA Ab which react to endothelium lead to activation of complement and formation of C4d which are deposits in peritubular capillary lead to endothelial injury.
AMR can be hyperacute happen within hours after vascular anastomoses.
Early acute rejection: happens within days.
Late acute rejection: happen within months.
Chronic acute rejection: from months to years.
Incidence of AMR recently declined by new immunological technology and using desensitisation protocol.
Current diagnostic Criteria of AMR:
1. Single antigen bead to detect HLA antibody
2. CDC
3. Electron microscopy help in diagnosis of AMR by morphological changes of graft.
4. Banff classification of allograft pathology.
– [ ] Diagnosis of AMR is still histological and according to Banff classification 2013 which are held in Brazil depend on presence or absence of C4d staining and presence of micro vascular inflammation and intimal arteries.
– [ ] Acute AMR: Stage I
a/ glomerulitis (g>0) or peritubular capillarities (ptc>0)
b/ intimal or transmural arteritis (v>0)
c/ acute TMA
d/ acute tubular injury.
– [ ] Stage II:
a/ linear C4d staining in ptc
b/ moderate micro vascular inflammation ( g, ptc >2)
c/ Increase expression of tissue gene transcription indicates endothelial injury.
3: detection of DSA in serum
– [ ] Diagnosis of chronic AMR is overlapping with acute AMR.
Chronic tissue injury diagnosing by histological evidence.
a/ presence of transplant glomerulopathy ( cg>0 in absence of chronic TMA.
b/ severe peritubular capillary basement membrane identifying by electron microscopy
c/ New onset arterial intimal fibrosis.
Redfield et al conducted his study by 123 patients and his conclusion chronic AMR is associated with poor graft survival after diagnosis.
criteria of diagnosis is chronicity score >8
DSA >2,500 MFI
S.Cr > 3 mg/d
Urine protein/ creatinine ratio > 1g
Moderate micro circulatory charge are classified according to banff ( g1> 25%
g2 26 to 50%
g3> 50% depend on involvement of glomeruli by leukocytes infiltration and endothelial enlargement which lead to complete occulsion of glomeruli.
– [ ] Phenotypes of AMR according to banff 2011.
Phenotype I: (early post transplant period) occur in pre sensitised patients
Phenotype II occur in late post transplant and it’s due to circulating de novo DSA and it’s maybe related to non adherence to immunosuppressive agents or inadequate doses.
Protocol for biopsy help to identify sub clinical AMR even in normal creatinine level and prevent risk of graft loss.
There’s no difference in graft survival outcome between C4d positive or negative according to banff classification but C4d positive have risk of early post transplant AMR in comparison to negative C4d.
Risk of graft loss more in AMR rather than T cell mediated rejection.
Presence of circulating non HLA Ab mediated rejection are associated with graft loss.
there’s 2 markers of non HLA Ab which are not involved in banff classification but associated with endothelial injury is Angiotensin type 1receptor and endothelial type A receptor Ab.
– [ ] Transplant glomerulopathy manifested by glomerular basement membrane duplication or splitting and associated with poor prognosis because irreversible damage.
Antibody removal for highly sensitised patients:
1/3 of patients awaiting deceased donor kidney transplant have high degree of circulating HLA Ab.
To reduce sensitisation should use desensitisation immunomodulating agents :
1. High dose of IV g; it’s mechanism inhibition of T cell proliferation and inhibition of cytokines synthesis, inhibition of complement activation and blocking actions of alloantibodies
2. Iv Rituximab monoclonal Ab against CD20 antigen and block B cell activation
3. Plasma exchanges and immunoadsorption both mechanisms same in removal of antibodies but immunoadsorption less side effects because no use Fresh frozen plasma and no use of Albumin.
4. Hyperacute rejection nowadays are completely eliminated by desensitisation protocol.
5. Bortezomib is Proteasome inhibitors
6. Eculizumab is complement inhibitors (anti C5 monoclonal antibody).
Treatment of chronic antibodies mediated rejection by pulse therapy of steroid and intravenous immunoglobulin and further trials on immunosuppressive agents to eliminate graft loss.
– [ ] Prevention of graft loss:
by technique for detection of C1q fixing DSA which are indicator of sensitised patients and risk of graft loss
1. to avoid rejection better avoid transplant in incompetent cross matches
2. If no compatible donor available should use desensitisation protocol but it’s very costly and short term coarse also may complicated with highly fatal infectious disease.
