II. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
It is a meeting report and expert opinion with level 5 of evidence. Despite modern immunosuppression, ongoing kidney injury and graft loss due to alloantibody-induced immunity remains an important issue. Driving this response are polymorphic HLA antigens. By 10 years, after kidney transplantation, up to 25% have developed de novo DSA (dnDSA). AMR is the common cause of graft loss in different studies. Biology of the alloimmune response In alloimmune naive individuals, the generation of antibody-secreting cells follows a series of events that ultimately leads to T cell activation and generation of memory B cells, plasma blasts and long-lived plasma cells. In presensitized patients, robust long-lived plasma cells constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid anamnestic antibody response. Memory B cells are derived from B cells with receptors that are less mutated and of lower affinity than those that are destined to become plasma cells. the repertoire of plasma cells and the antibodies they produce are up to 100-fold more restricted compared with the repertoire of memory B cells. As a result, treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells. The ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of presensitized recipients. The diversity at the level of antibodies is another challenge. Diagnostic criteria and histological features of AMR The important findings of AMR based on Banff 2017 are: histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause; histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and the presence of circulating DSA, predominantly anti-HLA antibody. The more important histologic findings of AMR is MVI in the form of glomerulitis or peritubular capillaritis. However, peritubular capillaritis alone in the presence of TCMR is insufficient for diagnosis. Clinical phenotypes of AMR AMR can present with abrupt allograft dysfunction early posttransplant but can also have an insidious or subclinical onset, presenting later posttransplant. Considering the timing of presentation, and type of DSA (preexisting or de novo), in relation to the histological classification is recommended. Early posttransplant (<30 days) active AMR In case of performed DSA or immunologic amnestic response, early AMR can occur in 30-days post-transplant. This active form of AMR presents with an abrupt increase in DSA accompanied with allograft dysfunction. If untreated it can lead to cortical necrosis and graft loss within days. Late (30 days) post-transplant AMR with preexisting AMR Patients with performed DSA can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy. When detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present. MVI tends to persist and is later accompanied by chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering. Late (30 days) AMR associated with dnDSA The most common form of AMR is associated with dnDSA. dnDSA formation occur after 3 months post transplantation, and in the context of inadequate immunosuppression which can be due to patient nonadherence. This form is usually presents with allograft dysfunction and concomitant or preexisting TCMR. AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA. Features associated with reduced allograft survival in late AMR Chronic histological features such as the presence of transplant glomerulopathy (Banff cg score >0) and the degree of interstitial fibrosis and tubular atrophy are predictive of allograft failure. In addition, concomitant TCMR, C4d positivity, and vascular lesions (Banff cv score >0) are associated with inferior allograft survival. Allograft dysfunction at diagnosis, proteinuria, and time of diagnosis posttransplant are also predictive of outcomes. Additionally, C1q positive and anti-class II DSA are associated with poor outcomes. Initial assessment for anti-HLA DSA Donor and recipient HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events (previous transplant, blood transfusion, and pregnancy) are initial assessment of renal transplant candidate. Monitoring for de novo DSA Monitoring for dnDSA is recommended in the setting of immunosuppression reduction by physician for any reason, known patient medication nonadherence, or at the time of rejection episode (TCM or AMR). Interpreting positive DSA results Although SAB test is most important test for detection of DSA but has some limitations. The positive cutoffs is different between laboratories. SAB tests are also prone to interference from external substances, bead saturation, and “shared-epitope” phenomenon, which can lead to a falsely low MFI. Additional DSA testing for risk stratification Crossmatch testing can be used with SAB testing for AMR risk stratification. Testing to assess the complement binding ability of DSA (C1q or C3d) are associated with AMR. DSA IgG subclass testing has been used for research purposes. Treatment of active and chronic active AMR Plasma exchange and IVIG are used removing circulating DSA and reducing DSA production. They are regarded as a standard of care for acute active AMR. Complement system is an important contributor to AMR. The main goal of using complement inhibitors is to avoid the downstream damage to the allograft from DSA. Eculizumab results in terminal complement blockade as a monoclonal antibody targeting C5. Despite prevention of early active AMR, the long-term incidence of chronic AMR and allograft survival is not affected by Eculizumab therapy. Rituximab, a B-cell–depleting agent, was suggested as a treatment option. Rituximab as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients. Imlifidase, an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA. Although data are lacking for using IdeS in AMR, this agent has been used safely in highly sensitized individuals for desensitization. After administration of IdeS, all previously positive crossmatches became negative. Antithymocyte globulin (ATG) or other T-cell–depleting antibodies have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. no benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy. Surgical splenectomy, splenic embolization, and splenic radiation has been used as a salvage procedure for severe early AMR. Bortezomib, a proteasome inhibitor, have no beneficial effect on treatment of AMR when it is used alone. Tocilizumab, an IL-6 inhibitor, is suggested as an option for IVIG and rituximab unresponsive AMR. Consensus for treatment of early active AMR The combination of PLEX, IVIG with corticosteroids could be regarded as standard of care. The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability. Consensus for treatment of late active and chronic active AMR Among patients with known preexisting DSA and active AMR without chronic features, PLEX, IVIG, and corticosteroids are recommended. The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR. Optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control are recommended. AMR in the setting of dn DSA is often initially detected with concomitant TCMR. The standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence. Treatment of concomitant TCMR is also recommended. PLEX, IVIG, and Rituximab is used in some centers.
Sahar elkharraz
2 years ago
Risk of AMR still remain problem Despite improving of immunosuppressive drug due to polymorphism of HLA antigen matching and protocol of renal biopsy may help to detect sub clinical rejection before clinical symptoms occur but still no specific guidelines help in diagnosis and prevention of AMR and specific protocol to prevent and treated AMR.
MICHAEL Farag
2 years ago
Summarise this article
What is the level of evidence? level V
INTRODUCTION
Despite modern immunosuppression, ongoing kidney injury and graft loss due to alloantibody-induced immunity remains an important issue. By 10 years, after kidney transplant, up to 25% have developed de novo DSA (dnDSA).5 Thus, it is not surprising that AMR was the most common cause of allograft failure in a cohort of renal transplant recipients with indication biopsies before graft failure.
Given the scope and severity of the problem, it is unfortunate that there are no commonly accepted guidelines for treatment. To date, clinical trials of AMR have been small or inconclusive, and there are no Federal Drug Administration (FDA)-approved therapies for the prevention and treatment of the condition. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
The salient features of active AMR based on the Banff 2017 classification14 are
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause;
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and
(3) the presence of circulating DSA, predominantly anti-HLA antibody
Clearly, the main histological manifestation of active AMR in renal allografts is MVI in the form of glomerulitis (g) and peritubular capillaritis (ptc). The presence of either (g + ptc > 0) satisfies criterion 1, and a (g + ptc) sum score of ≥2 also satisfies criterion 2. The exception is that peritubular capillaritis alone is insufficient for diagnosis in the presence of T-cell–mediated rejection (TCMR), including borderline rejection. Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the context of glomerulitis and thrombotic microangiopathy. To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR. Signs of chronic tissue injury include transplant glomerulopathy (Banff chronic glomerulitis [cg] score > 0), severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause. CLINICAL PHENOTYPES OF AMR The Banff classification has 3 AMR diagnostic categories (including chronic AMR with transplant glomerulopathy and current or prior DSA but no MVI or C4d file:///C:/Users/micha/AppData/Local/Temp/msohtmlclip1/01/clip_image002.jpg AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR As recommended by guidelines,56 most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies file:///C:/Users/micha/AppData/Local/Temp/msohtmlclip1/01/clip_image004.jpg
Assafi Mohammed
2 years ago
Despite the scope and severity of AMR, there is no approved therapy nor guidelines to direct the management plan. Transplantation society gathered expertise from all around the world to create a consensus to guide the Management of AMR. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR: based on the Banff 2017 classification
Evidence of tissue injury
Evidence of antibody-endothelial interaction
Evidence of circulating DSA
CONSENSUS FOR MEASURING AND MONITORING OF DSA:
obtaining a history of allo-sensitizing events
Initial Assessment for Anti-HLA DSA for donors and recipients
The first-line screening for allo-antibody would be with single-antigen bead (SAB) solid-phase assays to b the first line screening for allo-antibody.
Monitoring for De Novo DSA in the setting of rejection, non-adherence to medication and immunosuppression reduction.
Interpreting Positive DSA Results
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Plasma Exchange and IVIG.
Complement Inhibitors eg;Eculizumab
Rituximab; a B-cell–depleting agent
Imlifidase, an IgG-degrading enzyme of Streptococcus pyogenes (IdeS)
Antithymocyte Globulin
Splenectomy
Proteasome Inhibitor: Bortezomib
Cyclophosphamide
Interleukin-6 Inhibitors
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
The consensus view was that the combination of PLEX, IVIG with corticosteroids could be regarded as standard of care.
The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability.
Where TCMR is present, it should be treated.
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Preexisting DSA: the consensus treatment recommendations include PLEX, IVIG, and corticosteroids.
De Novo DSA: concomitant TCMR is oftenly detected with de novo DSA, so treatment for TCMR should combine AMR treatment in this setting.
Level of evidence: expertise opinion( level 5)
Alyaa Ali
2 years ago
AMR is a major cause of allograft failure. Antibody-mediated damage caused allograft dysfunction late post-transplant in about 60% of renal transplant patients.
there are no standard management for AMR. Biology of the allo-immune response
The development of antibody secreting cells, starts with the initial encounter of alloantigen with B cells, which activates B-cell migration to the T- and B-cell interface in the lymph node, where it receives help from alloreactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells. Some of B cells differentiate into memory B cells or short-lived plasmablasts, while the rest enter into germinal centers to emerge as high-affinity and class switched memory B cells, plasmablasts, and long-lived plasma cells. Presensitized individuals have a robust long-lived plasma cells
constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid antibody response. Diagnostic criteria and histological features of AMR
The salient features of active AMR based on the Banff 2017 classification are:
Histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause;
Histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI;
The presence of circulating DSA, predominantly anti-HLA antibody
The main histological manifestation of active AMR in renal allografts is MVI in the form of glomerulitis (g) and peritubular capillaritis (ptc).
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR. Clinical phenotypes of AMR Early post-transplant (<30days) active AMR
Early post-transplant AMR occurs in up to 40% of patients with preformed DSA and
a positive flow cytometric crossmatch.
It typically presents with an abrupt increase in DSA accompanied by allograft dysfunction
If not recognized and treated quickly, it can lead to cortical necrosis and allograft loss within days. Late (>30 days) post-transplant AMR With preexisting DSA
Indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy for mild allograft dysfunction. Late (>30 days) AMR associated with dnDSA
dnDSA is a new DSA detected after >3 months post-transplant in the context of inadequate immunosuppression. It presents with allograft dysfunction and concomitant or preexisting TCMR.
studies suggested that AMR with dnDSA is associated with inferior allograft survival
when compared with AMR from preexisting DSA.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Treatment studies for AMR are rarely comparable,and the available evidence is generally of low quality.
Most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies) Plasma Exchange and IVIG
This treatment regimen is most commonly used to treat active AMR, although frequency, modality, and dosing may vary
(KDIGO) in 2010 suggest that PLEX and IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy.
the studies demonstrated their ability to improve short-term outcomes , while their results on long-term effects remain variable, emphasizing the need for new alternatives or adjunctive therapy for the treatment of AMR. In addition, there is a need to better
define the amount of PLEX and dosing of IVIG.
The rationale for using PLEX and IVIG is to combine
removal of circulating DSA with immunomodulation of the antigraft immune response and in particular modulation of the B-cell response. Complement inhibitors
The main goal of using complement inhibitors is to avoid the downstream damage to the
allograft from DSA.
Eculizumab results in terminal complement blockadeas a monoclonal antibody targeting C5.
one study showed that among patients who received positivecrossmatch HLA-incompatible transplants, the incidence of early active AMR was decreased from approximately 40% in historical controls to 7% among treated patients.Despite these promising results, long-term follow-up of eculizumab-treated positive crossmatch patients in a single-center study has shown that despite prevention of early active AMR, the long-term incidence of chronic AMR and allograft survival is comparable to historical controls. Rituximab
Rituximab, a B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines. Despite its frequent use, the evidence is low and 3 small randomized
trials have investigated its utility without demonstrating a clear benefit
a single-center non randomized study suggests that Rituximab as an add-on therapymay prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.but the doses and number of cycles is uncertain. Imlifidase An IgG-degrading enzyme of Streptococcus pyogenes (IdeS) that can rapidly
reduce or even eliminate anti-HLA DSA .
unfortunately 7–10 days of administration, patients often experience a rebound in DSA and anti-IdeS antibodies develop after 1 or 2 doses, thereby preventing repeated administrations. Thus, IdeS will unlikely be an isolated treatment for active
or chronic active AMR, but rather an adjunct to other therapies aiming to reduce DSA in the long term. Anti-thymocyte globulin
Although depleting antibodies were proposed by KDIGO guidelines as potential treatmentoptions, no benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy. Splenectomy
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR. It must be performed
rapidly after the onset of early AMR to be effective. Bortezomib
is a proteasome inhibitor that directly targets antibody-producing plasma cells making it an attractivecandidate for the treatment of active AMR. Data supporting its use are limited to case series suggesting a positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting antibodies. Cyclophosphamide
Previous anecdotal reports describe its use within a multimodal treatment regimen for
the treatment of refractory rejections. While it is relatively inexpensive, there are no trial data to support its use. Interleukin-6 Inhibitors
A single-center, nonrandomized trial of tocilizumab (anti-interleukin-6 receptor monoclonal antibody) was undertaken in 36 patients with chronic active AMR that had failed IVIG plus rituximab. Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function.
INTRODUCTION: There are no commonly accepted guidelines for treatment of ABR, though the PROBLEM IS COMMON. By 10 years, after kidney transplant, up to 25% have developed de novo DSA. Thus, it is not surprising that AMR was the most common cause of allograft failure Caused allograft dysfunction late posttransplant in nearly 60% of renal transplant recipients. BIOLOGY OF THE ALLOIMMUNE RESPONSE: The initial encounter of alloantigen with B cells expressing the appropriate BC This event activates B-cell migration to the T- and B-cell interface in the lymph node, Where it receives help from alloreactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells. Some of B cells differentiate into memory B cells or Short-lived plasmablasts, while the rest enter into germinal centers to emerge as high- Affinity and classe witched memory B cells, plasmablasts, and long-lived plasma cells. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR: Based on the Banff 2017 classification are: (1) Histologicalevidence of graft injury: -microvascular inflammation (MVI). – Intimal or transmural arteritis (v > 0). – Acute thrombotic microangiopathy. -or acute tubular injury. 2) Histological evidence of antibody-endothelial interactions either by C4d deposition or At least moderate MVI; and 3) The presence of circulating DSA, predominantly anti-HLA antibody. Chronic active AMR, morphological features of chronic tissue injury are present in Addition to criteria 2 and 3 for active AMR. CLINICAL PHENOTYPES OF AMR: AMR can present with abrupt allograft dysfunction early posttransplant but can also have An insidious or subclinical onset, presenting later posttransplant. Early Posttransplant (<30 Days) Active AMR> (<30 Days) Active AMR>less than 30 Days) active AMR: OCCURE IN 40%.MORE WITH HIGH PRETRANSPKANT DSA and positive FXCM. Typically presents with an abrupt increase in DSA accompanied by allograft dysfunction (Increased creatinine and oliguria with or without proteinuria). Late (>30 Days) Posttransplant AMR with Preexisting DSA Indolent . progressive form of AMR. Late (>30 Days) AMR Associated With dnDSA: The most common form of AMR is associated with dnDSA. In general, dnDSA is a new DSA detected after >3 months posttransplant in the context Of inadequate immunosuppression. Often presents with allograft dysfunction and concomitant or preexisting TCMR. Associated with inferior allograft survival when compared with AMR from preexisting DSA. AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR: Most studies describe the use of a variable mix of interventions (egg, variable intensity of Plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of Steroid pulses together with or without different T-cell–depleting and B-cell–depleting Antibodies. Plasma Exchange and IVIG: Regarded as a standard of care for acute active AMR BY FDA Antibody-Mediated Rejection Workshop in 201767 as well as KDIGO. Low evidence. Complement Inhibitors: Eculizumab results in terminal complement blockade as a monoclonal antibody Targeting C5. Among patients who received positive crossmatch HLA-incompatible transplants, the Incidence of early active AMR was decreased. Long-term follow-up of Eculizumab-treated positive crossmatch patients in a single- Center studyhas shown that despite prevention of early active AMR, the long-term Incidence of chronic AMR and allograft survival is comparable to historical controls. Proximal complement inhibition: Has also been studied as a therapeutic target. The plasma C1 esterase inhibitors Berinert (CSL Behring) and Cinryze (Takeda/Shire/ ViroPharma) have been tested in 2 Pilot studies and indicate a possible improvement in allograft function in kidney Recipients with AMR. Rituximab: A B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines. Despite its frequent use, the evidence is low and 3 small randomized trials have Investigated its utility without demonstrating a clear benefit. Some positive effects of Rituximab in multimodal treatment regimens together with steroids, plasmapheresis, and High-dose IVIG, especially on patients with vascular AMR. Imlifidase: An IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or evenEliminate anti-HLA DSA. it has been used safely in highly sensitized individuals for Desensitization. An adjunct to other therapies aiming to reduce DSA in the long term. The unique feature of this drug is that it permits any highly sensitized patient to undergo Transplantation within hours of a donor being identified regardless of the crossmatch Status. Antithymocyte Globulin: No benefit has been demonstrated for treatment of pure AMR with T-cell–depleting Therapy. Splenectomy: There are several case series of surgical splenectomy, splenic embolization, and splenic Radiation being used as a salvage procedure for severe early AMR. Proteasome Inhibitor: Bortezomib: Data supporting its use are limited to case series suggesting a positive Effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting Antibodies. Side effect preclude its use. Cyclophosphamide: There are no trial data to support its use. Interleukin-6 Inhibitors: Tocilizumab (anti-interleukin-6 receptor monoclonal antibody) was undertaken in 36 Patients with chronic active AMR that had failed IVIG plus rituximab. Patient and graft survival at 6 years (91% and 80%, respectively) were found to be Superior to historical controls, with significant reductions in DSA and stabilization of renal Function. Clazakizumab, an anti-interleukin-6 monoclonal antibody, is evaluating now for the Treatment of chronic active AMR. CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT): Preexisting DSA (or no immunologically naïve) Active AMR: Plasmapheresis (daily or alternative day × 6 based on DSA titer) (1C) IVIG 100mg/kg after each plasmapheresis treatment or IVIG 2 g/kg at end of Plasmapheresis treatments (1C) Corticosteroid. Consider adjunctive therapies: Complement inhibitors (2B) Rituximab 375mg/m2 (2B) Splenectomy Late (>30 days posttransplant) Preexisting DSA Active AMR Plasmapheresis (daily or alternative day × 4–6 based on DSA titer) (2C) IVIG 100mg/kg after each plasmapheresis treatment or IVIG 2 g/kg at end of Plasmapheresis treatments (2C) Corticosteroids. Consider adjunctive therapies: Rituximab 375mg/m2 (2B). De novo DSA Active AMR Optimize baseline immunosuppression (egg, add steroids if on A steroid-free regimen) (1C) Evaluate and manage nonadherence. Consider adjunctive therapies: Plasmapheresis and IVIG (3C) Rituximab. Chronic AMR: Optimize baseline immunosuppression (egg, add steroids if on a steroid-free regimen) Consider adjunctive therapies: IVIG CONCLUSIONS: The consensus opinion of those present at the meeting was based largely on Observational studies, low-level evidence, and expert opinion. Further studies are Needed. Level of evidence 5.
mai shawky
2 years ago
Summary
The 2019 Transplantation Society Working Group consensus guidelines of ABMR:
• ABMR is a major cause of allograft loss.
• the advances in immunology to detect anti HLA antibodies and understanding in histopathological diagnosis made the ABMR a well-recognized problem.
• Diagnosis of acute ABMR requires:
o Evidence of tissue damage as microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic micro-angiopathy (TMA), ATN (acute tubular necrosis), after exclusion of any other causes.
o Circulating DSA.
o Positive c4d.
• Diagnosis of chronic active ABMR requires:
o Evidence of chronic tissue damage as transplant glomerulopathy (Banff chronic glomerulitis [cg] score > 0), multilayering of the peritubular capillary basement membrane on E/M, or new arterial intimal fibrosis without another obvious cause.
o Circulating DSA.
o Positive c4d.
• Clinical phenotypes of ABMR:
o Early post-transplant ABMR: during 1st month- post transplant due to pre-existing DSA, positive cross match, uncommon as those cases are not 5transplanted without desensitization. prognosis depends on the degree and strength of antibody positivity.
due to memory B cell.
Presented with increasing titer of DSA, oliguria, graft dysfunction with or without proteinuria.
Early appropriate treatment can reverse histological damage completely. However, inappropriate treatment can turn it into chronic active ABMR with worse graft outcome.
Inappropriate or delayed treatment leads to graft loss within days.
o Late ABMR with pre-existing DSA
Less aggressive form, not presented early.
due to pre-existing plasma cell response.
mild or no graft dysfunction.
Aggressive but indolent course, progressive proteinuria and GFR decline till graft loss years post transplantation.
Diagnosis by protocol biopsy.
Inappropriate or delayed treatment leads to graft loss within months to years.
o late ABMR with de novo DSA:
Occurs late (more than 1 month-post transplantation).
Most common.
Formation of de novo dsa.
Main cause is inadequate therapy and non adherence (predicted from prior non adherence to CKD medications).
Worse graft outcome than those with pre-existing DSA.
• Poor prognostic factors of late ABMR (either with pre-existing or de novo DSA):
Histological markers of chronicity as tubular atrophy, transplant glomerulopathy and interstitial fibrosis.
Presence of vascular injury, c4d positive and concomitant TCMR.
Graft dysfunction and marked proteinuria.
C1q positive DSA34,35,52 and anti class II DSA and the level or strength of DSA.
• Screening for pre-existing DSA by solid phase SAB luminex is essential, and for sensitized persons we need 4 digit or high resolution antibody screening.
• Screening for de novo DSA: done prior to reduction of therapy, at time of reduction or regular screening in highly sensitized patients.
• Positivity of DSA by SAB is variable between labs (no definite cut off point). However, general saying that MFI > 1500 may be significant.
• Positive complement-dependent cytotoxicity (CDC) crossmatch is at higher risk of rejection than positive flow cytometric crossmatch than negative crossmatch.
• Treatment of acute ABMR and chronic active ABMR;
Usually mix of pulse steroids, IVIG, PEX and B , T cell depleting agents.
Most common is PEX to remove DSA and IVIG to abolish their effects and modulate B cell response, as recommended by the KDIGO 2010. however, the number of PEX sessions and dose of IVIG are not well defined.
Ecluizimab (inhibit last step of complement activation) may be beneficial in acute ABMR, but long term effect on the incidence of chronic active ABMR and graft survival need further studies.
Rituximab may be beneficial, but low evidence exist and appropriate dose is still unknown and needs further justification.
New therapeutic options as Ides, bortezomib are still under investigations and need longitudinal follow up studies. till now used as adjuvant therapy.
Ides effectively cleave human IgG and inhibit both CDC and antibody-dependent cellular cytotoxicity, mainly used for desensitization (not in ttt of acute ABMR). the main drawbacks are the rebound in DSA and development of anti-IdeS antibodies after 1 or 2 doses, so can not be given repetitively.
ATG (T cell depleting agent) used in steroid refractory TCMR, vascular rejection and mixed rejections, but not effective in pure ABMR.
Proteasome Inhibitor: Bortezomib (directed against plasma cells), 1st described in multiple myeloma (used now combined with other thaerpies).
Cyclophosphamide (1st used in ANCA vasculitis and proliferative lupus nephritis) can be used as adjuvant in refractory rejection.
Tocilizumab (anti-interleukin-6 receptor monoclonal antibody) may be beneficial in chronic active ABMR.
Conclusion consensus guidelines for acute ABMR:
o Standard ttt of acute ABMR is combination of PLEX, IVIG with corticosteroids plus or minus other adjuvants.
o The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability.
o Concomitant TCMR should be treated.
Conclusion consensus guidelines for chronic active ABMR:
o Combined PLEX, IVIG, and corticosteroids is the standard (in absence of any evidence of chronicity).
Conclusion consensus guidelines for chronic ABMR:
o Just optimization of maintenance therapy.
o Return to steroids in steroid free regimen.
o control systemic diseases as DM and hypertension.
o The aim here is just to delay progression of graft dysfunction by conservative management.
o Avoidance of aggressive immunosuppressive therapy that can cause hazardous adverse effects without benefit.
Level of evidence
consensus or expert opinion (level Iv) , as it based on reviewing multiple case control studies.
Last edited 2 years ago by mai shawky
Ahmed Omran
2 years ago
Expert consensus: level of evidence 4/5 Measuring and Monitoring of DSA
Initial assessment for DSA should include HLA typing, anti-HLA ab screening, history of sensitization .SAB solid phase assay must be implemented.
Antibody screening ; should be done by SAB solid phase assay.
In case of decreased immune-suppression and rejection, de novo DSA must be checked.
Interpreting positive DSA should consider that SAB is affected by factors like bead
saturation& shared epitopes. Dilution and EDTA are used to detect interference.
More DSA Testing for risk stratification depends on XM test, complement DSA binding, and IgG subclasses.. Treatment for early active AMR;< = 30 Days Post-transplantation :
Combination therapy :IVIG ,PE& steroids, adjuvant therapy ; implemented in case of risk of graft loss. and treatment of associated TCMR. Treatment of late active and chronic active AMR ; >=30 Days Post-transplantation:
In case of previous DSA , following to be implemented
Stabilize or retardation of rate of deterioration in GFR, proteinuria, and control of pressure, blood sugar, and dyslipidemia.
Tac > 5 ng/ml
In case of de Novo DSA , the following must be implemented:
Optimization of immune-suppression
Treatment of associated TCMR
To Conclude: This is a consensus expert opinion on observational studies basis, with low level evidence. Other larger scale studies are needed.
Wee Leng Gan
2 years ago
Recommended Treatment for Antibody-mediated Rejection ( AMR ) After Kidney Transplantation: The 2019 Expert Consensus From the Transplantation Society Working Group.
Pathogenesis
Plasma cell in pre sensitized kidney transplant recipients continuously produce anti HLA antibodies. Stimulation of resting plasma B cell upon antigens exposure.
Classification Base on Duration Post Transplant as Suggested by Transplant Society Working Group.
1) Early ( Acute )
Less then 30 days after transplant, usually first 10 days post transplant.
Due to memory B-cell response towards DSA.
Sudden graft dysfunction post transplant.
Treatment : 6 cycles of plasmapheresis base on DSA titer / IV IG / Steroid.
Treatment : Plasmapheresis 4-6 cycles depend on DSA titers, IV IG, Steroid if on non-steroid regimen.
Adjuvant therapy : Active AMR; Rituximab. Chronic AMR ; IV IG.
Evaluate and manage compliant issue.
Furthermore, consensus opinion suggested management should focus on optimizing immunosuppression keep tacrolimus level at least 5 ng/mL with steroids (if on a steroid-free regimen). Regular monitor blood pressure, blood glucose, and lipid level is essential.
In conclusion, this is level 4-5 evidence articles which solely base on expert opinion. Individualization in the management of AMR is the key for better outcome.
manal jamid
2 years ago
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
Meeting was being organized by Transplantation Society, participant are international experts The aim is to develop a consensus for appropriate treatment of active and chronic active AMR.
They discussed, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes.
Despite modern immunosuppression AMR was the most common cause of allograft failure
Understanding of complexity of immune system is essential to understand the different presentations of AMR and potential treatment options. BIOLOGY OF THE ALLOIMMUNE RESPONSE
starts when alloantigen encounter with B cells which expressing the appropriate B-cell antigen receptor leads to the activation of B-cell migration to the T- and B-cell interface in the lymph node, where it receives help from alloreactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells. Some of B cells differentiate into memory B cells or short-lived plasma blasts, while the rest enter into germinal centers to emerge as high-affinity and class switched memory B cells, plasma blasts, and long-lived plasma cells, secreting anti-HLA antibodies. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
Based on the Banff 2017 classification are
(1) histological evidence of graft injury.
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI
(3) the presence of circulating DSA. CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories including
1. Abrupt allograft dysfunction early post-transplant.
2.Insidious or subclinical onset.
3. late post-transplant.
Anti-HLA antibody can be present before transplant (preexisting DSA) or develop after transplant (dnDSA) in the setting of under-immunosuppression. In some circumstances, the histological features suggestive of AMR are present, but anti-HLA antibody is not detected. Early Post transplant (Abrupt) active AMR occurs within 30 days, preexisting measurable DSA or immunologic amnestic response due to previous exposure to allo-antigens. The risk increases with DSA (MFI), the degree of positive flow cytometry cross match, and the number or breadth of cross-reactive DSA specificities, Pathophysiology memory B cell response
the criteria for Banff active AMR, C4d is usually positive and thrombotic micro angiopathy usually present. with prompt diagnosis and treatment, patients can recover allograft function and histological features of active AMR frequently resolve. Late (>30 Days) Post transplant AMR with Preexisting DSA
Usually There are preexisting DSAor Denovo antibodies
Banff 2017 classification of active or chronic active AMR with C4d staining may or may not be present, concomitant TCMR are often present.
Clinical presentation: allograft dysfunction and proteinuria due to pre-existing plasma response or under immunosuppression (Denovo Abs), prognosis graft loss within months to year Features associated with reduced allograft survival in late AMR (Preexisting or Dee novo antibodies)
Chronic histological features of transplant glomerulopathy (Banff cg score >0), the degree of interstitial fibrosis and tubular atrophy, concomitant TCMR, C4d positivity, vascular lesions (Banff cv score >0), and clinical factors such as graft dysfunction at diagnosis, proteinuria, and time of diagnosis post-transplant, under-immunosuppression, medication non adherence, C1q positive DSA, titer and MFI with C1q positivity cross match and anti-class II DSA. CONSENSUS FOR MEASURING AND MONITORING OF DSA
The essential immunological workup of recipient and donor are Molecular typing for HLA includes A; B; C; DRB1; DRB3, DQA1/DQB1; and DPA1/DPB1
Obtaining a history of allo sensitizing events, and screening for anti-HLA antibody
by high-resolution level (“4-digit” typing) screening for alloantibody would be with single-antigen bead (SAB) solid-phase assays or multi antigen beads. Patients with no history of allo sensitizing events, negative anti HLA antibody are at low risk for AMR.
Monitoring for dnDSA is recommended in the following settings: immunosuppression reduction by physician for any reason, patient medication non adherence, or at the time of rejection (T cell or antibody mediated.
The presence of dnDSA is indicator of under-immunosuppression so reevaluation of maintenance immunosuppression is needed., close monitoring of allograft function and kidney biopsy is also recommended to detect T-cell or AMR (clinically evident or subclinical).
Interpreting Positive DSA Results
Positive cut off MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies. But false low MFI can present due to external substances, bead saturation, and “shared-epitope” phenomenon, which need serum dilution or using ethylene diamine tetra acetic acid. for Risk Stratification cross matching plus SAB are used.
Risks of AMR from highest to lowest based on cross match and SAB-positive testing are the following: positive complement-dependent cytotoxicity (CDC) cross match, positive flow cytometry cross match, and negative cross match, Importantly, hyper acute AMR is also associated with having a positive CDC cross match. EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Challenges of treatment of AMR are due to Small and heterogeneous available studies. As recommended by guidelines the use of a variable mix of interventions (e.g., variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies treatment effects. plasma exchange (PLEX) and IVIG
It is the most common regimen used for removing circulating DSA and reducing DSA production. Recommended by FDA 2017 in combination with low- or high-dose IVIG (immunomodulation) and by KDIGO 2010 for PE and IVIG in association with corticosteroids, its regarded as a standard of care for acute active AMR. Complement Inhibitors
Through which we can avoid the downstream damage to the allograft from DSA.
Eculizumab is a monoclonal antibody results in terminal complement blockade as a targeting C5
Many studies confirmed the protective effect of eculizumab for preventing early active AMR in positive cross match HLA-incompatible living and deceased donor populations. Rituximab
B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines.
Several retrospective analyses have suggested some positive effects of rituximab in combination with steroids, plasmapheresis, and high-dose IVIG, especially on patients with vascular AMR
A single-center study suggests that Rituximab as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.
In 3 small randomized trials its utility investigated without demonstrating a clear benefit. Imlifidase
An IgG-degrading enzyme can rapidly reduce or even eliminate anti-HLA DSA and is undergoing clinical trials in AMR. Anti thymocyte Globulin
T-cell–depleting antibodies used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. proposed by KDIGO guidelines as potential treatment options no benefit has been demonstrated for treatment of pure AMR, Side effects (higher risk of infectious-associated death), particularly when its combined with B-cell depletion. Splenectomy
It must be performed rapidly after the onset of early AMR Proteasome Inhibitor: Bortezomib
It has positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting antibodies. Cyclophosphamide
Its use within a multimodal treatment regimen for the treatment of refractory rejections. While there are no trial data to support its use. Interleukin-6 Inhibitors
Tocilizumab (monoclonal antibody) traid in patient with chronic active AMR. CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
The combination of PLEX, IVIG with corticosteroids regarded as standard of care, with adjunctive therapy with other agents such as complement inhibitors, Rituximab 375mg/m2 and Splenectomy depending on availability, where concomitant TCMR is present, it should be treated CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT) Preexisting DSA.
With preexisting DSA and active AMR, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids plus adjuvant (Rituximab 375mg/m2) chronic active AMR or chronic transplant vasculopathy,
Goals of therapy should be to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, and titer of DSA while minimizing drug toxicity. The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR De Novo DSA
AMR in this setting is initially detected with concomitant TCMR. the standard management is to optimize baseline immunosuppression and manage potential medication non adherence. Treatment of concomitant TCMR is recommended treatment with PLEX, IVIG, and Rituximab is used in some centers, although the evidence level is low. CONCLUSIONS
There were no clear treatment regimens to recommend and there are no approved treatments. The consensus opinion of those present at the meeting was based largely on observational studies, low-level evidence, and expert opinion.
level of evidence 4/5 , based on expert opinion
CARLOS TADEU LEONIDIO
2 years ago
Summarise this article
This publication is a summary of that meeting and includes up-to-date information about the pathogenesis of the condition, the criteria for diagnosis, prognosis, and long-term outcome.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
In alloimmune naive individuals, the generation of antibody-secreting cells follows a scripted series of checkpoint events involving T- and B-cell interface. And in the context of transplantation, presensitized individuals have a robust long-lived plasma cells constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid anamnestic antibody response. For this second the differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells. Likewise, the absence of DSA does not imply the lack of memory B cells and the potential for an anamnestic response. Thus, the ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of presensitized recipients susceptible for an active AMR early posttransplant.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
The salient features of active AMR based on the Banff 2017 classification are: (1) histological evidence of graft injury via microvascular inflammation (MVI); (2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and (3) the presence of circulating DSA, predominantly anti-HLA antibody.
Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the context of glomerulitis and thrombotic microangiopathy. To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR.
CLINICAL PHENOTYPES OF AMR Further complicating the diagnosis and management of AMR are various clinical phenotypes: – abrupt allograft dysfunction early posttransplant – insidious or subclinical onset, presenting later posttransplant – Anti-HLA antibody can also be present before transplant (preexisting DSA) – Anti-HLA develop after transplant (dnDSA) in the setting of under-immunosuppression – histological features suggestive of AMR are present, but anti-HLA antibody is not detected.
Incorporating these clinical features of AMR into the current Banff classification while considering the likely underlying immunologic mechanisms is critical to appropriately guide therapeutic decisions and ultimately design efficient and effective therapeutic clinical trials.
A – Early Posttransplant ( < 30 days) active AMR
This aggressive form of active AMR typically presents with an abrupt increase in DSA accompanied by allograft dysfunction (increased creatinine and oliguria with or without proteinuria). If not recognized and treated quickly, it can lead to cortical necrosis and allograft loss within days.
From a histological perspective, the criteria for Banff active AMR are met and C4d is usually positive. There is often interstitial hemorrhage, glomerular fibrin thrombi, and microvascular coagulative necrosis. With prompt diagnosis and treatment, patients can recover allograft function and histological features of active AMR frequently resolve completely.
B – Late ( > 30 days) Posttransplant AMR With Preexisting DAS
While many patients with preexisting DSA do not develop an aggressive early AMR as described above, they can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy (in the setting of stable function) or on a for-cause biopsy for mild allograft dysfunction. Histological findings are dependent on the timing of the biopsy.
C- Late (>30 Days) AMR Associated With dnDSA
In the current era of sensitive DSA testing and a general avoidance of preexisting DSA, the most common form of AMR is associated with dnDSA. In general, dnDSA is a new DSA detected after >3 months posttransplant in the context of inadequate immunosuppression which is either due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs. This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR. In patients who have routine surveillance DSA testing or surveillance biopsies, the presentation can be more indolent and is similar to that of late posttransplant AMR in patients with preexisting DAS. Results from 2 recent studies have suggested that AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA after adjusting for clinical, histological, and immunologic characteristics.
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA) The histological, clinical, and alloantibody features associated with reduced allograft survival are similar between them. Allograft histology is key to document the chronicity and extent of injury. A – Are predictive of allograft failure: – Chronic histological features such as the presence of transplant glomerulopathy (Banff cg score >0) – the degree of interstitial fibrosis – tubular atrophy – concomitant TCMR -C4d positivity; – Vascular lesions (Banff cv score >0) Not surprisingly, clinical factors are also predictive of outcome including allograft dysfunction at diagnosis: -Proteinuria; – Time of diagnosis posttransplant; CONSENSUS FOR MEASURING AND MONITORING OF DSA Initial Assessment for Anti-HLA DSA The first-line screening for alloantibody would be with single-antigen bead (SAB) solid-phase assays (LABScreen [one Lambda] or LifeScreen [LifeCodes-Immucor]), but multiantigen beads can also be used . Patients with no history of allosensitizing events and with negative anti-HLA antibody testing using single-antigen or multiantigen bead solid-phase assays are at low risk for AMR. Molecular HLA typing ideally includes A; B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; and DPA1/DPB1. Monitoring for De Novo DAS
Monitoring for dnDSA is recommended in the following settings: immunosuppression reduction by physician for any reason, known patient medication nonadherence, or at the time of rejection episode (T cell or antibody mediated).The presence of dnDSA is a general indicator of under-immunosuppression and signals the need to reevaluate maintenance immunosuppression.
Based on the strong relationship between dnDSA, AMR, and graft loss, transplant patients with dnDSA should undergo close monitoring of allograft function. A kidney biopsy is also recommended to detect T-cell or AMR (clinically evident or subclinical).