3. Extensive monitoring of de novo DSA
4. Using class II HLA epitope matching
5. Shift patients who are having incompatible donor to Parried kidney exchanges program.
6. Protocol of biopsy.
Q2 Evidence 2 cohort study
Sorry! it’s Evidence II Review Article
Evidence 1a
ABMR is one of the laeding causes of graft loss after kidney transplantion,
in the last two decades increaseing recognition of molecular and histological changes gave us better understanding of this process and potential therapuetic options .
what is current diagnostic criteria of ABMR?
1-ACUTE ANTIBODEY MEDIADTED REJECTION,
since inovation of single antigen beads which give us an idea about DSA pre and post kidney transplant this helped the transplant physicians a lot undersatnding the behavior and monitoring of DSA levels and classifing the patient with high risk transplantion which needs more meticulous observations after transplantion.
BANF classification and its updates had made a favourable change understanding AR episodes and,improving sensitivity and diagnosis of allograft rejection .
BANF CRITERIA FO ACUTE ANTIBODY MEDIATED REJECTION
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
2. Histologic evidence of current/recent antibody interac- tion with vascular endothelium, defined by at least one of
the following:
3. Detection of DSAs (HLA or non-HLA) in the serum
BANF CRITERIA FOR CHRONIC ANTIBODY MEDIATED REJECTION
. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
2. Histologicevidenceofantibodyinteractionwithvascular
endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ
ptc >2)
c. Increased expression of tissue gene transcripts
indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Two phenotypes was idinetified by BANF for acute antibody mediated rejection
PARADIGMS OF ANTIBODY MEDIATED REJECTION
A-SUBCLINCIAL AMR,
B-C4D POSITIVE AND C4D NEGATIVE
C-ANTIBODY MEDIATED VASCULAR INJURY
D-NON HLA ANTIBODY MEDIATED REJECTION
what is meant by transplant glomerulopathy?
glomeural basment membrane duplication, double contouriing, splitting .which is considerd as a late stage of ABMR.
HOW CAN ABMR BE TREATED?
1-IV IGG commonly used for AMR tretment inhibiting t cell proliferation, inhbiting cytokine synthesis, inhbiting complement activation .
2-IV IGG WITH RITUXIMAB, which induce b cell lysis and prevent b cell matuartion and formation of antibodies, this combination was effective than iv igg alone .
3-PLEX WITH IV IGG AND RITUXIMAB,The combination of the three agents is considered better than the IVIG alone.
4-Proteasome Inhibitor.
used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging result.
5-Complement Inhibition.
eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition still need more studies and keep in mind the cost aspect.
HOW TO AVOID ABMR?
What is the level of evidence provided by this article?
level 2 evidence , rivew article
Antibody-Mediated Rejection
INTRODUCTION
Antibody mediated rejection (AMR) is considered one of the most common cause of allograft failure , early it is defined by presence of neutrophils in peritubular capillaries , serological markers of de novo donor -specific antibody DSA and c4d attached o endothelial cells which identified as antibody activity.
Allograft rejection is a complex process which started by activation of immunological cells(B-cells, plasma cells )against HLA or Non-HLA antigens then complement system become activated and many inflammatory cells and markers aggregated with in the graft and lead to inflammatory process inside it (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis) all theses reaction if not treated , ended by graft loss.
Understating of the immunological mechanisms and innovation in immunosuppressive drugs and techniques of antibodies detection lead to change in the graft outcome.
CURRENT DIAGNOSTIC CRITERIA
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following:
a. Glomerulitis or peritubular capillaritis .
b. Intimal or transmural arteritis .
c. Acute thrombotic microangiopathy (TMA) .
2. Histologic evidence of current/recent antibody interaction with vascular endothelium.
3. Detection of DSAs (HLA or non-HLA) in the serum.
Chronic Antibody-Mediated Rejection
Which depends on same criteria except presence of chronic histological changes as transplant glomerulopathy in the absence of chronic TMA , Severe peritubular capillary basement membrane multilayering identified by electron microscopy or New-onset arterial intimal fibrosis with no other known etiology.
Chronicity scores >8, DSA >2,500 mean fluorescence intensity, serum creatinine >3 mg/dL, and urine protein/creatinine ratio >1 g/g were associated with an increased risk of allograft loss.
Phenotypes of Antibody-Mediated Rejection
Type I:pre-sensitized patient with DSA which developed early.
Type II:patient with de novo DSA which developed later mainly due to non-adherence or inadequate immunosuppressive drugs.