Interpreting Positive DSA Results
The SAB test detecting DSA has been an important advancement to the field; however, the test has limitations that must be identified for correct interpretation. Methods to identify interference and bead saturation include performing serum dilution or using ethylenediaminetetraacetic acid. We recommend the routine use of these methods in the following situations: transplant candidates/recipients who are not immunologically naive, unexpected positive crossmatch, or AMR with unexpectedly low DSA MFI.
Additional DSA Testing for Risk Stratification.
Remains unclear whether complement binding assays outperform antibody titers for AMR risk stratification. For this reason, we do not recommend routine use of complement binding assays unless it is used as a means of predicting high strength DAS.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
As recommended by guidelines, most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies). Obviously, these different interventions create a challenge in the interpretation of treatment effects. As a consequence, treatment studies for AMR are rarely comparable, and the available evidence is generally of low quality.
Plasma Exchange and IVIG
PLEX and IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy. The rationale for using PLEX and IVIG is to combine removal of circulating DSA with immunomodulation of the antigraft imune response and in particular modulation of the B-cell response.
Complement Inhibitors
Several studies have been undertaken to evaluate the ability of various complement inhibitors to prevent and treat AMR. The main goal of using complement inhibitors is to avoid the downstream damage to the allograft from DSA.
Eculizumab has protective effect for preventing early active AMR in positive crossmatch HLA-incompatible living and deceased donor populations.
Rituximab
Despite its frequent use, the evidence is low and 3 small randomized trials have investigated its utility without demonstrating a clear benefit in B-cell–rich rejections. Despite this, any trials and prospectives studies there were no differences between treatment and control groups in estimated glomerular filtration rate decline, level of proteinuria, Banff score on biopsy, or MFI of the immunodominant DAS. In contrast, several retrospective analyses have suggested some positive effects of rituximab in multimodal treatment regimens together with steroids, plasmapheresis, and high-dose IVIG, especially on patients with vascular AMR.
Imlifidase
It´s an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA and is undergoing clinical trials in AMR. Although data are lacking for using IdeS in AMR, this agent has been used safely in highly sensitized individuals for desensitization. After administration of IdeS, all previously positive crossmatches became negative and all studied patients received a transplant.
Antithymocyte Globulin
It´s a T-cell–depleting antibodies and have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. Side effects are well described with a higher risk of infectious-associated death, particularly when ATG was combined with B-cell depletion.
Splenectomy
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR. Most of these AMR cases occur in the first week after transplantation and result in profound graft dysfunction and a sudden rise in DSA strength, usually from an anamnestic response.
Proteasome Inhibitor: Bortezomib
It´s directly targets antibody-producing plasma cells making it an attractive candidate for the treatment of active AMR. Data supporting its use are limited to case series suggesting a positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting antibodies, although the only prospective randomized, double-blind, placebo-controlled trial was in “late” AMR and did not demonstrate any beneficial effect of bortezomib alone.
Cyclophosphamide:
There are no trial data to support its use. It is is used for the treatment of antibody mediated diseases such as anti-neutrophil cytoplasmic antibody vasculitis or lupus nephritis.
Interleukin-6 Inhibitors Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function.
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
The current evidence for treatment options in active AMR is of limited quality. The consensus view was that the combination of PLEX, IVIG with corticosteroids could be regarded as standard of care. The trials had many limitations, and most evidence comes from small retrospective studies with different combination therapies using different AMR definitions in different populations.40,55,62,83 Thus, the available evidence supporting the use of any adjunctive agents is of low quality with the best evidence relating to drug toxicity and costs.
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT) Preexisting DSA Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids. Although, has not been shown to improve outcomes in patients with chronic active AMR (as distinct from acute active AMR) and has to be balanced against increased risk of adverse events such as infection and cost.
De Novo DSA
dnDSA generally occurs in the context of reduced immunosuppression whether from patient nonadherence or a physician-directed change in immunosuppression. AMR in this setting is also often initially detected with concomitant TCMR. Therefore, the standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases. Similar to patients with chronic active AMR in the context of preexisting antibodies, treatment with PLEX, IVIG, and Rituximab is used in some centers, although the evidence level (3C) is low
CONCLUSIONS
Despite the severity of the problem and poor outcomes for patients who develop AMR, there is very little highlevel evidence to support the use of any therapy.
The consensus opinion of those present at the meeting was based largely on observational studies, low-level evidence, and expert opinion. Despite the clear lack of evidence, it was considered important to define a standard of care for AMR, which could be used as a benchmark for future studies and prospective trials.
What is the level of evidence?
This consensus has level 05, because is a expert opinion consensus.
Filipe prohaska Batista
2 years ago
This paper is recommendations from the Transplantation Society Working Group to seek uniformity in the treatment of antibody-mediated rejection after kidney transplantation. After ten years, 25% of patients had de novo DSA, with antibody rejection the leading cause of graft rejection in biopsies collected before its failure.
The histological criteria described by the international Banff classification, separate the diagnosis of chronic active AMR with signs of chronic tissue injury such as transplant glomerulopathy, electron microscopy showing basement membrane with severe peritubular capillaritis, or intima arterial fibrosis with no obvious cause. These findings are predictive of allograft failure.
Acute AMR will not necessarily become chronic, as histologic findings typical of transplant glomerulopathy develop renal dysfunction, proteinuria, and eventually graft loss. Allograft survival at 8 years post-transplant was only 56%, compared with 88% subclinical TCMR and 90% if the biopsy was normal.
Anti-HLA antibodies may occur before transplantation or after (de novo DSA) due to inadequate immunosuppression. de novo DSA is a general indicator of under-immunosuppression and signals the need to reevaluate its maintenance. We should routine dosing at transplant candidates who are not immunologically naive, unexpected positive crossmatch or AMR with unexpectedly low DSA MFI.
There is no specific protocol for chronic active AMR, but there is a need for some immunosuppressive strategy. Classically, rituximab associated with plasma exchange and immunoglobulin has been used, with specific situations including bortezomib, eculizumab, IdeS, rATG, cyclophosphamide, and IL6 inhibitors, and the use of each of these drugs should be individualized.
Despite the lack of evidence, immunosuppressive treatment is superior to observational strategies.
saja Mohammed
2 years ago
Summary:
AMR continued the key cause of graft loss despite the improvement in the immunosuppressive medication and the new advances in molecular genetic testing, still 25% of the kidney transplant recipient developed denovo- DSA over times and increased the risk of acute and chronic ABMR with progressive graft loss.
Till date no FDA approved prevention and treatment therapy for the AMR, yet no standardized guideline for the treatment of AMR due to lack of evidence most of the studies are limited to small observation with inconclusive results that hampered the introduction of novel new immunosuppression, so this review give summary of the recommendation from the expert meeting based on the best available evidence for treatment and prevention of active and chronic ABMR. BIOLOGY OF THE ALLOIMMUNE RESPONSE The production of the antibodies in immunologically naïve or presensitized candidate undergo a complex immunological process including T and B cells activation prefiltration in peripheral lymphoid Tissues following sequences of checkpoints events with T and B cells crosstalk with alloantigen recognition by APC like B cells dendritic cells which some will be short-lived plasma blast cells or memory B cells and rest enter the GC to further differentiated to high affinity plasmablast and long live B memory cells with low affinity receptors compared to plasma cells ,in presensitized kidney transplant candidate will have robust high affinity anti -HLA- antibody production upon re-exposure to antigens and lead to antibody antigen immune response .
Quantification of the donor specific memory B cells may help in risk stratification and aid in treatment for those at risk of AMR.
DSAs level another limiting factor with different FC receptors binding capacity with heterogenicity in expression, Public and private cross reactivity and specificities considered other challenges in the diagnosis and treatment of AMR. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
International clinicopathological Banff CLASSIFICATION evolved over years since 1997, AMR classification entered in 2003, in 2017 addition of the salient features of Active AMR criteria which includes: Microvascular inflammation (MVI, g, pct >0), intimal endarteritis(V>0 ), ATN and ,or TMA in the absence of other cause , C4D staining and Positive DSA anti HLA antibodies .
Chronic active antibody mediated rejection (CABMR)
In addition to the criteria 2,3 of AMR need the addition of chronic histological injuries like chronic transplant glomerulopathy Cg with PCTGB multilayering in EM and new arteriolar intimal hyalinosis in the absence of other causes.
AMR is very complex and started from the time of DSA formation but not all DSA s leads to active AMR some tend to be subclinical and progressive overtime lead to chronic active AMR This adds to the challenges for the diagnosis and treatment of AMR
Also, the AMR phenotypes. Early AMR < 30 days usually acute aggressive within days post-transplant ,due to performed DSA rebound and the memory B cells recalls with positive XCM and high MFI, CPRA %,associated with C4D staining and characterized by sudden oliguric acute graft dysfunction, positive DSA with or without proteinuria, can lead to immediate graft loss if not treated. Late AMR > 30 days still could be due to preformed DSA with Banff classification 2017 of active and chronic ABMR, c4d +VE with preformed DSA positive, proteinuria with progressive graft dysfunction within months to years Late > 30 days due to denovo DSA with subclinical or progressive chronic allograft injuries with negative C4D or positive sometimes with TCMR, with proteinuria, triggers by nonadherence to immunosuppression in > 40% with class 11 denovo DSA. Associated with progressive graft loss over months – years. Less responsive to treatments.
Predictors for inferior graft survival
Histological degree of chronic transplant glomerulopathy C g>0 and IFTA, combination with TCMR, C4D +ve , chronic vascular injury VC >0 .
Clinical proteinuria and allograft dysfunction
Time of the diagnosis, C1q positive DSAs and class 11 Denovo DSA
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Donor and recipient HLA typing with historic sensitization for the recipient (1A).
The Standard molecular genetic HLA typing for class 1HLA-A, B-C, class11 DRB1, DR3,4,5, DQA1, DQB1, DPA1, DPB1, (B2).
In HLA sensitized Patients preferred to do high resolution molecular HLA typing for 4digit HLA typing with ALLEL specificity.
Preferred using single antigen bead (SAB) solid phase assay (Lab screen, one lambda).Both C1q DSA monitoring based on center policy and IgG subclasses assay are not yet recommended only for research level.
However, the risk stratification for AMR still based on the crossmatch results (CDC, FXCM) and the level of DSA.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
We know that so many factors that impact the graft outcome and survival like type and time of the rejection, type of DSA so not only the treatment, that’s why most of the available treatments based on evidence from small studies with heterogenous population selections and not taken in consideration the above-mentioned important factors that can impact the response to treatments.
Till date we have low quality of evidence regarding the treatment of AMR, mixed rejection, Chronic active AMR. different protocols different combinations with different dosing which is challenging to conclude a specific guideline or protocol
Standard of care for treatment of active AMR < 30 days with performed DSAs is the use of combination of plasmapheresis and IVIG (KDIGO2010, expert consensus updated work shop in 2017).as it was shows good efficacy to improve short term outcome based on weak evidence studies as the combination of plasma therapy with IVIG help in removal of the antibodies and immunomodulation of the B cell response but such treatment loose its efficacy overtime due to the rebound effect.
So, using multiple adjunctive treatments that inactivate the complement like using eculizumab monoclonal AB ant c5 complement its use limited as salvage therapy to refractory AMR, its use limited due to the cost and also the duration of treatment not yet determined. B cell depleting agents again the evidence is limited to the use of rituximab, BORTOEZMAB as adjuvants therapy to prevent the rebound effects with safety concern due to the increased risk pf infections, hematological side effects.
Chronic Active ABMR > 30 days with performed DSA preferred optimization of the maintenance immunosuppression (add steroid in case of steroid free protocol), consider IVIG (3c) Deno DSA and Chronic active ABMR again address the nonadherence and optimization of the maintenance IS, may consider trial of PLSAMAPHERSIS, IVIG with or without rituximab (case by case )3C. Concomitant TCMR with CABMR with preexistent DSA standard of care as per the expert consensus to go for plasmapheresis, IVIG, steroid +/- rituximab
Chronic AMR optimization of IS will focus on control of BP, proteinuria, stabilize the GFR, aviod nephrotoxic drugs, treat infections and may consider trial of IVIG alone (3C).
to conclude: that treatment of Acute and chronic AMBR not yet standardized and its based on weak evidence from limited studies and its a call for more clinical trials and research with better designs adding a newer agents and better characterization of the AMR.
What is the level of evidence?
level of evidence 4/5 ,the evidence based on expert opinion case series and pilot studies .
Nandita Sugumar
2 years ago
Summary
This article is about the diagnostic features of AMR and the recommended expert guided evidence based treatment for active AMR and chronic active AMR.
AMR can be identified through the following features
HE of graft injury – microvascular inflammation, intimal or transmural arthritis, acute thrombotic microangiopathy in the absence of another cause, acute tubular injury without any apparent cause.
C4d deposition – positive C4d staining
Presence of circulating DSA.
AMR timing
Within 30 days post transplant : Previously sensitized patient with measurable DSA. There can be sudden increase in serum creatinine and oliguria with or without proteinuria. Without intervention, graft loss can occur in a matter of days.
Histological features seen :
AMR histological criteria are met
Interstitial hemorrhage
glomerular fibrin thrombi
microvascular coagulative necrosis
After 30 days post transplant with pre-existing DSA : Detected on surveillance biopsy.
Features :
Microvascular inflammation in glomeruli and peritubular capillaries
Positive C4d staining possibly but not necessary for diagnosis
Transplant glomerulopathy
peritubular basement membrane multilayering.
After 30 days post transplant with dnDSA : dnDSA is a new DSA detected after 3 months of post transplant when there is inadequate immunosuppression.
The causes for these could be :
Non-adherence by the patient
physician directed inadequate IS
genetically determined variability in metabolism of IS drugs.
AMR in this category would present as allograft dysfunction with TCMR. Increased proteinuria is a key feature.
Prognosis is poor.
Treatment of active and chronic active AMR
Plasma exchange and IVIG
Complement inhibitors
Rituximab
Imlifidase
Antithymocyte globulin
splenectomy
Bortezomib (Proteasome inhibitor)
cyclophosphamide
IL 6 inhibitors
Level of evidence :
4/5 since this article is a consensus based on observational studies, low level evidence and expert opinion.
Theepa Mariamutu
2 years ago
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
25 % of patients will develop denovo DSA after a decade of kidney transplantation, so AMR was the most common cause of allograft failure. Sadly, there is no standard protocol of treatment of AMR.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
The generation of antibody-secreting cells follows series of checkpoint events; alloantigen with B cells expressing the appropriate B-cell antigen receptor, B-cell migration to the T- and B-cell interface in the lymph node and alloreactive T cells present alloantigen indirectly on recipient dendritic cells.
Some of B cells differentiate into memory B cells or short-lived plasma blasts, while the rest enter germinal centres to result in high-affinity class switched memory B cells, plasma blasts, and long-lived plasma cells which secrete large amounts of antibody upon antigen reexposure.
Differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production. Thus, the ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of pre sensitised recipients susceptible for an active AMR early post-transplant.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
AMR is diagnosed based on:
Histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
Histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI
The presence of circulating DSA, predominantly anti-HLA antibody.
The exception is that PTC alone is insufficient for diagnosis in the presence of T-cell–mediated rejection (TCMR)
Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the presence of glomerulitis and TMA
Signs of chronic tissue injury include transplant glomerulopathy, severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause.
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to active AMR criteria.
CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories:
Early Post-transplant (<30 Days) Active AMR
Increasing DSA strength or breadth at the time of transplant (DSA mean fluorescence intensity (MFI)), the degree of flow cytometric crossmatch positivity, and the number or breadth of cross-reactive DSA specificities has been risk for developing AMR, however it is an uncommon form.
Late (>30 Days) Post-transplant AMR with Preexisting DSA
Patients with preexisting DSA who don’t develop an aggressive early AMR can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy for mild allograft dysfunction.
If detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present.
MVI may persist and is later accompanied by chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering.
Late (>30 Days) AMR Associated With dnDSA
This is the most common form of AMR
associated with dnDSA (due to sensitive DSA testing and a general avoidance of preexisting DSA).
dnDSA is a DSA detected after >3 months post-transplant owing to inadequate immunosuppression due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs
Allograft survival was 63% in patients with preexisting DSA while only 34% in patients with dnDSA, 8 years post rejection diagnosis.
dnDSA tend to have increased proteinuria and increased expression of interferon-γ–inducible, natural killer cell, and T-cell transcripts at presentation when compared with preexisting DSA
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
Allograft histology has been important in the chronicity and extent of injury.
Chronic histological features – presence of transplant glomerulopathy and the degree of interstitial fibrosis and tubular atrophy are predictive of allograft failure.
Under-immunosuppression is a major risk factor for dnDSA, medication nonadherence is independently associated with inferior allograft survival among patients with dnDSA.
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Initial assessment for Anti-HLA DSA (previous transplant, blood transfusion, and pregnancy)
Monitoring for dnDSA
The presence of dnDSA – indicator of under immunosuppression
Interpreting positive DSA (a positive cut-off MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies).
Shared-epitope phenomenon, which can lead to a falsely low MFI.
Additional DSA Testing for Risk Stratification (All patients with DSA are at some risk for AMR: Crossmatch testing, complement-dependent cytotoxicity, testing to assess the complement binding ability of DSA (C1q or C3d)).
Available evidence for the treatment of active and chronic active AMR despite not FDA approved
Plasma Exchange and IVIG:
PLEX -removes circulating DSA and reducing their production along with immunomodulation of the antigraft immune response and in particular modulation of the B-cell response.
IVIG has been shown to inhibit B-cell responses by the Fc portion of the Ig binding the Fc fragment of IgG2b receptor on B cells, and sialylated IVIG binds CD22, inducing apoptosis of mature B cells. It also functions as a scavenger of activated complement.
Complement Inhibitors
Eculizumab (monoclonal antibody targeting C5), has a protective effect of eculizumab for preventing early active AMR in positive crossmatch HLA-incompatible in living and deceased donor populations.
also has effectiveness in treating early active AMR that occurs within the first month posttransplant.
Rituximab
B-cell–depleting agent, used as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients
evidence is low and 3 small, randomized trials have investigated its utility without demonstrating a clear benefit.
Imlifidase
IgG-degrading enzyme of Streptococcus pyogenes (IdeS) can rapidly reduce or even eliminate anti-HLA DSA.
cleaves human IgG at a highly specific amino acid sequence within the hinge region producing Fc and F (ab) 2 fragments and effectively blocking CDC and antibody-dependent cellular cytotoxicity.
Evidences are lacking for using IdeS in ABMR, it was used for desensitization and its use was complicated by antibody rebound within 7-10 days of the administration, thus it is unlikely to be used as an isolated treatment for ABMR
permits any highly sensitized patient to undergo transplantation within hours of a donor being identified regardless of the crossmatch status
Antithymocyte Globulin
T-cell–depleting antibodies have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR
Side effects are higher risk of infectious associated with death
Interleukin-6 Inhibitors Toclizumab and Clazakizumab
Tocilizumab found that patient and graft survival at 6 years is superior over controls, with a significant reduction in DSA and stabilization of renal function.
large multicentre randomized control trial has been initiated to evaluate Clazakizumab for the treatment of chronic active AMR.
Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids.
Those who has chronic active AMR or chronic transplant vasculopathy, goals of therapy should be to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, and titer of DSA while minimizing drug toxicity.
Treatment should focus on optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control.
dnDSA: standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence.
Reem Younis
2 years ago
.– Antibody-mediated damage caused allograft dysfunction late posttransplant in nearly 60% of renal transplant recipients.
-The features of active AMR based on the Banff 2017 classification are:
(1) histological evidence of graft injury .