PARADIGMS IN ANTIBODY-MEDIATED REJECTION
-Subclinical Antibody-Mediated Rejection
Which appeared mainly with protocol biopsy and till now no strong evident guidelines for treatment and its associated with poor graft survival.
C4d-Positive and C4d-Negative Rejection
C4d a poor marker for the diagnosis of AMR due to complement-independent pathways, the low sensitivity and poor interinstitutional reproducibility.
C4d negative AMR with histological tissue injury and positive DSA.
Antibody-Mediated Vascular Rejection
Endarteritis is histological features of both TCMR and AMR but more common in AMR.
Non-HLA Antibody-Mediated Rejection
Two categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor and antibodies that recognize self-antigens or autoantibodies.
Transplant Glomerulopathy
Is histological descriptive term which mainly characterized by doubling of GBM which mainly due to recurrent endothelial injury and repair associated with chronic AMR with poor graft survival.
ANTIBODY REMOVAL FOR HIGHLY SENSITIZED PATIENTS
High-Dose Intravenous Immunoglobulin
One of the most common agents used in desensitized patients which acting on several mechanism .
Intravenous Immunoglobulin and Rituximab
Rituximab is anti-CD 20 and prevent plasma cell to produce antibodies and with IVIG combination they give good result as per studies.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
The combination of the three agents is considered better than the IVIG alone as per Lefaucheur et al study but still need more clinical trials and to keep cost aspect in mind.
Immunoadsorption for Rapid Cross-match Conversion
IA more specific and effective than PEX and less side effects especially without plasma or albumin substitution.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
1-Plasmapheresis.
Which is considered the cornerstone in all protocols of AMR treatment depend on removal of performed antibodies and the good results came mainly when using with IVIG.
2-Intravenous Immunoglobulin.
When using with PEX give good result.
3-Rituximab.
Used in combination with PEX and IVIG, alone shown no effect.
4-Proteasome Inhibitor.
used in combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR with some encouraging result.
5-Complement Inhibition.
eculizumab (an anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition still need more studies and keep in mind the cost aspect.
PREVENTION OF ANTIBODY-MEDIATED REJECTION
1-several strategies to prevent AMR.
Avoiding transplantation for highly sensitized patients.
Better stratifying immunologic risk by using sensitive donor-specific anti-HLA antibody screening.
Enrolling highly sensitized patients in a paired kidney exchange program, participating in special programs such as the Euro transplant Acceptable Mismatch Program, and combining kidney paired exchange programs with desensitization protocols.
2 Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies are also strategies used to reduce or early diagnose AMR and improve allograft survival.
3-Education for patients and community nephrologists is advised, as well as appropriate financial evaluations prior to transplantation to avoid drugs non-adherence.
Level of evidence II B
Allograft rejection can be hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring months to years after transplantation). Rejection can also be classified according to the pathophysiologic event: cellular and/or AMR.
AMR causes a broad range of allograft injuries (acute tubular injury, glomerulitis, capillaritis, and fibrinoid necrosis).
Significant progress has been made since the recognition of the role of DSAs, such as new techniques to detect antibodies, the use of desensitization protocols, and the introduction of new agents that interfere with complement-mediated allograft injury.
Diagnostic methods
Single-antigen bead testing, which is used to detect antiHLA antibodies, is the final step in the current techniques used to identify antibodies that can injure the allograft.
Electron microscopy is routinely used for the biopsies of transplant recipients because early changes cannot always be detected with light microscopy.
ABMR is diagnosed based on the presence of the following components:
1-Histologic evidence of acute tissue injury related to ABMR (peritubular capillaritis-ptc and/or glomerulitis-g, Intimal or transmural arteritis-v, TMA, ATN)
2-Evidence of circulating DSAs
3-Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or at least moderate microvascular inflammation (g + ptc >2)
Phenotypes of Antibody-Mediated Rejection based on the presentation:
Phenotype 1 which occurs acutely early in the post transplant period in previously sensitized patient .
Phenotype 2 usually occurs in the late post transplant period with progressive decline in kidney function due to the development of de novo DSAs.
Subclinical Antibody-Mediated Rejection
It is histology based definition detected during protocol biopsies when patients with normal creatinine having antibody mediated injury. It has the poorest graft survival at 8 years post transplant (56%) compared with the subclinical T cell–mediated rejection (88%) and no-rejection (90%) .
C4d-based definition of Rejection
C4d staining is the surrogate marker for complement dependent antibody mediated injury; but C4d negative rejection entity has been recently recognized. C4d positivity could vary from lab to other depending on the staining method and techniques.
There are no clinical parameters which can help in differentiating between C4d-negative and C4d-positive rejection.
Key points:
C4d-positive AMR occurs earlier post transplantation
C4d-positive AMR occurs 3 times more common than C4d negative AMR
Graft survival at 1 and 2 years is lower in C4d positive than C4d negative patients
C4d-negative AMR was associated with a 2.56-fold increased risk of allograft loss compared to AMR-free patients.
Antibody-Mediated Vascular Rejection
Vascular rejection carries poor prognosis to the allograft as the risk of graft loss was 9 times higher in antibody-mediated vascular rejection than in T cell–mediated rejection .
Non-HLA Antibody-Mediated Rejection
2 categories: Alloantibodies directed against angiotensin type 1 receptor and endothelin type A and autoantibodies have been implicated in the development of acute rejection. The effect of anti-endothelial cells AT1R antibodies have been demonstrated in few studies to cause acute rejection.
Transplant Glomerulopathy
Transplant glomerulopathy is a marker of antibody-mediated injury which is usually irreversible and causes proteinuria leading to graft loss in the majority of patients. It is manifested as glomerular basement membrane duplication, double contouring, or splitting.
Treatment of acute antibody mediated rejection:
The aim of treatment of AMR is:
-Reduce the inflammation in the allograft
-Eliminate the factors that cause inflammation
-Effectively prevent antibody formation without effecting the normal immune responses that protect patients from serious infections.
Types of treatment
-Plasmapheresis- is part of the standard therapy for rapid and efficient removal of preformed antibodies.
-Intravenous Immunoglobulin- used in combination therapy with PLEX for better inhibition of antibodies production and allograft outcomes.
-Rituximab- used for B cell depletion to prevent further differentiation into plasma cells. Graft survival better with combination of PLEX,IVIG and Rituximab.
-Proteasome Inhibitor(Bortezomib)- inhibit plasma cells production of antibodies. Results are better if used in combination with IVIG,PLEX or Rtiuximab.
-Complement Inhibition- Anti-C5 monoclonal antibody- Eculizumab and a C1 esterase inhibitor have been approved so far for refractory ABMR in complement dependent rejection.
Prevention of ABMR:
-Avoid transplantation in HLA incompatible pairs
-Match with better compatible donor through kidney allocation system or KPD if the patient has living donor
-Desensitization is indicated if there is no living donor and the patient is highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
-Desensitization is more effective when plasmapheresis, low dose IVIG and Rituximab are combined
-Post-transplant serial monitoring of DSA levels in presensitized patients, CNI level, and protocol biopsies
This is a review article with level of evidence 2
Please summarise this article
It is a review study that discusses the concept of antibody-mediated rejection and classifies it by time (hyperacute, acute, late acute, or chronic), clinical phenotype, and histopathologically using the Banff classification. Antibodies related to HLA or not (endothelium) increase the chance of graft rejection, even subclinical manifestations are sufficient for graft loss.
SABs and Complement Dependent Cytotoxicity are still considered the gold standard for detection of preformed antibodies, but the diagnosis of AMR is still dependent on histopathological findings.
As histopathological findings of interaction in vascular endothelium and detection of DSA in serum are indifferent when evaluating acute and chronic AMR. Tissue injury findings such as glomerulitis, acute tubular injury, and microangiopathic thrombosis for acute rejection (Phenotype 1) and findings of glomerulopathy, fibrosis, and de novo lesions suggest chronic rejection (Phenotype 2).
Although vascular rejection is considered a classic finding of rejection mediated by T lymphocytes, we cannot confuse this finding with vasculitis, which is directly related to B lymphocytes and has a higher OR 9.07 of rejection with specific treatment that should be started as early as possible.
Non-HLA-related rejection such as angiotensin 1 inhibitors and transplant glomerulopathy lesions should be considered in patients with worsening renal function.
The presence of C1q-fixing DSA is an independent predictor of graft loss. Pregnancy, blood transfusions, and previous transplantation are risk factors for sensitized patients at high risk of AMR. Monitoring de novo DSAs, class II HLA epitope matching, CNI level, and protocol biopsies improve graft survival.
What is the level of evidence provided by this article?
They did not describe how was the choice of the articles, but it appears to have raised cohort studies and clinical trials, so it would have level of evidence IIb.
Allograft rejection is a complex process which is due interaction of different cellular and molecular pathways leading to acute tubular injury, glomerulitis, and fibrosis.