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
(3) the presence of circulating DSA, predominantly anti-HLA antibody
-To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR. Signs of chronic tissue injury include transplant glomerulopathy (Banff chronic glomerulitis [cg] score > 0), severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause. CONSENSUS FOR MEASURING AND MONITORING OF DSA
-The initial assessment of a renal transplant candidate involves donor and recipient HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events (previous transplant, blood transfusion, and
pregnancy) ( 1A).
-Molecular HLA typing ideally includes A; B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; and DPA1/DPB1 (2B).
-The first-line screening for alloantibody would be with single-antigen bead (SAB) solid-phase assays (LABScreen [one Lambda] or LifeScreen [LifeCodes-Immucor]), butmultiantigen beads can also be used (1A).
-Monitoring for dnDSA is recommended in the following settings: immunosuppressionm reduction by physician for any reason, known patient
medication nonadherence, or at the time of rejection episode
(T cell or antibody mediated) (2B).
-Based on the strong relationship between dnDSA, AMR, and graft loss, transplant patients with dnDSA should undergo close monitoring of allograft function
(1B).
-The SAB test has a high coefficient of variation, and thus, the positive
cutoff varies among and within laboratories but a positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies.
. We recommend the routine use of these methods in the following situations: transplant candidates/recipients who are not immunologically naive, unexpected positive crossmatch, or AMR with unexpectedly low DSA MFI (2B).
-C1q and C3d binding positivity is associated with a high DSA titer. AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR Plasma Exchange and IVIG
-The strongholds for contemporary treatment of AMR are represented by plasma exchange (PLEX) and IVIG, although neither of these have FDA approval
-The expert consensus at the FDA Antibody-Mediated Rejection
Workshop in 201767 as well as Kidney Disease and KDIGO in 201068 was that PLEX and IVIG could be regarded as a standard of care for acute active
AMR, despite the weakness of evidence in support of efficacy.
-It improve short-term outcomes has been demonstrated by several studies while their results on long-term effects remain variable . Complement Inhibitors
-The main goal of using complement inhibitors is to avoid the downstream damage to the allograft from DSA.
-when Eculizumab used in patients who received positive crossmatch HLA-incompatible transplants, the incidence of early active AMR was decreased from approximately 40% in historical controls to 7% among treated patients. Rituximab
-several retrospective analyses have suggested some positive effects of rituximab in multimodal treatment regimens together with steroids, plasmapheresis,
and high-dose IVIG, especially on patients with vascular AMR.
-A single-center nonrandomized study suggests that Rituximab as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly
sensitized patients. Imlifidase
-Imlifidase (Hansa Biopharma AB), an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA and is undergoing clinical trials in AMR.
-It has been used safely in highly sensitized individuals for desensitization. After administration of IdeS, all previously positive crossmatches became negative and all studied patients received a transplant. Antithymocyte Globulin
-It has been used for treatment of refractory rejection, vascular rejection, mixed
rejections, and AMR.
– A large retrospective series suggests that T-cell depletion in combination with steroids has no effect on the outcome in vascular AMR. Splenectomy
– It must be performed rapidly after the onset of early AMR to be effective.
– Some patients who recover develop transplant glomerulopathy and premature graft loss. Proteasome Inhibitor: Bortezomib
Bortezomib is a proteasome inhibitor approved for the treatment of multiple myeloma that directly targets antibody-producing plasma cells making it an attractive candidate for the treatment of active AMR.
-The drug has well-documented side effects, and at the present time, there
are no trial data to support its use. Cyclophosphamide
-It is used within a multimodal treatment regimen for the treatment of refractory rejections.
– While it is relatively inexpensive, there are no trial data to support its use. Interleukin-6 Inhibitors
-Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function. CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
-The consensus view was that the combination of PLEX, IVIG with corticosteroids could be regarded as standard of care, consistent with the conclusions
of the FDA workshop and KDIGO guideline.
– The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability . CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT) Preexisting DSA
-Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids.
-The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR (as distinct from acute active AMR) and has to be balanced against increased risk of adverse
events such as infection and cost.
-The consensus opinion was that treatment should focus on optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control. De Novo DSA
-AMR in this setting is also often initially detected with concomitant
TCMR.
-The standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication
nonadherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases.
-Treatment with PLEX, IVIG, and Rituximab is used in some centers,
although the evidence level (3C) . -level of evidence :5
Zahid Nabi
2 years ago
There is no consensus on treatment of antibody mediated rejection either acute or chronic. Transplantation society held a meeting to review the available literature in this regard and have given their expert opinion published in the form of this paper.
The fact that by 10 years 25% of transplant patients develop DSA simply signifies the importance of acting early.
In the context of transplantation, presensitized individuals have a robust long-lived plasma cells constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid anamnestic antibody response.
The differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells.
The diversity at the level of antibodies presents an additional challenge. Alternatively, cross-reactive alloantibodies may be donor reactive but not donor specific, and some may bind multiple HLA molecules.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
The salient features of active AMR based on the Banff 2017 classification14 are
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute throm- botic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other appar- ent cause;
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and
(3) the presence of circulating DSA, predomi- nantly anti-HLA antibody .
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to crite- ria 2 and 3 for active AMR.
Signs of chronic tissue injury include transplant glomerulopathy (Banff chronic glomer- ulitis [cg] score > 0),
severe peritubular capillary basement membrane multilayering on electron microscopy,
or new arterial intimal fibrosis without another obvious cause.
Phenotype of AMR should be considered alongside Histo pathological interpretation for guiding any kind of therapy.
Early Posttransplant (30 Days) Posttransplant AMR With Preexisting DSA
While many patients with preexisting DSA do not develop an aggressive early AMR as described above, they can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy (in the setting of stable function) or on a for-cause biopsy for mild allograft dysfunction.
Histological findings are depend- ent on the timing of the biopsy.
Overtime, however, the GFR declines and the patient becomes proteinuric with graft failure often occurring several years after transplant.
Late (>30 Days) AMR Associated With dnDSA
In general, dnDSA is a new DSA detected after >3 months posttransplant in the context of inadequate immunosuppression which is either due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs.
This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR.
Recent studies have suggested that AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA after adjusting for clinical, histological, and immunologic characteristics. Despite these find- ings, it remains unclear whether it is the dnDSA itself that is associated with inferior allograft survival or a delay in AMR diagnosis.
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
Transplant glomerulopathy
Degree of IFTA
Concomitant TCMR
Vascular leison
C4d positivity
Allograft dysfunction
Proteinuria
Time of diagnosis post transplant
Class 2 DSA
C1 q binding
Level of DSA
Monitoring for De Novo DSA
immunosuppression reduction by physician for any reason
known patient medication non-adherence
the time of rejection episode (T cell or antibody mediated)
Interpreting Positive DSA Results
In general, a positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies.
SAB tests are also prone to interference from external substances
bead saturation
and “shared-epitope” phenomenon, which can lead to a falsely low MFI.
Methods to identify interference and bead saturation include performing serum dilution or using ethylenediaminetetraacetic acid.
We recommend the routine use of these methods in the following situations: transplant candidates/recipients who are not immunologically naive
unexpected positive crossmatch
or AMR with unexpectedly low DSA MFI
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Plasma Exchange and IVIG
expert consensus at the FDA Antibody-Mediated Rejection Workshop in 2017as well as Kidney Disease: Improving Global Outcomes (KDIGO) in 2010 was that
PLEX and IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy.
Complement Inhibitors
Despite prevention of early active AMR, the long-term incidence of chronic AMR and allograft survival is comparable to historical controls.
Rituximab
Rituximab, a B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines.Despite its frequent use, the evidence is low and 3 small randomized trials have investigated its utility without demonstrating a clear benefit.
Antithymocyte Globulin
Although depleting antibodies were proposed by KDIGO guidelines as potential treatment options,no benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
Splenectomy
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR. However in modern practice it’s role is questionable
Proteasome Inhibitor: Bortezomib
The drug has well-documented side effects, and at the present time, there are no trial data to support its use
Interleukin-6 Inhibitors
A single-center, nonrandomized trial of tocilizumab (anti-interleukin-6 receptor monoclonal antibody) was undertaken in 36 patients with chronic active AMR that had failed IVIG plus rituximab. Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function. Further trials are underway
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
PLEX
IVIG with corticosteroids could be regarded as standard of care, consistent with the conclusions of the FDA workshop and KDIGO guidelines
adjunctive therapy may be warranted especially when the risk of graft loss is considered high. The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Preexisting DSA
. Among patients with known preexisting DSA and active AMR without chronic features, the con- sensus treatment recommendations include PLEX, IVIG, and corticosteroids.
The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR (as distinct from acute active AMR) and has to be balanced against increased risk of adverse events such as infection and cost.
De Novo DSA
AMR in this setting is also often initially detected with concomitant TCMR. Therefore, the standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases.
PLEX, IVIG, and Rituximab is used in some centers, although the evidence level (3C) is low.
Conclusion
It is expert opinion only on the basis of
Observational studies and low level evidence
Ahmed Abd El Razek
2 years ago
By 10 years, after kidney transplant, up to 25% have developed de novo DSA (dnDSA) so AMR was the most common cause of allograft failure. Yet, there are no commonly accepted guidelines for treatment.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
The generation of antibody-secreting cells follows series of checkpoint events; alloantigen with B cells expressing the appropriate B-cell antigen receptor, B-cell migration to the T- and B-cell interface in the lymph node and alloreactive T cells present alloantigen indirectly on recipient dendritic cells.
Some of B cells differentiate into memory B cells or short-lived plasma blasts, while the rest enter into germinal centers to result in high-affinity class switched memory B cells, plasma blasts, and long-lived plasma cells which secrete large amounts of antibody upon antigen reexposure.
Differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production. Thus, the ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of presensitized recipients susceptible for an active AMR early post-transplant. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
AMR is a clinicopathological diagnosis;
(1) histological evidence of graft injury via microvascular inflammation(MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause.
(2) Histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
(3) The presence of circulating DSA, predominantly anti-HLA antibody.
The exception is that peritubular capillaritis alone is insufficient for diagnosis in the presence of T-cell–mediated rejection (TCMR).
Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the presence of glomerulitis and thrombotic microangiopathy.
Signs of chronic tissue injury include transplant glomerulopathy, severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause.
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to active AMR criteria.
CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories:
Early Post-transplant (<30 Days) Active AMR
The risk is indicated by increasing DSA strength or breadth at the time of transplant (DSA mean fluorescence intensity (MFI)), the degree of flow cytometric crossmatch positivity, and the number or breadth of cross-reactive DSA specificities. It is uncommon form.
Late (>30 Days) Post-transplant AMR with Preexisting DSA
Patients with preexisting DSA who don’t develop an aggressive early AMR can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy for mild allograft dysfunction. If detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present. MVI may persist and is later accompanied by chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering.
Late (>30 Days) AMR Associated With dnDSA
The most common form of AMR is associated with dnDSA (due to sensitive DSA testing and a general avoidance of preexisting DSA). DnDSA is a new DSA detected after >3 months post-transplant owing to inadequate immunosuppression (patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs).
Allograft survival was 63% in patients with preexisting DSA and only 34% in patients with dnDSA 8 years after the rejection diagnosis.
Compared with patients with preexisting DSA, those with dnDSA tend to have increased proteinuria and increased expression of interferon-γ–inducible, natural killer cell, and T-cell transcripts at presentation.
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
Allograft histology is key to the chronicity and extent of injury. Chronic histological features such as the presence of transplant glomerulopathy and the degree of interstitial fibrosis and tubular atrophy are predictive of allograft failure. Under-immunosuppression is a major risk factor for dnDSA, medication nonadherence is independently associated with inferior allograft survival among patients with dnDSA.
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Initial Assessment for Anti-HLA DSA (history of allosensitizing events as previous transplant, blood transfusion, and pregnancy).
Monitoring for De Novo DSA (Immunosuppression reduction either as a result of nonadherence or under physician direction is associated with development of dnDSA)
The presence of dnDSA is a general indicator of under-immunosuppression.
Interpreting Positive DSA Results (a positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies).
Shared-epitope phenomenon, which can lead to a falsely low MFI.
Additional DSA Testing for Risk Stratification (All patients with DSA are at some risk for AMR: Crossmatch testing, complement-dependent cytotoxicity, testing to assess the complement binding ability of DSA (C1q or C3d)).
Available evidence for the treatment of active and chronic active AMR.
Plasma Exchange and IVIG:
Itremoves circulating DSA and reducing their production along with immunomodulation of the antigraft immune response and in particular modulation of the B-cell response.
In experimental models, IVIG has been shown to inhibit B-cell responses by the Fc portion of the Ig binding the Fc fragment of IgG2b receptor on B cells, and sialylated IVIG binds CD22, inducing apoptosis of mature B cells. It also functions as a scavenger of activated complement.
Complement Inhibitors
Eculizumab a monoclonal antibody targeting C5.it has a protective effect of eculizumab for preventing early active AMR in positive crossmatch HLA-incompatible in living and deceased donor populations.it also has effectiveness in treating early active AMR that occurs within the first month posttransplant.
Rituximab
B-cell–depleting agent, used as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.
Imlifidase
An IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA. IdeS cleaves human IgG at a highly specific amino acid sequence within the hinge region producing Fc and F (ab) 2 fragments and effectively blocking CDC and antibody-dependent cellular cytotoxicity.
It is used as an adjunct to other therapies aiming to reduce DSA in the long term.
The unique feature of this drug is that it permits any highly sensitized patient to undergo transplantation within hours of a donor being identified regardless of the crossmatch status.
Antithymocyte Globulin
T-cell–depleting antibodies have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. Side effects are higher risk of infectious-associated with death.
Proteasome Inhibitor: Bortezomib
Directly targets antibody-producing plasma cells.
Interleukin-6 InhibitorsClazakizumab
Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids. In cases of chronic active AMR or chronic transplant vasculopathy, goals of therapy should be to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, and titer of DSA while minimizing drug toxicity.
Treatment should focus on optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control.
De Novo DSA: standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence.
CONCLUSIONS
It is obvious that new agents and clinical trials are needed urgently.
In addition, better characterization of the different forms of AMR based on pathophysiology, histology, as well as clinical and genetic phenotypes is needed.
Level of evidence (4 – 5)
Huda Al-Taee
2 years ago
Summarise this article
Despite the newly discovered IS medications, Graft loss due to alloimmunity is still a problem. It is well known that around 25% of kidney transplant recipients develop de novo DSA 10 years post-transplantation; this will lead to the development of ABMR, and because of this fact, ABMR is considered the most common cause of allograft failure.
There are no accepted guidelines for the treatment of ABMR, and to date, clinical trials of ABMR are either small or inconclusive, and there is no FDA approved therapy for prevention or treatment of ABMR.
Diagnostic criteria and histological features of ABMR:
ABMR is a clinicopathological diagnosis that was first described in 2003 in addition to the 1997 international Banff classification of kidney allograft rejection.
The salient features of active ABMR in Banff 2017 classification are:
histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the lack of any other apparent reason.
histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
the presence of circulating DSA, predominantly anti-HLA antibody.
The main histological manifestations are glomerulitis and peritubular capillaritis.
Clinical phenotypes of ABMR:
Early post-transplant Active ABMR( <30 days): the risk is increasing with increasing DSA strength and MFI, degree of FCXM positivity, and the number of cross-reactive DSA specificities. This form is uncommon, C4d positive, typically presents with increasing DSA with allograft dysfunction, if not treated early it will lead to graft loss. with prompt diagnosis and treatment, it can resolve completely.
Late post-transplant ABMR with preexisting DSA ( >30 days): pre-existing DSA can develop a progressive form of ABMR. At time of diagnosis there will be an MVI, C4d may or not be positive, clinically minimal or no deterioration in GFR or proteinuria. over time GFR decline and proteinuria developed and graft loss will happen several years later.
Late ABMR with de novo DSA ( >30 days): currently, this is the most common form of ABMR. De novo DSA are formed 3 months post-transplantation either due to non-adherence or under immunosuppression. this form of rejection presents with allograft dysfunction and concomitant or preexisting TCMR.
Features associated with reduced allograft survival in late ABMR:
The presence of TG
degree of IFTA
Concomitant TCMR
C4d positivity
vascular lesions
Allograft dysfunction at diagnosis
proteinuria
time of diagnosis post-transplant
C1q positive DSA
Anti-class II DSA
Strength of DSA
Consensus for measuring and monitoring of DSA
Initial assessment of DSA:
donor and recipient HLA typing( molecular typing).
anti-HLA antibody screening (SAB screening).
obtaining a history of allosensitization
Monitoring for de novo DSA:
Recommended in:
IS reduction
non-adherence
at the time of rejection.
Interpreting positive DSA results:
SAB testing has limitations that may interfere with the results such as:
high coefficient of variation
interference with external substances, bead saturation and shared epitope phenomenon.
Additional DSA testing for risk stratification:
The risk of ABMR from highest to lowest based on XM and SAB-positive testing are:
positive CDC XM, positive FCXM, and negative XM.
Positive complement-binding DSA is associated with ABMR and graft loss.
The available evidence for the treatment of active and chronic ABMR:
PE and IVIG: the rationale for using PE and IVIG is to combine the removal of circulating DSA with immunomodulation of the anti-graft immune response and in particular modulation of the B-cell response.
Complement inhibitors: eculizumab and C1 esterase inhibitor. For eculizumab, a study showed that among patients who received positive crossmatch HLA-incompatible transplants, the incidence of early active ABMR was decreased to 7% among patients treated with it. The plasma C1 esterase inhibitors have been tested in 2 pilot studies and indicate a possible improvement in allograft function in kidney recipients with ABMR.
Rituximab: the evidence is low and 3 small randomized trials have investigated its utility without demonstrating a clear benefit.
Imlifidase: data are lacking for using IdeS in ABMR, it was used for desensitization and its use was complicated by antibody rebound within 7-10 days of the administration, thus it is unlikely to be used as an isolated treatment for ABMR.
ATG: no benefit has been demonstrated for the treatment of pure ABMR.
Splenectomy: there are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR.
Bortezomib: Data supporting its use are limited to case series suggesting a positive effect within a multimodal treatment regimen of PE, IVIG, steroids, and depleting antibodies.
Cyclophosphamide: there are no trial data to support its use.
Interleukin-6 inhibitors: single-center, nonrandomized trial of tocilizumab found that Patient and graft survival at 6 years is superior to controls, with a significant reduction in DSA and stabilization of renal function. large multicenter randomized control trial has been initiated to evaluate Clazakizumab for the treatment of chronic active AMR.
What is the level of evidence?
Level 4/5
Wael Jebur
2 years ago
Despite the fact that Antibody mediated rejection is the most common advrse related to poor allograft outcome, there is no consunsus about the best management and treatment thereof.The transplantation society host an expert meeting to discuss and stratify the treatment strategy based on best available evidence.This article is a summary that meeting…
An important points to consider in Allosensitization:
After the encounter of B lymphocytes with an allo antigens in the transplanted kidney,B cells differentiate to memery cells or Plasma cells.The repertoir of memory cells is much different from that of plsma cells.therefore, treatment of plasma cell will not prevent the memory cell formation. similarly,absence of DSAs is not synonymous with absence of memory cells or the lack of potential amnestic reaction towards an allograft antigens.
Diagnostic criteria of AMR:
1]Histologic evidence of allograft injury in the form of MVI, Microangiophaic thrombosis, intimal or transmural arteritis.Or acute tubular injury in the absence of any other detectible reason.
2]Antibody -endothelial interaction evidence based on C4d or MVI.
3] DSAs
The presence of gloerulitis and PTC of more than 0 satisfy criterion 1 and g+ptc of equal or more than 2 is satisfing criterion 2.
Chronic active AMR:
include the presence of criteria 2 and 3 , in addition to features of chrinisity which are basically transplant glomerulopathy TG and peri-tubular multilayring PTCM.Or new arterial intimal fibrosis with no othe causes.
Phenotype of AMR:
DSAs anti HLA can often be associated with acute AMR ,but sometimes its not causing acute AMR. AMR is commonly a long term progressive disease, however , its not always progressing to chrinic active AMR after an episode of acute AMR.
DSAs cause active AMR ,which is commonly [but not limited to] MVI.
Chronic AMR, is the presence of TG with current or prior DSAs without C4d or MVI.
Overtime, histological features of chronic AMR in the form of TG and PTCM with IFTA is becoming increasingly evident with clinical features of allograft dysfunction and proteinuria with eventual allograft loss.
The course of the disease.its stage and histological features,are dependent entirely, on when the allograft biopsy is contemplated, So its basically the timing of biopsy reflecting the stage of disease ,rather than having different types of AMR.
DSAs:
Early [less than 30 days]:
Active AMR can occur in the first 30 days ,if there is detectable DSAs at time of transplantation or if there is an amnestic response.
depending on DSAs MFI and positivity on FCXM up to 40 % risk ratio.
Late [more than 30 days]posttransplant AMR with preexisting DSAs:
An indolent and progressive form of AMR can develop secondary to preexisting DSAs.
its associated with pooor allograft outcome.
Late more than 30 days, AMR associated with dn DSAs.:
DSAs developed after 3 months , due to noadherence to medication or physician directed.
The presentation of AMR in the context of dnDSAs is often present with concomitent TCMR, with clinically, indolent allograft dysfunction.
Two recent studies showd inferior graft survival with dnDSA associated AMR than AMR associated with pre existing DSAs.it could be relatred to delayed diagnosis of AMR.
Features associated with reduced allograft survival in late AMR [preexisting or dnDSAs]:
1}TG and IFTA.
2}Concomitant TCMR
3}C4d positivity.
4}Vascular lesion.
5}Allograft dysfunction at diagnosis.
6}Proteinuria.
7}TIME OF DIAGNOSIS POST TRANSPLANT.
8}C1q positive antibodies.
9}level of DSAs by MFI and FCXM.
10}anti class II HLA DSAs.
Monitoring of dnDSAs:
1- Immunosuppresion reduction.
2- nonadherence.
3-Rejection episode TCMR or AMR.
There is a strong correlation between dnDSAs, AMR and graft loss.therfore close follow up of DSAs are of prime significance.Similarly,renal function and kidney biopsy to be perforemd whenever needed.
Interpretation of positive DSAs:
SAB test was an important test for detection of DSAs.
A cut off of 1000 -1500 is associated with detection of specific HLA antibodies.
SAb isprone to interference with external substances, bead saturation and shared epitop phenomina which can lead to a falsely low MFI.
Treatment of Active AMR:
PP and IVIG are the main steps in the managment.:
to remove the DSAs and modulate the production of DSAs by inhibiting Blymphocytes.
Eculizumab is a monoclonal antibody targeting C5. To inhibit the complement system, as its involved in the AMR events.result in terminal complement blockade.
Bortizomib its a proteasome inhibitor targetting antibody producing Plasma cells.
Chronic Active AMR:
The aim of therapy is to stabilize or reduce the rate of decline of GFR,proteinuria,histological injury score,and titer of DSAs while minimizing drug toxicity.
IVIG, RITUXIMAB,PP were shown to be ineffective in improving the allograft outcome in chronic active AMR
Consus opinion was:
optimization of immunosuppresion.
reintroduction of steroid therapy.
to keep Tac.trough level more than 5 ng/ml.
blood pressure , glucose and lipid control.
In conclusion:
Despite the vast knowledge obtained about the immunology and pathogenesis of AMR , its still associated with worse prognosis and limited high level evidence studies to stratify its management .
☆The Transplantation Society brought together a group of experts from around the globe with the aim of producing a consensus document that outlined recommended treatments for active and chronic active AMR, based on the best available evidence.
◇BIOLOGY OF THE ALLOIMMUNE RESPONSE:
▪︎Presensitized individuals have a long-lived plasma cells which secrete anti-HLA Abs & resting memory B cells.
▪︎The repertoire of plasma cells and memory B cells are not identical. So, treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells.
▪︎Absence of DSA does not mean the lack of memory B cells.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR:
▪︎AMR is a clinicopathological diagnosis.
▪︎Features of active AMR based on the
Banff 2017 classifcation are:
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute TMA in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
(2) histological evidence of antibody endothelial interactions either by C4d deposition or at least moderate MVI
(3) the presence of circulating DSA, predominantly anti-HLA antibody.
▪︎Glomerulitis (g) and peritubular capillaritis (ptc) are the main forms of MVI
▪︎Histological manifestation of active AMR:
Criterion 1, (g + ptc > 0)
Criterion 2, (g + ptc) sum score of ≥2 ▪︎ptc alone is insufficient for diagnosis in the presence of TCMR. Recurrent or de novo GN must be considered as a DD.
▪︎Diagnosis of chronic active AMR: Morphological features of chronic tissue injury + criteria 2 and 3 for active AMR.
▪︎Signs of chronic tissue injury:
Transplant glomerulopathy (TG) (Banff chronic glomerulitis [cg] score > 0), severe peritubular capillary basement membrane multilayering on EM, or new arterial intimal fibrosis without another obvious cause.
◇CLINICAL PHENOTYPES OF AMR:
The Banff classifcation has 3 AMR diagnostic categories (including chronic AMR with TG & current or prior DSA but no MVI or C4d).
▪︎There are many clinical phenotypes of AMR (early and late) which complicate it’s diagnosis and management .
◇To design effcient and effective therapeutic clinical trials, the authors recommended:
1) considering the timing of presentation
2) Type of DSA (pre-existing or de novo), in relation to the histological classifcation.
◇Phenotypes:
1. Early posttransplant (30 Days) posttransplant AMR With Preexisting DSA
3. Late (>30 Days) AMR Associated With denovo DSA dnDSA
◇FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
▪︎In late AMR (preexisting or dnDSA), the histological, clinical, and alloantibody features associated with reduced allograft survival are similar .
▪︎Chronicity and extent of injury depend on allograft histology
▪︎Graft outcomes is associated with:
1. Chronic histological features such as the presence of TG (Banff cg score >0) and the degree of IFTA,
2. Presence of TCMR
3. C4d positivity
4. Vascular lesions (Banff cv score >0)
5. Clinical factors including allograft dysfunction at diagnosis, proteinuria, and time of diagnosis.
6. History of medication nonadherence (is associated with inferior allograft survival among patients with dnDSA).
7. Alloantibody characteristics.
◇AVAILABLE EVIDENCE FOR THE TTT OF ACTIVE AND CHRONIC ACTIVE AMR:
▪︎Most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of IVIG, variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting Abs).
1- Plasma Exchange and IVIG
▪︎Most commonly used to treat active AMR and regarded as standard care by FDA AMR-Workshop in 2017 as well as KDIGO in 2010.
▪︎Can improve short-term outcomes. But, their results on long-term effects remain variable, so there is a need for other
2- Complement Inhibitors
▪︎Are used avoid allograft damage
produced by DSA.
3- Rituximab: a B-cell–depleting agent
▪︎ Was suggested as a treatment option by KDIGO guidelines.
4- Imlifdase: an IgG-degrading
enzyme of Streptococcus pyogenes (IdeS), ▪︎Can rapidly reduce anti-HLA DSA
▪︎Is undergoing clinical trials in AMR.
5- Antithymocyte Globulin
▪︎Depletingantibodies
▪︎Proposed by KDIGO guidelines as a potential treatment options. But, no beneft has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
▪︎Side effects are well described with a higher risk of infectious-associated death 6- 6- Splenectomy: Used as a salvage procedure for severe early AMR.
7- Proteasome Inhibitor: Bortezomib
▪︎Data supporting its use are limited
8- Cyclophosphamide:
▪︎No trial data to support its use.
9- Interleukin-6 Inhibitors
▪︎A few numbers of study, in patients with chronic active AMR
◇CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
▪︎The combination of PLEX, IVIG with corticosteroids could be regarded as standard of care.
▪︎The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability. ▪︎Where concomitant TCMR is present, it should be treated.
◇CONSENSUS FOR TREATMENT OF LATE
ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
▪︎Preexisting DSA and active AMR without chronic features: PLEX, IVIG, and corticosteroids.
▪︎Chronic active AMR or chronic transplant
vasculopathy: treatment must focus on optimizing IS and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, & optimizing medical management with focus on BP, blood glucose & lipid control.
▪︎De Novo DSA (active or chronic active):
– Optimize baseline IS and manage potential medication nonadherence.
– Treatment of concomitant TCMR is recommended in all cases.
– Similar to patients with chronic active AMR in the context of preexisting antibodies, treatment with PLEX, IVIG, and Rituximab is used in some centers.
◇CONCLUSIONS:
▪︎There is very little high level evidence to support the use of any therapy, no clear treatment regimens to recommend and no approved treatments for AMR.
▪︎The consensus opinion was based largely on observational studies, low-level evidence, and expert opinion.
▪︎New agents and clinical trials for treatment of AMR are needed urgently. ▪︎Better characterization of the different types of AMR based on pathophysiology, histology, as well as clinical and genetic phenotypes is needed.
Mohamed Saad
2 years ago
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantation Society Working Group. INTRODUCTION: Delayed graft dysfunction is an obstacle for kidney recipients which has multifactorial causes but ABMR still one of the most common causes of graft failure specially with more laboratory evolution in DSA detection and BANFF criteria update. Still no strong based evidence guidelines or recommendation for treatment. BIOLOGY OF THE ALLOIMMUNE RESPONSE: Initial encounter of alloantigen with B cells , activates B-cell migration to the T- and B-cell interface in the lymph node, where it receives help from allo-reactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells then B cells differentiate into memory B cells or plasma cells, while the rest enter into a germinal center to emerge as high-affinity and class-switched memory B cells and plasma cell. Pre-sensitized patients produce large amount of antibodies against HLA with strong response. DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR (1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause. (2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI. (3) the presence of circulating DSA. With the above three criteria if there is chronic changes e.g arterial multi-layering or arterial intimal fibrosis to be considered chronic active ABMR. CLINICAL PHENOTYPES OF AMR: A-Early Post-transplant (30 Days) Active AMR. Occur in patient with performed DSA with high MFI and its clinically uncommon as those patient mostly avoided. Need aggressive treatment as it may led to cortical necrosis. B-Late (>30 Days) Post-transplant AMR With Preexisting DSA. Some patients have pre-exciting DSA but not devolped early AMR and may discovered by protocol biopsy if delayed in diagnosis it may progress to chronic changes. C-Late (>30 Days) AMR Associated With dnDSA De novo DSA is the most common cause of AMR at time being which detected mainly after 3 months due to many causes like patient non-adherence, physician directed , under-immunosuppression is a major risk factor for dnDSA . Some studies showed that AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA. CONSENSUS FOR MEASURING AND MONITORING OF DSA: 1-Initial Assessment for Anti-HLA DSA History of allo-sensitizing events (previous transplant, blood transfusion, and pregnancy). Donor and recipient HLA typing. Anti-HLA antibody screening. 2-Monitoring for De Novo DSA. Recommended in the following settings: immunosuppression reduction by physician , medication non-adherence, or at the time of rejection episode . 3-Interpreting Positive DSA Results Positive cutoff for SAB is variant from laboratories because high coefficient of variation, also interference from external substances, bead saturation, and “shared-epitope” phenomenon can lead to a falsely low MFI so in transplant candidates/recipients who are not immunologically naive, unexpected positive cross-match, or AMR with unexpectedly low DSA MFI we should routinely do serum dilution or using ethylenediaminetetraacetic acid. Additional DSA Testing for Risk Stratification Hyper acute AMR is also associated with having a positive CDC crossmatch,complement binding ability of DSA are associated with AMR and allograft loss. AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR The aim of treatment overall to remove circulating DSA and reducing DSA production. 1-Plasma Exchange and IVIG. Both considered the mainstay of treatment for acute active AMR but the evidence consists largely of case series and poorly controlled randomized trials. 2-Complement Inhibitors. Two multicenter randomized phase 2 trials confirmed the protective effect of eculizumab for preventing early active AMR in positive crossmatch HLA-incompatible living73 and deceased74 donor populations. 3-Rituximab. It is suggested by KDIGO but still no clear evidence regarding optimal doses, number of treatment cycles. 4-Imlifidase/(IdeS). Used in desensitization and all patients shifted from CM positive to negative but rebound in DSA and anti-IdeS antibodies develop after 1 or 2 doses but still not evident as a single treatment of ABMR. 5-Antithymocyte Globulin. No benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy. 6-Splenectomy. 7-Proteasome Inhibitor: Bortezomib. 8-Cyclophosphamide. 9-Interleukin-6 Inhibitors. CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)(table) Plasmapheresis (daily or alternative day × 6 based on DSA titer) (1C). IVIG 100mg/kg after each plasmapheresis treatment or IVIG 2 g/kg at end of plasmapheresis treatments (1C) Corticosteroids (EO). Adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability with high risk graft failure. CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT) Preexisting DSA Active AMR: same as acute ABMR less than 30 days. Chronic AMR:Optimize baseline immunosuppression (eg, add steroids if on a steroid-free regimen) (1C). De novo DSA: Optimize baseline immunosuppression (eg, add steroids if on a steroid-free regimen) (1C) Evaluate and manage nonadherence. CONCLUSIONS: AMR is considered the most common cause of graft dysfunction and still no strong based evidence for treatment and depending on expert consensus hence we need more randomized control trials looking for a powerful guidelines recommendation for improving patients and graft survival. LEVEL OF EVIDENCE 4/5.
amiri elaf
2 years ago
*** Summarise this article
AMR is major cause of kidney graft loss.
*HLA molecular typing and solid phase assays to detect DSA and a more advancing histological classification, the diagnosis of (AMR) has become more common.
* Transplantation Society developed recommendation for appropriate treatment of active and chronic active AMR.
*The aim is to help consensus in evaluation the standard care, treatment with new therapies, the underlying biology of AMR, criteria for diagnosis, clinical phenotypes and outcomes.
# DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
* Banff 2017 classification ofAMR are
(1) Histological evidence of graft injury
* microvascular inflammation (MVI)
* intimal or transmural arteritis (v > 0)
* acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
(2) Histological evidence of antibody-endothelial
interactions either by C4d deposition or at least moderate MVI
(3) The presence of circulating DSA, predominantly anti-HLA antibody.
# All 3 criteria for diagnosis of CAMR
1)Evidence of chronic tissue injury
2)Evidence of current/recent antibody interaction with vascular endothelium
3) Serologic evidence of (DSA, to HLA or other antigens).
.
# CLINICAL PHENOTYPES OF AMR
Early Posttransplant (30 Days) Posttransplant AMR With Preexisting DSA
* Itis indolent and progressive form of AMR that detected on biopsy.
* When detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present.
*MVI tends to persist and is later accompanied by chronic histological
features including transplant glomerulopathy and peritubular basement membrane multilayering.
* Itis minimal if any reduction in (GFR)or proteinuria even when mild chronic features are present.
# Late (>30 Days) AMR Associated With dnDSA.
* Most common form of AMR associated with dnDSA.
* DnDSA detected after >3 months posttransplant due to Inadequate immunosuppression.
*This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR.
* Subclinical, associated with inferior allograft survival or a delay in AMR diagnosis compared with preexisting DSA.
# FEATURES ASSOCIATED WITH REDUCED
ALLOGRAFT SURVIVAL IN LATE AMR
(PREEXISTING OR DNDSA)
* Chronic histological features such as the presence of transplant glomerulopathy, degree of interstitial fibrosis and tubular atrophy, concomitant TCMR, C4d positivity
Vascular lesions , proteinuria, time of diagnosis posttransplant, history of medication and nonadherence ,
the presence of C1q , positive DSA and anti class II DSA, he level or strength of DSA all are independently associated with inferior allograft out come
#CONSENSUS FOR MEASURING AND MONITORING OF DSA
* Initial Assessment for Anti-HLA DSA
*The initial assessment involve HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events.
* Molecular HLA typing ideally includes A;
B; C; DRB1; DRB3; DQA1/DQB1; and DPA1/DPB1.
* The first-line screening for alloantibody with single antigen bead (SAB) solid phase assays, but multiantigen beads can also be used.
* Patients with no history of allosensitizing, negative DSA are at low risk for AMR.
* Monitoring for De Novo DSA is recommended in the following conditions: immunosuppression reduction by physician for any reason, patient nonadherence and at the time of rejection episode.
* The SAB test detecting DSA has limitations due it’s variation between laboratories.
* Positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies.
* Falsely low MFIresult from external substances, bead saturation and“shared-epitope”.
# Additional DSA Testing for Risk Stratification
* Crossmatch testing can be used with SAB testing for AMR risk stratification.
* Hyperacute AMR is associated with having a positive CDC crossmatch, (C1q or C3d) positive results associated with AMR and allograft loss.
*C1q and C3d binding positivity is associated with a high DSA titer.
# AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
* Most studies recommended the use of plasmapheresis & [IVIG], variable use of steroid pulses together with or without different Tcell depleting and Bcell depleting antibodies).
# Plasma Exchange and IVIG
* It removing circulating DSA and reducing DSA production.
*(PLEX) and IVIG Most commonly used to treat active AMR recommended by the expert consensus at the FDA Antibody-Mediated Rejection Workshop in 2017, Kidney Disease, (KDIGO) in 2010 despite the weakness of evidence supporting itis efficacy.
#Complement Inhibitors
* It use to avoid the downstream damage to the allograft from DSA.
* Eculizumab results in terminal complement blockade as a monoclonal antibody targeting C5.
* Study showed that patients with positive crossmatch HLA i the incidence of early active AMR was decreased from approximately 40% to 7%.
# Rituximab
*Is B cell depleting agent, was suggested by KDIGO guidelines.
* Studies suggested the use of rituximab together with steroids, plasmapheresis,
and high dose IVIG, in vascular AMR had some positive effects.
# Imlifidase
* An IgG degrading enzyme of Streptococcus pyogenes (IdeS), rapidly
reduce or eliminate DSA and is undergoing clinical trials in AMR.
* Safely used in highly sensitized patients for desensitization and after administration historic positive crossmatches became negative, within 7–10 days
* Rebound in DSA and anti-IdeS antibodies develop after 1 or 2 doses.
# Antithymocyte Globulin
(ATG) or other Tcell depleting antibodies have been used for
treatment of refractory rejection, vascular rejection, mixed rejections, and AMR.
* No benefit has been showed for treatment of pure AMR with Tcell depleting therapy.
* Rretrospective study suggests the use of ATG in combination with steroids has no effect on the outcome of vascular AMR.
* Side effects is higher risk of infectious & death if it combined with B cell depletion.
# Splenectomy
*In several case it used as a salvage procedure for severe early AMR.
* Must be performed rapidly after the onset of early AMR to be effective.
* Patients had splenectomy are historic sensitized, or recived desensitization therapy.
#Proteasome Inhibitor: *Bortezomib directly targets plasma cells
* Limited data for Its use suggesting a positive effect within treatment regimen of PLEX, IVIG, steroids, and depleting antibodies.
# Cyclophosphamide
* Used for the treatment of antibodymediated diseases( anti neutrophil cytoplasmic antibody vasculitis or lupus nephritis), but there are no trial data to support its use.