Allograft rejection can be hyperacute, acute , late acute it can occur 3 months after transplantation, or chronic
Rejection can be classified also into cellular or AMR
Diagnostic criteria
SAB testing fordetecting HLA antibodiesand is diagnostic
CDC is still the standard for Ab detection.
EM for graft biopsies to detect the rejection changes.
Banff classification enhanced the sensitivity of diagnosing AMR and indicating graft survival outcome.
Acute Antibody-Mediated Rejection
According to the Banff 2013 classification those 3 features are needed for the diagnosis
1. Histologic evidence of acute tissue injury estimated by
: a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute TMA of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of recent antibody interaction with vascular endothelium, manifested by:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
According to the revised Banff 2013 classification,it needs 3 criteria :
1. Histologic evidence of chronic tissue injury, manifested by
a. Transplant glomerulopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis
2. Histologic evidence of antibody interaction with vascular endothelium, presented by:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Moderate microcirculatory changes
Introduced by Banff 2013 classification as highly suspicious for antibody injury. Vasculitis and increased number of inflammatory cells in the microcirculation indicate poor graft outcome.
Phenotypes of Antibody-Mediated Rejection In the 2011 Banff stated 2 phenotypes of acute AMR .
Phenotype 1 occurred during the early post transplant period in the presensitized cases .
Phenotype 2 existed due to of de novo DSAs in the late posttransplant period and it’s main reason is nonadherence or inadequate immunosuppression.
Subclinical Antibody-Mediated Rejection
Protocol biopsies revealed patients with histologic evidence of antibody-mediated injury despite stable creatinine, they have the worst graft survival at 8 years posttransplant.
C4d-Positive and C4d-Negative Rejection
C4d was a marker for antibody injury on the other hand C4d-negative rejection was detected with microcirculatory inflammation so it is now a poor indicator of AMR.
Orandi et al found that rejection occurred earlier in patients with C4d positive AMR cases then C4d negative AMR cases and the former group had worse graft survival.
Antibody-Mediated Vascular Rejection
Endarteritis is accompanied with cellular rejection; studies showed that vasculitis occur in both T cell– mediated rejection and AMR
Non-HLA Antibody-Mediated Rejection
It has 2 categories:
-alloantibodies directed against polymorphic antigens of the donor
-antibodies that recognize self-antigens or autoantibodies.
Angiotensin type I receptor and endothelin type A receptor antibodies are markers of endothelial injury as mentioned in some studies.
Loupy et al demonstrated that patients with donor-specific anti-HLA antibodies with complement binding capacity had lower graft survival .
Transplant Glomerulopathy
Presented by glomerular basement membrane duplication, double contouring, or splitting.
It is associated with proteinuria and with denovo or prexsiting DSA.
It indicates a late stage of antibody-mediated injury that is irreversible and is of poor graft survival.
Antibody removal for highly sensitised patients
Desensitization is done through immunomodulating therapies to decrease levels of anti-HLA antibodies enabling tranplanation.
High-Dose IVIG
It acts through inhibition of T cell proliferation, and inhibiting of cytokine synthesis, complement activation, and leads to blockade of alloantibodies.
It reduces anti-HLA antibody levels and improves transplantation rates in highly sensitized patients.
IVIG and Rituximab
It leads to B cell lysis by CDC and antibody-mediated cellular cytotoxicity. It blocks B cell activation and Ab forming plasma cells .
The combination of IVIG and rituximab was an effective desensitization regimen.
Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
It was concluded that the combination therapy was more effective rather than IVIG alone .
Immunoadsorption for Rapid Crossmatch Conversion
Was an effective method for desensitization in deceased-donor transplantation more than plasma exchange.
Treatment of antibody medicated rejection
Different treatment options are rabbit antithymocyte globulin, methylprednisolone, PLEX, IVIG, B cell–depleting agents, muromonab and maintenance therapy with CNIs, antiproliferative agents, and oral steroids.
Subclinical AMR was associated with increased risk of allograft loss.
Plasmapheresis
Slatinska et al mentioned that the combination of PLEX and IVIG gave better results than PLEX on it’s own.
Proteasome Inhibitor
Effectively reversed AMR , including reductions in DSA levels.
Complement Inhibition
eculizumab (anti-C5 monoclonal antibody) and a C1 esterase inhibitor (C1-INH), for complement inhibition.
Wongsaroj et al noticed that TMA patients recovered fully or partially after eculizumab while all TMA-positive patients treated with IVIG, rituximab, and PLEX experienced graft failure.