# Interleukin-6 Inhibitors
*Tocilizumab suggested to be used in patients with chronic active AMR that
had failed IVIG plus rituximab.
# CONSENSUS FOR TREATMENT OF EARLY ACTIVE
AMR (≤30 DAYS POSTTRANSPLANT)
*The consensus was suggested that the combination of PLEX, IVIG with corticosteroids may regarded as standard of care, while in some centers corticosteroids is reserved for patients with concompetant TCMR.
* They recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability and may be indicated only when the risk of graft loss is high.
# CONSENSUS FOR TREATMENT OF LATE
ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS
POSTTRANSPLANT)
* Preexisting DSA
* Patients with preexisting DSA and active AMR without chronic features, recommended to use PLEX, IVIG and corticosteroids.
* In chronic active AMR or chronic transplant vasculopathy, the aim of therapy to stabilize the GFR, proteinuria, histological injury score, DSA titer and to prevent drug toxicity.
* Un like acute active AMR the use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in chronic active AMR.
* The consensus focus on optimizing immunosuppression
and supportive care, with reintroduction of
steroids when free regimen is used, maintaining trough tac levels >5 ng/mL, blood pressure, blood glucose, and lipid control.
# De Novo DSA
*The standard for managing AMR in case of denovo DSA in case of active or chronic active is to optimize baseline immunosuppression and manage nonadherence.
*Treatment of concomitant TCMR is recommended in all cases .
* As in chronic active AMR with preexisting antibodies, treatment Included PLEX, IVIG, and Rituximab.
*** What is the level of evidence?
Level of evidence 4/5
Manal Malik
2 years ago
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group Introduction:
AMR was the most common cause allograft failure in what of renal transplant recipients with indicated biopsies before graft failure
No guideline for treatment of AMR
The transplant society brought together a group of expert from around the globe for 1-5 days meeting that outlined recommended treatment for active and chronic active AMR BIOLOGY OF THE ALLOIMMUNE RESPONSE:
Generation of antibody secreting cells follow a series events:
1) Alloantigen with B cells expressing the appropriate B cell antigen receptor
2) This event activate B cell migration to the B and T cell interface in the lymph node
3) Where it receive help from alloreactive T cells encountered alloantigen presented indirectly on recipient dendritic cells
4) Some of B cells differentiate into:
a) Memory B cells
b) Short-lived plasmablast
c) Long-lived plasma cells
In presensitized patients have long-lived plasma cells, secreting anti-HLA antibodies and memory B cells secrete large amount of antibody upon antigen expressive leading to rapid antibody response
Receptors of plasma cells and memory B cells are not identical so this difference predict that treatment to prevent plasma cell generating and subsequent DSA production may not stop
The generation of memory B cells Diagnostic criteria and histological features of AMR:
Features of active AMR based on the Banff 2017 classification are:
1) Evidence of grafting via microvascular inflammation acute TMA in the absence of another apparent cause ATN =of any other cause
2) Antibody-endothelial interaction either by c4d deposition or moderate MVI
3) Presence of circulating DSA
Chronic AMR (transplant glomerulopathy)(Banff chronic GN)
1) TG
2) Severe peritubular capillary basement membrane multilayering on electron microscopy 3) New arterial intimal fibrosis without another obvious cause Clinical phenotypes of AMR:
The Banff classification has 3 AMR diagnostic categories:
1) Chronic AMR with TG and current or prior DSA without MVI or c4d AMR
2) Acute sudden allograft =early post renal transplant or subclinical or sublate
3) Anti-HLA antibody can also be pre-existing DSA or develop after transplant(dn DSA) in the setting of under immunosuppression Early post transplant(<30 days) active AMR:
Active AMR can occur in the first 30 days post renal transplant
This form of AMR is uncommon as can be available (pretransplant)
Factors increase the risk of early post transplant AMR:
1) Presence of DSA at time of transplant
2) Crossmatching positive
3) Presence of cross-relative DSA
Speciality presenting:
1) Sudden =and oliguria with or without proteinuria
2) If untreated quickly can lead to graft loss within days
If treated properly and in time graft can received completely Late (>30 days) post -transplant AMR with pre-existing DSA:
This type of AMR is subclinical and progressive form inspite of pre-existing DSA diagnosis on surveillance biopsy
Graft factors it can be stable or mild dysfunction
Histological finding are dependant on the timing of the biopsy
1-=MVI in the glomeruli and PTC +- c4d standering
2-if late include
i)TG
ii ) multilayering late >30 days AMR associated with dn DSA:
de novo DSA detected after 3 months due to inadequate =
it present with allograft dysfunction with pre-existing TCMR
It has subclinical presentation
Graft survival is inferior to AMR with dn DSA compared with AMR from pre-existing DSA Features associated with reduced allograft survival in late AMR(pre-existing or dn DSA):
Predictive of graft failure are:
1) TG
2) Intestinal fibrosis and tubular atrophy
Histological features associated with inferior allograft survival:
1) Concomitant TCMR
2) C4d positive
3) Vascular lesion
Clinical factors associated poor graft outcome:
1) Allograft dysfunction at diagnosis
2) Proteinuria
3) Time of diagnosis post renal transplant
Non adherence and under immunosuppression is major risk factor for dn DSA
Alloantibody characterized associated with graft outcome:
1. CIq positive DSA and anti class2DSA
2. DSA level
3. Flowcytometry cross-match positive Consensus for measuring and maintain of DSA:
Initial assessment for anti-HLA DSA
The initial assessment of renal transplant candidate involve donor and recipient
1. HLA typing
2. Anti-HLA antibody screening
3. History of allo sensitizing event
Anti-HLA-sensitized recipient, high level of typing called 4 digit typing (allelic level)
First line for alloantibody is single antigen head SAB Maintain for de novo DSA:
Development of dn DSA is result from immunosuppression reduction (Non adherence or under==
Maintaining for dn DSA in recommended in the following :
1. Immunosuppression reduction by physician for reason
2. Patients Non adherence to medication
3. At the time of rejection(T cell antibody mediated)
To early predict AMR and avoid graft loss dn DSA close monitoring and kidney biopsy can be done Interpretating positive DSA result:
Positive SAB test detecting DSA varies among laboratory
Positive cut off MFI of 1000-1500
Showed epitope phenomena can lead to falsely low MFI Additional DSA testing for MSK stratification:
The MSKs of AMR from highest to lowest based on crossmatch and SAB-positive testing the following:
1. Positive CDC crossmatch
2. Positive flowcytometric crossmatch and -ve crossmatch
Hyperacute AMR associated with having appositive CDC crossmatch
C1q and C3d banding positivity is associated with a high DSA titre but not applicable for clinical use Available evidence for the treatment of active and chronic active AMR: Plasma exchange and IVIG:
Different intervention create a challenge in the interpretation of treatment effects
Treatment studies for AMR are rarely compatible and the available evidence low quality plasma exchange and IVIG
Aim of plasma exchange to remove circulating DSA
PLEX and IVIG never have FDA approach
The effect of PLEX short term outcome but long term effects remain variable
IVIG combined with PLEX to modulate B cells response Complement inhibitors:
Goal complement inhibitors to avoid graft injury from DSA
A single =small case series has also shows eculizumab effective in the first month post transplantation Active AMR treatment
But still long term or include a clear AMR and allograft survival remain variable
Plasma C1 esterase (-) for treatment of AMR evaluating reassement to FLEX and IVIG in renal transplant recipient is on goining Rituximab:
B cell depleting agents suggest treatment by KDIGO guidelines
Several retrospectives analysis have suggested some positive effects of rituximab in multi-model treatment regimens together with steroids, plasmapheresis, and high dose IVIG especially patients with vascular AMR Imlifidase:
IgG-degrading enzymes of streptococcus pyogens (Ides)
Can rapidly reduce or even eliminate anti-HLA-DSA
Under goining clinical trial in AMR
It has been used safely in highly sensitized patients for desensitization but still clinical trial ongoing in AMR
Disadvantages:
1. Rebound DSA of 7-10 days
2. Anti-Ides antibodies left 1 or 2 days
Advantages:
Highly sensitized patients undergo transplantation within hours of donor regardless of crossmatch status Antithymocyte Globulin:
T cell depleting antibodies
Indications:
1. Refractory rejection
2. Vascular rejection
3. Mixed rejection and AMR
No benefit for treatment of pure AMR have been demonstrated Splenectomy:
Splenectomy used as salvage procedure for some early AMR
It must be performed rapidly after the onset of early AMR to be effective Proteasome Inhibitor: Bortezomib:
Bortezomib is a protease inhibitor approval for the treatment targeting antibodies
Producing plasma cells
No trial data to support it use Cyclophosphamide:
No trial data to support it use nterleukin-6 Inhibitors:
large multicentre randomized control trial for tocilizumab has been started to evaluate it
clazakizumab:
Is an anti-interleukin-6 monoclonal antibody for the treatment of chronic active AMR CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT):
Limited data and quality for treatment option of active AMR
Standard of care for treatment of AMR are combination of PLEX ,IVIG with corticosteroid
Because of limitation of trials of different combination therapies for AMR
No available drug evidence to support its use as adjunct
Adjunctive agents in treatment of AMR:
The recommended adjunctive therapy include complement inhibitors , rituximab or splenectomy depend on availability
Concomitant TCMR should be treated CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT): preexisting DSA:
Active AMR without chronic features and no preexisting DSA the treatment recommendation include : PLEX,IVIG and corticosteroids
Chronic active AMR or chronic transplant vasculopathy stabilized the eGFR ,proteinuria by:
1. Optimizing immunosuppression
2. Reduction of steroids (if steroids-free regimens)
3. TAC trash level>5 ng/ml
4. Optimize the Bp, blood glucose and lipid control De Novo DSA:
dnDSA occurs of reduction of immunosuppression
AMR usually associated with TCMR
Treatment of concomitant TCMR is recommended in all cases of AMR Conclusion:
AMR usually has poor outcome low high level of evidence to support the use of any therapy
There were no clear treatment regimens to recommend and there is no approved treatment
Level4/5
Thank You, you need to shorten your summary Dr Manal
Mohamed Mohamed
2 years ago
II. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group Summarise this article Introduction This expert group produced these consensus recommendations to overcome the lack of evidence-based guidelines for the treatment of active & chronic active AMR. Diagnostic features of AMR Banff 2017 features of active AMR: (1) histological evidence of graft injury: – MVI, – intimal or transmural arteritis (v > 0), – acute TMA in the absence of any other cause, or – acute tubular injury in the absence of any other apparent cause (2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and (3) the presence of circulating DSA, predominantly anti-HLA antibody. To diagnose CA-AMR, morphological features of chronic tissue injury are present in addition to criteria 2 & 3 for active AMR. Signs of chronic tissue injury include:
– TG (Banff cg score > 0),
– Severe PTC BM multi-layering on EM, or
– New arterial intimal fibrosis with no other cause. AMR is frequently a chronic progressive process that starts with the formation of DSA. DSA may or may not lead to active AMR, & not all active AMR will progress to CAMR. Over time, chronic histological features such as TG become evident, & eventually, the patient develops allograft dysfunction, proteinuria, & may be graft loss. Early posttransplant (<30 Days) active AMR DSA present at the time of transplant or there is an immunologic amnestic response due to previous exposure to allo-HLA. The risk increases with growing DSA strength (mean MFI), the degree of FCM-XM positivity, & the number or breadth of cross-reactive DSA specificities. This form of AMR is uncommon, as transplant is usually avoided if preformed DSA is found. Late (>30 Days) posttransplant AMR with preexisting DSA A more indolent & progressive form of AMR Detected on a protocol biopsy or on biopsy for mild graft dysfunction. MVI in glomeruli & PTCs is the predominant finding C4d staining may or may not be present. MVI persists & later chronic histological features , including TG & PTC BM multi-layering occurs. Late (>30 Days) AMR associated with dnDSA
It the most common form of AMR. dnDSA usually appear after >3 months post-transplant in the context of inadequate IS(non-adherence, iatrogenic, or genetically determined variability in metabolism of IS drugs). Presents with allograft dysfunction & concomitant or preexisting TCMR. Inferior allograft survival when compared with AMR from preexisting DSA. There is tendency to increased proteinuria, increased expression of interferon-γ–inducible, NK cell, & T-cell transcripts at presentation compared with patients with preexisting DSA. Features associated with reduced allograft survival in late AMR (preexisting or dnDSA)
– Presence of TG & the degree of IF/TA
– Concomitant TCMR
– C4d positivity
– Vascular lesions (Banff cv score >0)
– Proteinuria
– Time of diagnosis post-transplant.
– Non-adherence
– The presence of C1q positive DSA
– Anti-class II DSA
– The level or strength of DSA Initial Assessment for Anti-HLA DSA HLA typing Anti-HLA antibody screening H/O previous transplant, blood transfusion, & pregnancy. Molecular HLA typing ideally includes A; B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; & DPA1/DPB1 SAB is the 1st-line screening method for alloantibodies Multiantigen beads can also be used. Monitoring for dnDSAisrecommended in the following: IS reduction by physician for any reason. Known patient non-adherence. At the time of any rejection episode. Interpreting positive DSA results A positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies. Falsely low MFI SAB can result from interference from external substances, bead saturation, & “shared-epitope” phenomenon.
========================================== Available evidence for the treatment of active & chronic active AMR: Plasma Exchange & IVIG Remove circulating DSA & reduce DSA production. Are the most commonly used treatments(not FDA approved). Expert consensus at the FDA AMR Workshop in 2017 as well as KDIGO in 2010 state that PLEX & IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy, especially on long-term outcomes. Complement Inhibitors Eculizumab is a monoclonal antibody that targets C5 & blocks the terminal complement system. Decreased early active AMR in positive XM HLA-i transplants (single center study). Two multicenter randomized phase 2 trials confirmed its protective effect for preventing early active AMR in positive XM HLA-i living & deceased donor transplants. Long-term effect was comparable to controls(single-center study). C1 esterase inhibitors indicate a possible improvement in graft function in AMR (2 pilot studies). An ongoing trial (NCT03221842) is evaluating a C1 esterase inhibitor for the treatment of AMR that is resistant to PLEX & IVIG. Rituximab (B-cell–depleting agent) Suggested as a treatment option by KDIGO guidelines. No clear benefit was seen in 3 small randomized trials. A reasonable safety profile. Other studies showed no difference between rituximab & control groups or standard of care populations. Several retrospective studies suggested some positive effects of rituximab in multimodal treatment regimens together with steroids, PP, & high-dose IVIG, especially on patients with vascular AMR. Imlifidase (an IgG-degrading, IdeS): Reduces or even eliminate anti-HLA DSA Is undergoing clinical trials in AMR. IdeS cleaves human IgG at a highly specific amino acid sequence & effectively blocking CDC & antibody dependent cellular cytotoxicity. Was safely for desensitization in highly sensitized patients. Rebound DSA & anti-Ides antibodies develop within 7-10 days, thus preventing repeated administrations. Unlikely to be used alone as treatment for active or chronic active AMR. It can allow highly sensitized patient to transplanted within hours of a donor being identified irrespective of the XM status. Antithymocyte Globulin Proposed by KDIGO as potential treatment option. No benefit has been shown for treatment of pure AMR. No prospective trial for use in AMR. A large retrospective trial showed no effect on outcome in vascular AMR when used combined with steroids. Higher risk of infectious-associated death. Splenectomy Used as a salvage procedure for severe early AMR (several case series) It must be performed rapidly after the onset of early AMR to be effective. Proteasome Inhibitor: Bortezomib Limited data (case series) suggest a positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, & depleting antibodies. A single prospective randomized trial in “late” AMR did not show any beneficial effect. Interleukin-6 Inhibitors Tocilizumab was superior to historical controls in the treatment of CA-AMR that had failed IVIG plus rituximab (a single-center, nonrandomized trial). Consensus for treatment 1. Early active AMR (≤30 days posttransplant) Combination of PP, IVIG & steroids could be regarded as standard of care (consistent with the conclusions of the FDA workshop & KDIGO guidelines). Some centers use steroids only when there is concomitant TCMR. In the absence of trial data, adjunctive therapy may be used only when the risk of graft loss is considered high. The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy. 1. Late active & CA-AMR (≥30 days posttransplant) Preexisting DSA The consensus treatment recommendations include PP, IVIG, & steroids.
The aim is to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, & titer of DSA while minimizing drug toxicity. The consensus also focuses on optimizing IS & supportive care, reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, & optimizing control of BP, blood glucose, & lipid. De Novo DSA The standard in this setting (active or chronic active) is to optimize baseline IS & manage potential non-adherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases. Similar to patients with CA-AMR in the context of pre-existing antibodies, treatment with PP, IVIG, & Rituximab is used in some centers, though the evidence level is low. ======================================= What is the level of evidence?
Despite advances in transplant immunology, implementation of high resolution single antigen bead in antibody screening, and standardization of immunosuppression, AMR remains the most common cause of allograft failure.
The current recommendation on immunosuppression lack prospective studies and strong evidence, and most of the recommendation and suggestion are based on low evidence and retrospective studies.
AMR diagnosis according to Banff 2017 classification:
Active AMR features:
1-Histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis , acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
2- Histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI
3- The presence of circulating DSA, predominantly anti-HLA antibody
AMR clinical phenotypes
Early Posttransplant (<30 days ) Active AMR
Early AMR occurs in patients who are presensitized. The risk increases with increasing DSA level at the time of transplant (high MFI), the degree of flowcytometry crossmatch positivity, and other factors.
This type of AMR became uncommon because of advances in detection of preformed DSA, desensitization protocols and prescription of aggressive induction and maintenance therapies.
Late (>30 Days) Posttransplant AMR With Preexisting DSA
It is an indolent form and commonly subclinical detected in a protocol biopsy. When detected early, MVI in glomeruli and peritubular capillaries is predominant and C4d staining may or may not be present. MVI tends to persist and is associated with chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering. There is minimal if any reduction in GFR or proteinuria even when mild chronic features are present
Late (>30 Days) AMR Associated With dnDSA
This is the most common form of AMR which leads to chronic allograft failure.new Detection of de nove DSA >3 months posttransplant due to inadequate immunosuppression ether due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs.
The presentation is subclinical and slowly progressive. AMR with de novo DSA is associated with inferior allograft survival compared with AMR from preexisting DSA.
Consensus for DSA monitoring
Initial Assessment for Anti-HLA DSA
HLA typing an antibodies screening
For anti-HLA–sensitized recipients, a high-resolution level of typing.
Patients with no history of sensitization and negative antibody testing using solid-phase assays are at low risk for AMR.
Monitoring of De Novo DSA is preferable in cases, requiring immunosuppression reduction for specific reasons, nonadherence, or at the time of rejection episode.
Positive DSA Results assessment
SAB test has limitations, because it is liable to interference from external effectors
Positive cut off MFI of 1000–1500 is associated with anti-HLA antibodies presence.
DSA Testing for Risk Stratification
Hyperacute AMR is associated with positive CDC crossmatch.
C1q and C3d binding positivity is associated with a high DSA titer
Evidence for treatment of active and chronic active AMR
Multiple studies addressed different mix of therapies as plasmapheresis, intravenous immune globulins , steroid pulses with or without different T-cell–depleting and B-cell–depleting antibodies.
Plasma Exchange and IVIG
First line treatment in active AMR.
PLEX and IVIG could be a standard treatment for acute active AMR according to the FDA Antibody-Mediated Rejection Workshop in 2017 and KDIGO.
Complement Inhibitors
Ecluzimab a monoclonal antibody targeting C5
Multiple trials revealed the preventive role of eculizumab for early active AMR in positive crossmatch HLA-incompatible living and deceased donor recipients.
C1 esterase inhibitors Berinert and Cinryze showed a possible improvement in allograft function in kidney recipients with AMR.
Rituximab
anti CD20 is used in combination with other therapies, as complementary effect. Some studies did not demonstrate any positive effect in combination with other modalities while other studies revealed some positive effect when used with IVGV high dose, plasma exchange and steroids particularly with vascular AMR.
Imlifidase
IgG-degrading enzyme of Streptococcus pyogenes (IdeS is used for desensitization in highly sensitized cases and also used in the treatment of resistant AMR.
ATG
Used in induction therapy for high risk patients, and also for the treatment of refractory rejection, vascular rejection, mixed rejections and AMR. If combined with B cell depleting agent it has high life threatening infection risk .
Splenectomy
it is no more used, and replaced by B cell depleting agent, Rituximab.
Proteasome Inhibitor: Bortezomib
bortezomib is effective as inhibitor of plasma cells, but does not have effect on produced antibodies. It is a candidate for the treatment of active AMR in a multimodal treating regimen.
IL6 inhibitors
Toclizumab revealed acceptable results in treating chronic active AMR after failure of IVIG and rituximab.Clazakizumab is studied for treating chronic active AMR
Treatment of early active AMR Consensus (≤30 days transplanation)
Standard treatment of care includes the combination of PLEX, IVIG with corticosteroids in agreement with KDIGO guidelines.
The adjunctive therapies include complement inhibitors, rituximab, or splenectomy can be needed especially when the risk of graft loss is high and concomitant TCMR is present.
Treatment of late active and chronic AMR consensus (≥30 days posttrasnplant)
For patients with chronic active AMR maintenance immunosuppression should be optimized with reintroduction of steroids (if on a steroid-free regimen), targeting higher trough tacrolimus levels >5 ng/mL.
INTRODUCTION
Despite current immunosuppression, alloantibody-induced kidney damage and transplant loss persist.
HLA antigens drive this response. The impact of HLA antibodies on kidney allograft survival has been known for some time, but the size of the problem has only recently been realized with the advent of sensitive solid-phase assays to detect donor-specific anti HLA antibodies (DSA) and the Banff diagnostic criteria for antibody-mediated rejection (AMR). Following 10 years, 25% had de novo DSA after a kidney transplant (dn DSA).
AMR was the leading cause of transplant failure in a Review Abstract group. With new solid-phase techniques to identify anti-HLA antibodies and a more exact histology categorization, antibody-mediated rejection (AMR) is a prominent cause of kidney transplant failure. No medicines are licensed, and treatment recommendations are based on low-quality research.
clinical manifestations of AMR
There are three different AMR diagnostic categories in the Banff classification, one of which is chronic AMR with transplant glomerulopathy and another is present or previous DSA without MVI or C4d.
AMR may manifest itself via acute allograft malfunction early on in the recovery process after a transplant, or it can have a subclinical beginning and manifest itself later on in the recovery process. Anti-HLA antibodies may be a preexisting DSA or develop after transplant (dn DSA) in the context of inadequate immunosuppression. Both of these scenarios are possible.
–
Early posttransplantation (less than 30 days after) AMR in use
Increased DSA levels at the time of transplant, as measured by DSA mean fluorescence intensity (MFI), the degree of flow cytometric crossmatch positive, and the number or breadth of cross-reactive DSA specificities are all factors that contribute to an increased risk of this condition.
This condition is very rare and is characterized by a sudden rise in DSA levels that is followed by allograft malfunction.
AMR after more than 30 days after the transplant with preexisting DSA
It was discovered via a surveillance biopsy that this forum is rather harmless.
When the disease is identified in its early stages, MVI predominates in the glomeruli and peritubular capillaries, and C4d staining may or may not be present. MVI has a tendency to persist and is linked with chronic histological characteristics such as peritubular basement membrane multilayering and transplant glomerulopathy.
Even in cases where only minor chronic characteristics are present, there is only a little, if any, drop in GFR or proteinuria.
AMR Associated With dn DSA That Is Late (Greater Than 30 Days)
Which of the following is the most prevalent type of antimicrobial resistance: new DSA detected after more than three months post-transplant as a result of inadequate immunosuppression brought on by either patient nonadherence, physician direction, or genetically determined variability in the metabolism of immunosuppressive drugs?
It manifests itself with allograft malfunction in addition to concurrent or previous TCMR.
Subclinical manifestations are seen, which are comparable to those of late posttransplant AMR in individuals with preexisting DSA.
When compared to AMR caused by preexisting DSA, AMR caused by dn DSA is linked with a worse rate of transplant survival.
The following characteristics, present in late-stage AMR (pre-existing or dn DSA), are associated with a worse allograft survival rate:
Chronic histological aspects such as transplant glomerulopathy, the degree of interstitial fibrosis, tubular atrophy, TCMR positive, and vascular lesions. Other chronic histological findings include C4d positivity.
-Patients who have no history of sensitization and who have anti-HLA antibody testing results that are negative utilizing single-antigen or multiantigen bead solid-phase tests are at minimal risk for AMR.
Monitoring of the newly developed DSA
Particularly during periods of immunosuppression decrease, known instances of patient medication nonadherence, or during episodes of rejection.
There is evidence for the treatment of active and chronic active AMR.
Multiple trials looked at various combinations of treatments, such as plasmapheresis, intravenous immune globulins (IVIG), and steroid pulses, with or without certain antibodies that deplete T cells and B cells.
Plasma Swap and Intravenous Immunoglobulin are routinely used in the treatment of active AMR.
-Both the FDA Antibody-Mediated Rejection Workshop in 2017 and the KDIGO in 2010 noted that PLEX and IVIG might become a routine therapy for acute active AMR; nevertheless, the effects that these treatments have over the long term are varied.
-Ecluzimab is a monoclonal antibody that targets the protein C5.
-Multiple clinical tests demonstrated that administering eculizumab before the onset of early active AMR in positive crossmatch HLA-incompatible live and dead donor recipients were effective.
-Imlifidase
an IgG-degrading enzyme found in Streptococcus pyogenes called IdeS, which may reduce anti-HLA DSA levels and is now being studied as a potential therapy for AMR but has been shown to cause a rebound rise in DSA levels.
In the most severe instances of hypersensitivities, it is used as a desensitizer.
The use of this medicine in highly sensitized patients enables transplantation to take place within hours of a donor being available, regardless of the crossmatch status. This is one of the drug’s many benefits.
-ATG
used as a therapy for AMR, refractory rejection, vascular rejection, and mixed rejections.
-Splenectomy
In order for it to be successful, it must be carried out promptly following the first signs of early AMR.
-Inhibitor of Proteasome Activity: Bortezomib
Is a candidate for the treatment of active AMR in a therapeutic regimen that utilizes several methods.
-IL6 inhibitors
In the treatment of chronic active AMR, tocilizumab showed outcomes that were tolerable after IVIG and rituximab were unsuccessful.
-Rituximab
Some studies did not find any evidence of a good benefit when IVGV was combined with other treatment modalities, whereas other studies did find some evidence of a favourable effect when IVGV was combined with high-dose IVGV, plasma exchange, and steroids, especially in the case of vascular AMR.
-The treatment of early active AMR Consensus (less than thirty days after transplantation)
In a manner analogous to the findings of the FDA workshop and the KDIGO recommendations, the combination of PLEX, IVIG, and corticosteroids may one day become the standard therapy of care.
-Treatment of late-stage active and chronic AMR consensus (less than 30 days post-transplant).
Treatment options include PLEX, IVIG, and corticosteroids for individuals who have preexisting DSA as well as current AMR that does not have chronic characteristics.
In situations with chronic active AMR, optimal immunosuppression requires the return of steroids (if the patient was previously following a steroid-free regimen), while also maintaining trough tacrolimus levels of more than 5 ng/mL.
Optimizing immunosuppression and treating probable drug nonadherence and concomitant TCMR is also important in situations with de novo DSA.
Diagnosis of ABMR according to Banff 2017 Three components are required for the diagnosis of acute ABMR:
1-Histologic evidence of acute tissue injury (capillaritis and/or glomerulitis) or unexplained TMA or ATN
2-Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs]) or at least moderate MVI
3-Serologic evidence of circulating DSAs
Three components are required for the diagnosis of chronic active ABMR :
1-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
2-Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or At least moderate microvascular inflammation (g + ptc >2)
3-Serologic evidence of circulating DSAs CLINICAL PHENOTYPES OF AMR: Early Posttransplant (<30 Days) Active AMR
Preexisting DSA (or nonimmunologically naive), Usually C4d+,Thrombotic microangiopathy often present
Abrupt allograft dysfunction correlating with increased DSA MFI or titer usually 7–10 days post transplant Late (>30 Days) Posttransplant AMR With Preexisting DSA
Preexisting DSA, May be C4d± Allograft dysfunction and proteinuria, Late (>30 Days) AMR Associated With dnDSA
De novo DSA, May be C4d± Concomitant TCMR often present Consensus for measuring and Monitoring of DSA ;
DSA should be monitored once in early post-transplant period (first 3 month) in all patients. Includes donor and recipient HLA typing, anti HLA antibody screening with SAB. For sensitized patients, high resolution typing. Monitoring for dnDSA: whenever there is reduction of immunosuppression, suspected non adherence or at time of rejection episode.Interpretation of positive DSA results: SAB test has several limitations as positive cutoff values varies between labs, may lead to falsely low MFI due to “shared epitope phenomenon” and bead saturation. Hyperacute AMR is associated with positive CDC crossmatch.C1q and C3d binding positivity is associated with a high DSA titer .Routine use of complement binding assays is not recommended. DSA IgG subclass is not clinically validated.
Initial assessment for anti-HLA DSA ; This should include HLA typing, anti-HLA antibody screening, history of allo-sensitization (IA). Treatment of active & chronic active rejection:
PLEX & IVIG
Complement inhibitors
rituximab
Imlifidase
ATG
Splenectomy
Proteosome inhibitors( bortezumib)
Cyclophosphamide
IL-6 inhibitors
1) For Early active AMR: Standard of care includes plasmapheresis with IVIG and corticosteroids Other adjunct therapies include Complement inhibitors, Rituximab and Splenectomy.
2) For Late active AMR with pre-existing DSA: Standard of care includes plasmapheresis with IVIG and corticosteroids while Rituximab can be used as adjunct therapy.
3) For Late active AMR with de novo DSA: Standard of care includes optimization of immunosuppression and strict compliance in case of non-adherence, if any. Plasmapheresis, IVIG and Rituximab are useful as adjunct therapies.
4) For Late chronic AMR with pre-existing or de novo DSA: Standard of care includes optimization of immunosuppression while IVIG can be used as adjunct therapy Level of evidence 4/5
Despite advances in renal transplant management , antibody mediated injury to graft is a significant factor of graft loss. With the development of SAB and Banff system, the magnitude of problem has been realized. There no well agreed guideline of management to antibody mediated rejection. This publication is the outcome of transplant society meeting inviting people from around the globe.
Diagnostic criteria and Histological feature of Acute AMR
As per Banff 2017
1- Histological evidence of injury via microvascular injury- MV1, intimal or transmural arteritis,, acute TMA, in the absence of any other cause.
2- Antibody endothelial interaction -C4d deposition or at least MV1
3- Presence of circulating DSA
Diagnosis of Chronic AMR
1- TG or multilayering of PTC basement membrane, or Chronic arteriopathy, no acute inflammation.
2- C4d staining in PTC or M
3- Presence of DSA
Phenotypes of AMR
Early post transplant active AMR – < 30 days
Presents as early graft dysfunction. Usually DSA present before transplant. Occurs < 30 days, Related with mean channel shift and MFI. C4d positive.
Late AMR with pre existing DSA- >30 days
It is progressive and can diagnosed clinically of by protocol biopsy. C4d may be positive. It has poor outcome
Late AMR with denovo DSA- >30 days
It is most common and can be due to non adherence or improper immune suppression . C4d may be positive. Diagnosis can be clinical or by protocol biopsy.
Consensus for monitoring of DSA
It should include –
HLA typing -A,B,C,DR, DQ, DP (2B)
Anti HLA antibody check by SAB ( it cab be affected by shared epitope, bead saturation or external factors)
Check for denovo DSA in suspected rejection or less immune response.
Further testing for Risk stratification will depend on cross match result IgG subclasses and Compliment binding DSA
Consensus for treatment of early active AMR (≤30 days post transplant)
Consensus was combination of PLEX, IVIG and steroid in line with KIDGO guidelines. Use adjuvant therapy if risk of graft loss is high(complement inhibitors, Rituximab, or Splenectomy). Concomitant TCMR should be treated
Consensus for treatment of late active and chronic active AMR (≥30 days post transplant)
Pre Existing DSA
Control medical conditions and Optimize immunosuppression
Keep tacrolimus trough levels more than 5 ng/ml
Denovo DSA
Optimize immunosuppression
Control medical conditions and treat concomitant TCMR
Conclusion.
AMR is a significant challenge in renal transplantation , there is lack of high level of evidence to support therapies available. This Conesus statement is based on observational studies, low level evidence, but still it was necessary to establish a benchmark for future research. New agents and clinical trials are required
Level of Evidence -4/5
Amit Sharma
2 years ago
Summarise this article
The Transplantation Society Working Group recommended expert consensus treatment for active and chronic active antibody-mediated rejection (AMR) in kidney transplant recipients after evaluating the underlying biology of AMR, diagnostic criteria, clinical phenotypes and their outcomes as well as the evidence of different treatments. By 10 years post-transplant, 25% of patients develop de novo DSA. AMR is one of the most common etiology of graft failure.
Biology of AMR: The alloantigen presents to B cell antigen receptor on B cell which migrates to T/B cell interface in lymph node giving rise to memory B cells and short-lived plasma cells. The B cell enters germinal centre of lymph node producing high affinity and class switched memory B cells, plasmablasts and long-lived plasma cells giving rise to antibodies. In an immunologically naïve individual, this is how antibody secreting formed. In a pre-sensitized individual, the presence of preformed long-lived plasma cells (secreting anti-HLA antibodies) and resting memory B cells (which can secrete large number of antibodies on exposure to antigen) can lead to rapid anamnestic antibody response.
Diagnostic criteria of AMR: The diagnostic criteria for AMR (active, chronic active and chronic AMR) are as per the Banff 2017 classification.
Clinical phenotypes of AMR: The clinical phenotypes of AMR include either an early post-transplant AMR having an abrupt, rapid graft dysfunction or a late post-transplant AMR with slow, subclinical onset having.
a) Early onset (<30 days) active AMR: It is due to pre-existing DSA (response to memory B cells) and is seen in up to 40% of patients with preformed DSA and a positive flowcytometry crossmatch. Biopsy usually reveals C4d positivity and interstitial hemorrhage, glomerular fibrin thrombi and microvascular coagulative necrosis. Prompt treatment can reverse these changes, but if urgent action not taken, it can lead to cortical necrosis and graft loss within days.
b) Late (>30 days) posttransplant AMR with pre-existing DSA: It is in response to pre-existing plasma cells, presenting with progressive and indolent graft dysfunction having microvascular inflammation with or without C4d positivity leading to chronic changes later on and graft loss within months to years.
c) Late (>30 days) posttransplant AMR with de novo DSA: It is the most common form of AMR, usually caused by underimmunosuppression, leading to graft loss within months to years.
AMR with de novo DSA has poorer outcomes as compared to pre-existing DSA. Features associated with decreased graft survival include positive pretransplant crossmatch (T cell CDC positive or high flowcytometry crossmatch); biopsy features of Banff cg>0, higher degree of IFTA, concomitant T cell mediated rejection, Banff cv score >0 and C4d positivity; proteinuria, underimmunosuppression, high DSA MFI, anti-class II DSA and C1q positive DSA.
Measuring and monitoring DSA: Initial evaluation should include history of prior sensitization, donor and recipient HLA typing (including A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1/DQB1 and DPA1/DPB1) and anti-HLA screening using single antigen bead (SAB) solid phase assay. Patients with DSA are at some risk for AMR; hence crossmatch testing can be used for risk stratification with a positive CDC crossmatch having higher risk than a positive flow cytometry crossmatch. Monitoring for de novo DSA is recommended in setting of rejection, non-adherence or immunosuppression reduction.
Evidence for treatment of active and chronic active AMR: a) Plasma exchange and IVIG: Anti-HLA antibody removal has been shown to be associated with better graft outcomes and IVIG has pleiotropic effects, although the evidence is largely involving case series and poorly controlled randomized trials b) Complement inhibitors: Eculizumab use has been shown to decrease early active AMR incidence, but no change in long-term incidence of chronic AMR or graft survival. c) Rituximab: Randomized trials have not shown benefit although retrospective studies have shown a positive effect especially in patients with vascular AMR. d) Imlifidase/ Ides: Can be an adjunct to other therapies to decrease DSA in long term. e) ATG: No benefit in pure AMR. f) Splenectomy: Used as a salvage procedure, but must be done early to be effective. g) Proteasome inhibitor: Bortezomib use has not been supported by trail results. h) Cyclophosphamide: No trial data to support its use. i) Interleukin-6 inhibitors: Tocilizumab in AMR refractory to IVIG and rituximab has been shown to have marked decrease in DSA and stabilization of graft function. Consensus treatment: There is very little high level evidence to support any treatment modality. 1) For Early active AMR: Standard of care includes plasmapheresis with IVIG with corticosteroids and adjunct therapies include Complement inhibitors, Rituximab and Splenectomy 2) For Late active AMR with pre-existing DSA: Standard of care includes plasmapheresis with IVIG and corticosteroids while Rituximab can be used as adjunct therapy. 3) For Late active AMR with de novo DSA: Standard of care includes optimization of immunosuppression and managing nonadherence, if any. Plasmapheresis, IVIG and Rituximab are useful as adjunct therapies. 4) For Late chronic AMR with pre-existing or de novo DSA: Standard of care includes optimization of immunosuppression while IVIG can be used as adjunct therapy.
AMR is a major cause of graft dysfunction with no evidence based guidelines for prevention and treatment, so a consensus was developed to recommend treatment for active and chronic active AMR. Diagnostic criteria of AMR:
According to Banff 2017 classification (all 3 criteria must be present) Active AMR: 1-Histological evidence of acute tissue injury, 2-evidence of current/recent antibody interaction with vascular endothelium and 3-serological evidence of DSA which can be substituted by C4d staining or expression of validated transcripts. Chronic active AMR: Histological evidence of chronic tissue injury with criteria 2 and 3 of active AMR Clinical phenotypes of AMR: Early active AMR:
<30 days post transplant, present with acute dysfunction and rising MFI of DSA within 7-10 days post transplant, usually C4d positive.
mediated by memory B cell response
With prompt diagnosis and treatment, kidney functions may be restored and the histological features resolve.
Cortical necrosis and graft loss may occur within days if not well treated. Late AMR with preexisting DSA:
After 30 days post transplant, present with indolent progressive course with mild decline in GFR and proteinuria.
Histological findings show MVI in glomeruli and PTC, C4d may be positive.