It was concluded that splenectomy plus eculizumab can be effective for preserving allograft function in early severe AMR cases.
Eculizumab usage before advanced renal injury can improve allograft survival.
Chronic Antibody-Mediated Rejection Treatment
Fehr et al demonstrated that steroid pulse ,rituximab then IVIG showed improved allograft function.
Biopsy-proven chronic AMR, treatment with steroids/IVIG was associated with improved graft survival.
Prevention of antibody mediated rejection
-C1q-fixing DSAs are an independent predictor of allograft loss.
-Djamali et demonstrated methods to prevent AMR, as avoiding transplantation for highly sensitized patients, assessing immunologic risk by detecting sensitive donor-specific anti-HLA antibody screening, involving highly sensitized patients in a paired kidney exchange program .
-Monitoring de novo DSAs, using class II HLA epitope matching, and performing protocol biopsies
-It was concluded that DSA can be detected before allograft affection.
-nonadherence to immunosuppressive therapy can lead to rejection
the level of evidence is level 2
Chronic Antibody mediated rejection remains the strongest barrier against favorable graft outcome.
In spite of advancement in the technology developed to detect HLA and non-HLA antigen, still we face a lot of cases of AMR with negative impact on graft survival.
It can be diagnosed clinically by rising serum creatinine and presence of proteinuria, and pathologically by graft biopsy by presence of transplant glomerulopathy TG proved by double contour, splitting or duplication of GBM.
Current treatment of AMR include plasmapheresis , immunoadsorption or immunomodulation, IVIg, rituximab, bortezomib which is proteasome inhibitor-based therapy, new agents like eculizumab (an anti-C5 monoclonal antibody).
Acute Antibody-Mediated Rejection According to the Banff 2013 classification, all of the following 3 features are required for the diagnosis of acute AMR:
1. Histologic evidence of acute tissue injury defined by the presence of one or more of the following: a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0)
b. Intimal or transmural arteritis (v >0)
c. Acute thrombotic microangiopathy (TMA) of no other obvious cause
d. Acute tubular injury of no other obvious cause
2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Chronic Antibody-Mediated Rejection
acute AMR has been shown to be a major risk factor for the development of chronic AMR.
According to the revised Banff 2013 classification, the diagnosis of chronic, active AMR requires 3 features:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg >0) in the absence of chronic TMA
b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in the peritubular capillaries
b. At least moderate microvascular inflammation (g þ ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Detection of DSAs (HLA or non-HLA) in the serum
Phenotypes of Antibody-Mediated Rejection In the 2011 Banff report:
1-presensitized patient and occurs in the early posttransplant period.
2- emergence of de novo DSAs in the late posttransplant period and is thought to be related primarily to nonadherence or inadequate immunosuppression.
C4d deposition and its importance
C4d is degradation from complement cascade activation and it is binds covalently to endothelium so its presence denoting complement binding DSA, and its non-presence indicate non-complement binding DSA, so it is poor marker to diagnose AMR.
Non-HLA AMR
It can be:
alloantibodies directed against polymorphic antigens that differ between the recipient and donor. or
antibodies that recognize self-antigens or autoantibodies.
angiotensin type I receptor and endothelin type A receptor antibodies have been implicated as markers of potential endothelial injury.
Desensitization protocols:
1- High-Dose Intravenous Immunoglobulin
2- Intravenous Immunoglobulin and Rituximab
3- Plasmapheresis, Intravenous Immunoglobulin, and Rituximab
4- Immunoadsorption
level of evidence II
· Q. Summary
· AMR leads to Chronic AMR rejection which is a major contribution of graft loss.
· Mechanism of AMR:
o B cell activation to antibody producing plasma cells (DSA) which can interact with endothelium and disrupt graft microcirculation (activation of cellular pathway).
o Also complement activation which is evidenced by (C4D deposition in ptc) which can recruit neutrophils, monocytes and macrophages and eventually cause graft damage.
· Source of antibodies:
o Preformed DSA in sensitized patients.
o De-novo DSA due to non -compliance to immunosuppressive therapy.
o Non –DSA developed against polymorphic epitopes or autoantibodies formed against endothelium (released self antigen after surgical trauma) as anti (angiotensin type 2 receptors and anti endothelin type A). No standardized method yet for their detection, but treatment the same as DSA.
· Phenotypes of AMR:
o Type 1= preformed DSA, occurs early post-transplant.
o Type 2= de nono DSA, occurs late post-transplant due to non adherence to maintenance immunosuppression.
· Timing of AMR:
o Hyper acute (within minutes/ on table)
o Acute (days or weeks )
o Late after 3 months and up to 1year post transplant.
o Chronic (months or years post-transplant): manifested by creeping creat and proteinuria, with poor long term outcome.
· Clinical presentation:
o Clinical (rising creat + proteinuria).
o Subclinical (detected in protocol biopsy) despite stable creat, no consensus about value of its treatment on long term outcome.
· Recent advances in diagnosis of AMR:
o Luminex SAB is best method to detect DSA in AMR and follow its titer after treatment.
o CDC cross match is best to detect preformed DSA.
o E/M is best and most sensitive for biopsy examination (early detection of AMR).
· Banff 2013:
o Incorporate serological (DSA ) and histology with immunohistochemistry to increase its sensitivity.
o In 2015, they incorporated (antibody reaction with endothelium) with histopathology and DSA in serum.
o Chronic AMR : detected by transplant glomerulopathy ,double contour of peritubular capillaries BM and intimal fibrosis+ DSA detected in serum.
· AMR according to C4d deposition in ptc:
o C4d +ve (evidence of antibody reaction with endothelium)
o C4d –ve: detected in 50 % of AMR (low sensitivity).
o AMR can be diagnosed in context of c4d –ve , in case of histopathological evidence of graft injury as (glomerulitis, peritubular capillaritis and TMA)
o C4 +ve more prone to occur earlier than c4d –ve.
o C4d positivity depends on:
§ Method used for detection (IF is more sensitive than immune-histochemisty).
§ C4d threshold.
o Use of molecular genetic endothelial markers may help in diagnosis of AMR (rather than c4d +ve)
· Any histopathological evidence of microvascular inflammation(even in single capillary) is considered marker of AMR
· Poor prognostic criteria of chronic AMR (associated with graft loss):
o Creat > 3 mg/dl
o Proteinuria (p/c ratio > 1 g/g)
o Chronicity > 8
o DSA with MFI > 2500
o
· Vascular injury vasculitis can be part of both TCMR and AMR. Evidenced by neutrophils infiltration under endothelium.
· Desensitization protocols in HLA and ABO incompatible transplantation:
o No consensus on best protocol.
o PEX is standard component of various regimens.
o PEX, IvIg ± rituximab (may be mostly utilized protocol till now).
o IvIg and rituximab.
o High dose IvIg.
o IA (single session pre and one session after transplant ): rapid removal of antibodies and avoid PEX side effects of plasma infusion.
o Desensitization protocols are very coasty and full of massive side effects as infections and malignancy, so better limited to those with high PRA > 90% and very prolonged time on waiting list.
o Best option for highly sensitized is paired kidney donation in living donor and KAS in deceased donor.
· Treatment of AMR:
o Not standardized, due to heterogeneous immunological risk of transients in various studies, induction and maintenance therapy.
o PEX followed by IVIG high dose ( 2g/kg) , with or without B cell depleting agent like rituximab or plasma cell depleting agent Bortezomib.
o Combination IVIG and PEX is preferred over monotherapy with either of them.
o In addition, modification of maintenance therapy like tacrolimus instead of ciclosporin, MMF replacing azathioprine or adding steroid in case of steroid free or minimization protocols, DSA monitoring and address the compliance with immunosuppression.
o Eculizumab (distal complement inhibition) and C1 esterase inhibitor (C1-INH), (proximal complement inhibition can be used in refractory AMR but very expensive.
· Prevention of AMR:
o Use best matched donor-recipient couples.
o Address compliance to immunosuppressive therapy especially in adolescents
o Denovo DSA monitoring monthly in highly sensitized and every 3 months early post transplant then every 6 months for early detection of AMR and timely intervention.
o Protocol biopsy to detect subclinical rejection.
Q. level of evidence: review article of cohort studies (level II)
ABMR is the commonest cause of graft loss
ABMR can be classified according to the time of detection into phenotype 1 which occur due to preformed DSA detected in the patient serum before transplantation and phenotype 2 which occur due to de novo DSA which is detected post-transplantation.
The incidence of occurrence of early ABMR with subsequent graft loss is markedly increased in the patients with preformed DSA, including those who received desensitization.
DSA either preformed or denovo attacks the endothelium of the graft leading to
• Acute ABMR
• Chronic ABMR
• Subclinical rejection
All cause subsequent reduction of graft survival
Risk factors for developing preformed DSA includes pregnancy, blood transfusion, previous transplant
The most important risk factors for developing denovo DSA are HLA mismatch and non-adherence to immunosuppressive medications
DSA can be directed to one of the following targets
• HLA antigens (HLA class I, II)
• Non- HLA antigens expressed on endothelial cells
Acute ABMR
Active ABMR occurs due to binding of circulating antibodies to donor alloantigens located on graft endothelium (HLA class I, HLA class II, ABO – antigens or non HLA antigens on endothelial cells)
Ag-Ab complexes activate classical complement pathway with final production of c5b, c3b, c3a, c5a leading to inflammation, cell damage and graft dysfunction
One of degradation products of classical pathwaty is C4b which is converted to C4d, the later binds covalently to endothelium of peritubular capillaries (PTCS) and act as a food print for complement activation and ABMR
3 components are required for the diagnosis of ABMR :
• Histologic evidence of acute tissue injury (peritubular capillaritis-ptc and/or glomerulitis-g, Intimal or transmural arteritis-v, TMA, ATN)
• Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or At least moderate microvascular inflammation (g + ptc >2)
The g score: according to percent of glomeruli involved: g1 =1%-25%, g2= 26%-50%, and g3= >50%.
• Serologic evidence of circulating DSAs
If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have ABMR, this means C4d staining can replace DSA, and C4d negative ABMR exists (ABMR without activation of complement cascade)
Patients with DSA who are C4d positive are 3 folds more common than C4d negative ones and tends to occur earlier than Cd negative ABMR
Patients with C4d positive ABMR has lower graft survival than those who are C4d negative, this means that it is a marker for severity and has prognostic implication. but C4d negative patients have higher rate of developing transplant glomerulopathy if untreated
Indications for treatment of ABMR
1- Presence of histologic features of ABMR plus either detection of circulating DSA or C4d staining even if creatinine is normal (subclinical ABMR)
2- Rapid increase of DSA with normal or near normal biopsy in in patients who received desensitization to render cross match negative
Current treatment
· Intensification of maintenance immunosuppression
· Decreasing inflammation produced by rejection: high dose steroids
· Decreasing production of antibodies (IVIG)
· Depleting B cells (rituximab)
· Removing DSA (6 sessions of plasmapharesis daily or every other day), better outcome if used early < 1 year post transplant
· 2nd line agents includes : Bortezomib and eculizumab which may have rule in treatment of acute resistant ABMR
Chronic active ABMR
Chronic ABMR is the most common cause of graft failure, tends to occur late > 6 months with or without previous history of acute ABMR
3 components are required for the diagnosis of chronic active ABMR :
• Histologic evidence of chronic tissue injury (transplant glomerulopathy-cg, multilayering of the PTC BM or chronic arteriopathy with fibrous intimal thickening) and no evidence of acute inflammation
• Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or At least moderate microvascular inflammation (g + ptc >2)
• Serologic evidence of circulating DSAs
If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have chronic active ABMR, this means C4d staining can replace DSA, and C4d negative chronic active ABMR exists
So evidence of chronic tissue injury with C4d staining in a patient with DSA and history of acute ABMR before is typical for chronic active ABMR
Transplant Glomerulopathy
· TG is an irreversible histologic finding that occur in late stages of ABMR, best diagnosed using EM
· Nearly around half of high risk transplant recipients will develop TG
· Present by gradual decline of renal functions together with proteinuria
· Once occur it indicate poor graft survival
Treatment of chronic active ABMR
No optimal treatment is set for chronic active ABMR, and treatment is difficult since there it is associated with irreversible tissue damage Current treatment is directed against the following:
· Intensification of maintenance immunosuppression
· Decreasing inflammation produced by rejection (high dose steroids)
· Decreasing production of antibodies (IVIG)
· Depleting B cells (rituximab)
· Removing DSA (plasmapharesis) play no rule in chronic active ABMR
· 2nd line agents includes : Bortezomib and eculizumab showed no benefit in treatment of chronic active ABMR
Prevention of ABMR:
1- Whenever possible avoid transplantation of HLA incompatible pairs
2- Always try to rely on finding compatible donor through kidney allocation system or KPD if the patient has living donor, and try to avoid desensitization
3- Desensitization is indicated if there is no living donor and the patient is highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
4- Several regimens are used for desensitization, the most effective is combination of plasmapheresis, low dose IVIG and Rituximab
5- Post-transplant monitoring including serial DSA levels, CNI level, and protocol biopsies
level of evidance 2