Leads to graft loss over years. Late AMR associated with dnDSA:
The most common form, dnDSA are DSA detected after 3 months post transplant mostly due to inadequate immunosuppression and present with graft dysfunction and proteinuria
Associated with concomitant or pre-existing TCMR
Leads to poorer graft survival than late AMR with preexisting DSA. Features associated with decreased allograft survival in late AMR:
Allograft histology determine the chronicity and extent of injury
TG, degree of IF/TA, concomitant TCMR, C4d positivity and vascular lesions
Graft dysfunction at diagnosis, proteinuria and timing of diagnosis
Underimmunosuppression and nonadherence. Consensus for measuring and monitoring of DSA: Initial assessment for anti-HLA DSA:
Includes donor and recipient HLA typing, anti HLA antibody screening with SAB
For sensitized patients, high resolution typing. Monitoring for dnDSA:
Recommended when there is decrease in immunosuppression, suspected non adherence or at time of rejection episode. Interpretation of positive DSA results:
SAB test has several limitations as positive cutoff values varies between labs, may lead to falsely low MFI due to “shared epitope phenomenon” and bead saturation. Additional DSA testing for risk stratification:
Crossmatching and SAB tests are used with highest risk with positive CDC crossmatch, moderate risk in positive FCXM and the lowest risk in negative crossmatch.
Routine use of complement binding assays is not recommended.
DSA IgG subclass is not clinically validated. Available evidence for the treatment of active and chronic active AMR:
Available evidence is of low quality. Plasma exchange (PLEX) and IVIG:
Considered as a standard of care for acute active AMR, however, not FDA approved.
They remove circulating DSA with immunomodulation.
The amount of PLEX and doses of IVIG are not well defined. Complement inhibitors, Eculizumab, cause terminal complement blockade with promising results but with no studies on long-term graft and patient survival. Rituximab, B cell depleting agent, evidence for its use is low, the optimal dose and effect on patient is still unclear. Imflidase, an IgG degrading enzyme, still under clinical trial with no available data about its use in AMR. Anti-thymocyte globulin (ATG) used for treatment of refractory rejection, vascular rejection, mixed rejections and AMR. However, its use in treatment of pure AMR showed no benefit. Splenectomy was used as salvage procedure for severe early AMR. Poteasome inhibitor, Bortezomib, target antibody producing plasma cells, no available trial data to support its use in AMR. Cyclophosphamide, used for treatment of antibody mediated disease but no trial data to support its use IL-6 inhibitors, Tocilizumab, still under trial for use in treatment of chronic active AMR. Consensus for treatment of early active AMR:
The consensus considered PLEX, IVIG and steroids as standard of care.
Adjunctive therapy (including complement inhibitors, rituximab or splenectomy) is recommended when there is high risk of graft loss
Concomitant TCMR should be treated. Consensus for treatment of late active and chronic active AMR: Preexisting DSA: No chronic features: PLEX, IVIG and steroids are recommended. Chronic active AMR: optimizing immunosuppression, supporting care, reintroduction of steroids, maintaining Tac level>5ng/mL and optimizing medical management as control of BP and lipid profile aiming to decrease proteinuria and the decline in GFR with decreasing drug toxicity De novo DSA:
Optimization of baseline immunosuppression and management of potential non-adherence
Treatment of concomitant TCMR
Evidence of using PLEX, IVIG or rituximab is low.
Summary:
AMR is a leading cause of graft loss ( acute & chronic). No accepted guidelines for treatment of AMR & there are no FDA approved therapy for prevention & treatment.
The Transplantation Society produce recommendation for treatment of active & chronic active AMR ( based on beast available evidence).
In immune naive individual, activation of antibody-secreted cells follow series of check point events:
expressing of B cells to B cell Ag receptors.
migration of B cells to lymph nodes ( with help of reactive T cells & present it of dendritic cells).
differentiation in to memory cells( or short lived plasmablast) & class switch memory B cells, plasma blast & long lived plasma cells.
In presensitized patients, they have long lived plasma cells that secret anti-HLA Abs & resting memory B cells which can release large amount of Abs where re-exposed to Ags.
Memory B cells have less mutation & lower affinity than plasma cells, plasma cells & Abs they produce are more restricted ( up to 100 fold) than memory B cells. These differences predict that treatment to prevent plasma cells activation & subsequent Abs production not affect memory B cells activation.
Histological diagnosis of acute rejection according Banff classification:
histological evidence of raft injury(MVI), intimal or transmural arteritis, acute TMA( in absence of other causes) or acute tubular injury.
Histological evidence of Ab- endothelial interaction ( C4d deposition or at least modest MVI).
presence of circulating DSA.
Diagnosis of chronic active AMR had same criteria 1 & 2 of acute AMR in addition to TG, capillary basement membrane multilayering or new intimal fibrosis.
Clinical phenotypes of AMR:
Early post transplant (<30 days) active AMR: This can occur in patients with preformed DSA (sensitized patients). The risk of this type increased with DSA strength , degree of FCXM positivity & number of cross reactive DSA specificities. It is uncommon type, with C4d positivity, if diagnosed early with proper treatment can be resolved completely, but in some cases histological changes can persist to chronic AMR leading to graft loss.
Late post transplant (>30 days) with preformed DSA: developed as indolent & progressive which can detected by protocol biopsy( graft function normal) or by for cause biopsy( mild graft dysfunction). C4d may be positive or negative, it can progressed to TG & multilayering of PT basement membrane & over time GFR reduced with evident proteinuria & end with graft loss ( several years post transplant).
Late (>30 days) AMR with dnDSA: usually dnDSA occur >3 months due to inadequate immunosuppression ( non adherence, physician directed or genetically determined variability in drug metabolism). It associated with inferior outcome when compared with AMR & preformed DSA.
Inferior graft outcome associated with:
TG.
agree of IFTA.
TCMR.
C4d positivity.
Vascular lesion.
graft dysfunction at diagnosis
proteinuria.
time of diagnosis post transplant.
Abs characteristics ( C1q-positive DSA, class II DSA)
Measuring & monitoring of DSA:
Initial assessment for anti-HLADSA: assessment of transplant candidate include donor & recipient HLA typing ( -A, -B, -DRB1, -DRB3,4,5, DQA1, DQB! & DPA! &DPB1), anti-HLA Ab screening ( SAB, multiAg beads) & history of sensitization events ( pregnancy, blood transfusion & previous transplantation).
Monitoring of de novo DSA: recommended in following situation: reduction of immunosuppression by physician, known patient non compliance, & at time of rejection.
Interpretation of positive DSA results: SAB had several limitation ( high coefficient variation, interference with external substances & shared epitopes phenomenon ), so the serum dilution or using of ethylendiaminetetraacetic acid to identify interference & bead saturation .
additional DSA testing for risk stratification: risk of AMR is high when CDC & FCXM are positive & SAB positive, & low risk when CX is negative. C1q & C3d binding positive assay associated with high DSA.
Treatment of active & chronic active rejection:
PLEX & IVIG
complement inhibitors
rituximab
Imlifidase
ATG
splenectomy
proteosome inhibitors( bortezumib)
cyclophosphamide ( primary use in ANCA vasculitis & SLE, previous report used for refractory rejection)
IL-6 inhibitors
Treatment of early active AMR (<30 days) by PLEX, IVIG with corticosteroids regarded standard
Treatment of late active & chronic active (>30 days):
With preformed DSA: PLEX, IVIG, CS,with or with out rituximab.
De novo DSA: optimizing immunosuppression , manage non adherence & treatment of concomitant TCMR. Some center use PLEX, IVIG & retuximab ( level 3C)
3 components are required for the diagnosis of acute ABMR:
Histologic evidence of acute tissue injury (capillaritis and/or glomerulitis) or unexplained TMA or ATN
Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs]) or at least moderate MVI
Serologic evidence of circulating DSAs
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 the first criteria and only one of the other 2 criteria, the patient is considered to have ABMR
Phenotypes
ABMR is classified according to timing and type of DSA into 3 categories
Category 1 : Early ABMR (<30 days)
· Uncommon
· Occur due to the presence of preexisting DSA and is closely related to related to the DSA MFI and MCS (the degree of positivity of FCM)
· Presented by acute graft dysfunction which is associated with rapid increase in DSA
· Usually C4d positive Category 2 : Late ABMR (>30 Days) associated with preexisting DSA
Uncommon
It is characterized by being indolent and progressive
May be asymptomatic and detected only in protocol biopsy or present by gradual mild decline of kidney functions associated with mild proteinuria and persist leading to a chronic form of ABMR with development of transplant glomerulopathy later on
May be C4d positive
Associated with poor graft survival
Category 3 : Late ABMR (>30 Days) associated With denovo DSA
It is the most common form of ABMR
Related to inadequate immunosupression either due to non compliance or planned subtherabiotic reduction of immunosupressuin due to infection or malignancy
It may be associated with TCMR
May be asymptomatic and detected only in protocol biopsy (subclinical) or it may present by graft dysfunction
May be C4d positive
De novo DSA associated AMR has poorer graft survival when compared to pre-existing DSA associated AMR .
Risk factors for developing ABMR
1. HLA mismatches especially class II
2. Presence of preformed DSA before transplantation
3. Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
4. Noncompliance on immunosuppressive medication ( very significant risk factor)
Poor prognostic factors in late ABMR
Transplant glomerulopathy
High degree of IFTA
Association with TCMR
Presence of vascular lesions
The presence of proteinuria
Noncompliance to immunosuppressive medications
Type of DSA (C1q positive DSA)
Target of DSA (DSA against class II)
MFI (high MFI)
DSA monitoring
DSA should be monitored once in early post-transplant period (first 3 month) in all patients
After the first 3 month, no further testing is required except in the following situations
Modification of immunosuppression
Suspicion of non-adherence
Graft dysfunction
All patients with detectable DSA should undergo renal biopsy
C1q assay is a new assay that is capable of detecting only complement fixing IgG DSA , maybe usd to predict graft survival since complement fixing DSA are associated with poor graft survival
Treatment of acute and chronic ABMR
Standard of care treatment
Intensification of maintenance immunosuppression targeting tacrolimus level trough between 5-7, optimize MMF dose used in all categories
Decreasing inflammation produced by rejection: high dose methylprednisolone can be used in all categories
Removing DSA using plasmapheresis 4-6 sessions daily or in an alternate day according to DSA level
Decreasing production of antibodies using IVIG in a dose of 100 mg /kg after each plasmapheresis session or 2 gm/kg after the end of plasmapharesis sessions
The combination of plasmapheresis and IVIG represents the main therapy for treatment of acute ABMR, no rule of plasmapharesis in chronic ABMR
Depleting B cells (one dose of rituximab 375mg/m2) may have benefit only if there is biopsy evidence of active microvascular inflammation
ATG used mainly for the treatment of mixed rejection.
The combined use of Rituximab and ATG is associated with life-threatening infections
Salvage treatment
Eculizumab which is is a monoclonal antibody, fully humanized, directed against C5, It binds C5 and inhibits its cleavage to C5a, C5b so inhibit the formation of MAC. In early severe ABMR use of eculizumab may be effective in preserving graft function after HLA incompatible transplantation.
Splenectomy : Used as salvage therapy and hould be done as early as p[possible after the occurrence of acute ABMR
Imlifidase which is an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), was tried in desensitization and may have a rule in ABMR but the problem is rebound increase in the DSA .
Tocilizumab which is a monoclonal antibody against IL-6 receptor showed better graft, patient survival and significant reduction of DSA when used as a salvage therapy for treatment of chronic ABMR after failure of initial therapy, Clazakizumab is studied for treating chronic active AMR
Bortezomib : no clear recommendation but if used will be in refractory rejection
Cyclophosphamide : no clear recommendation but if used will be in refractory rejection.
Conclusion
Treatment of early active AMR (≤30 days transplanation)
Standard of care treatment : plasmapharesis, IVIG and pulse steroids
Adjuvant: complement inhibitors, Rituximab, or splenectomy
Treatment of late active ABMR (≥30 days posttrasnplant)
Standard of care treatment : plasmapharesis, IVIG and pulse steroids
Adjuvant: Rituximab
Treatment of chronic ABMR
Standard of care treatment : Optimize immunosuppression, add corticosteroids if withdrawn
Very nicely summarized. Why do you think that it is level 4/5 evidence and not 5? It is expert opinion consensus guidelines. I would still accept your answer as level 4/5 evidence.
Summery:
50% of renal graft lost by 10 years post transplantation. Chronic graft loss can result from immune or non immune cause. TG is the most common finding of protocol biopsy( in glomerular disease). IFTA can be a sequel of :
cellular &/or AMR
recurrent pyelonephritis
BK nephropathy
poor quality donor kidney
ureteral stenosis
CNI nephrotoxicity.
Immunological causes:
life long low grade exposure to donor Ags may lead to chronic immunological injury
late onset acute rejection ( due to non compliance & dnDSA)
Chronic injury commonly involve Ab-mediated endothelial injury go glomeruli, PTC & small- medium size vessels. persistent endothelial injury lead to duplication of PT basement membrane to give TG.
TG is non specific finding can occur in: AMR, TMA, recurrent autoimmune GN, & hepatitis-C related GN.
Recurrence of glomerular disease is a common cause of graft loss 10 years post transplant ( 3rd cause). FSGS can recur in early post transplant period with graft loss in 50-80% of cases, aHUS recurrence differ according to complaint abnormality ( 15% in MCP mutation, & 80% in circulatory protein mutation). But IGA nephropathy can recur in 40% of transplant but rarely lead to early graft loss. So through protocol biopsy early diagnosis & treatment can improve long term graft survival.
Infections can can cause chronic injury to the graft due to directly or indirectly through activation of innate immune response. CMV infection can cause rejection.
Poor quality donor graft: due to expansion of donor pool that include kidneys from donor after cardiac death, elderly, or co-morbidities( HT, DM) can affect graft survival due to pre-existing injury, low nephron mass, mismatch between donor & recipient size associated with HT, proteinuria & poor graft outcome.
non invasive biomarkers ( till now used only on research setting)
protocol biopsy: it is important for detection of early changes without clinical evidence of rejection ( stable serum creatinine).
Prevention of AMR:
Using alternative to CNI e.g. belatacept, mTOR-I in addition to good control of blood pressure.
prevention of non compliance: risk factors for non compliance include poor social support, missed appointment, fluctuating drug level, differences between prescribed & dispense drug, unexpected late rejection, psychiatric disease, substance abuse, adolescent, increased time since transplantation & financial crises.
Management of AMR:
prevention of chronic rejection: prevention of acute ABMR & proper treatment of acute AMR ( IVIG+ rituximab, PP, bortezumib, eculizumab).
-Summary Introduction
AMR was the most common cause of allograft failure in a cohort of renal transplant recipients with biopsies taken before graft failure.
There isn’t an accepted standard for treatment of AMR so it is difficult for industry to initiate phase 2 and 3 clinical trials for novel treatments or prevention of AMR. Alloimmune response biology
Activated B cells migrate to the T- and B-cell interface and receive T-cell help. Some of the helped B cells differentiate into memory B cells or plasma cells,the rest enter into a germinal center to emerge as high-affinity and classswitched memory B cells and plasma cells. Memory B cells have lower B-cell receptor (BCR) affinity compared with plasma cells, and cells generated pre-GC tend to be of lower affinity than cells generated post-GC. AMR histological feautres
The active AMR features based on the Banff 2017 classification are
1-histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis , acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause;
2- histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and
3- the presence of circulating DSA, predominantly anti-HLA antibody .
Chronic active AMR diagnosis include chronic tissue injury in addition to criteria 2 and 3 for active AMR. AMR clinical phenotypes
The Banff classification has 3 AMR diagnostic categories including chronic AMR with transplant glomerulopathy and current or prior DSA without MVI or C4d.
AMR can present by sudden allograft dysfunction early posttransplant also it can have a subclinical onset, presenting later posttransplant. Anti-HLA antibody can also be preexisting DSA or develop after transplant (dnDSA) in the setting of under-immunosuppression. Early Posttransplant (<30 days ) Active AMR
It’s risk increases with increasing DSA level at the time of transplant as detected by DSA mean fluorescence intensity (MFI), the degree of flow cytometric crossmatch positivity, and the number or breadth of cross-reactive DSA specificities.
It is uncommon, it is manifested by an abrupt increase in DSA accompanied by allograft dysfunction. Late (>30 Days) Posttransplant AMR With Preexisting DSA
It is an indolent forum , detected on a surveillance biopsy.
When detected early, MVI in glomeruli and peritubular capillaries is predominant and C4d staining may or may not be present. MVI tends to persist and is associated with chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering.
There is minimal if any reduction in GFR or proteinuria even when mild chronic features are present Late (>30 Days) AMR Associated With dnDSA
Which is the most common form of AMR,new DSA detected after >3 months posttransplant due to inadequate immunosuppression ether due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs.
It presents with allograft dysfunction and concomitant or preexisting TCMR
The presentation is subclinical , similar to that of late posttransplant AMR in patients with preexisting DSA
AMR with dnDSA is associated with inferior allograft survival compared with AMR from preexisting DSA. Features accompanied by reduced allograft survival in late AMR( pre existing or dnDSA) are
Chronic histological features as transplant glomerulopathy , the degree of interstitial fibrosis ,tubular atrophy , TCMR ,C4d positivity and vascular lesions.
clinical factors are proteinuria and time of diagnosis posttransplant
other major risk factors are underimmunosuppression and medication nonadherence
Consensus for DSA monitoring Initial Assessment for Anti-HLA DSA
By HLA typing and HLA screening
For anti-HLA–sensitized recipients, a high-resolution level of typing.
Patients with no sensitisation history and with negative antiHLA antibody testing using single-antigen or multiantigen bead solid-phase assays are at low risk for AMR. Monitoring of De Novo DSA
Specially with immunosuppression reduction, known patient medication nonadherence, or at the time of rejection episode. Positive DSA Results assessment
SAB test has it’s limitations , liable to interference from external effectors
Positive cut off MFI of 1000–1500 is associated with anti-HLA antibodies presence. DSA Testing for Risk Stratification
Hyperacute AMR is associated with positive CDC crossmatch.
C1q and C3d binding positivity is associated with a high DSA titer Evidence for treatment of active and chronic active AMR
Multiple studies addressed different mix of therapies as plasmapheresis, intravenous immune globulins [IVIG], steroid pulses with or without different T-cell–depleting and B-cell–depleting antibodies. Plasma Exchange and IVIG
commonly used to treat active AMR.
The FDA Antibody-Mediated Rejection Workshop in 2017 and KDIGO in 2010 mentioned that PLEX and IVIG could be a standard treatment for acute active AMR, meanwhile their long-term effects are variable.
PLEX and IVIG removes circulating DSA with immunomodulation of the antigraft immune response Complement Inhibitors
Ecluzimab a monoclonal antibody targeting C5
Multiple trials revealed the preventive role of eculizumab for early active AMR in positive crossmatch HLA-incompatible living and deceased donor recipients.
C1 esterase inhibitors Berinert and Cinryze showed a possible improvement in allograft function in kidney recipients with AMR. Rituximab
Some studies did not demonstrate any positive effect in combination with other modalities while other studies revealed some positive effect when used with IVGV high dose, plasma exchange and steroids particularly with vascular AMR. Imlifidase
an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), which can lower anti-HLA DSA levl and is studies in AMR treatment but rebound increase in DSA level is noted .
It is used for desensitisation in highly sensitised cases.
The benefit of this drug is that it allows highly sensitized cases to undergo transplantation within hours of a donor being available regardless of the crossmatch status. ATG
used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR.
If combined with B cell depleting agent it has high life threatening infection risk . Splenectomy
It need to be done rapidly after the onset of early AMR to be effective. Proteasome Inhibitor: Bortezomib
Is a candidate for the treatment of active AMR in a multimodal treating regimen. Cyclophosphamide
It was mentioned anecdotaly its use with multimodal treatment regimen for the treatment of refractory rejections. IL6 inhibitors
Toclizumab revealed acceptable results in treating chronic active AMR after failure of IVIG and rituximab.
Clazakizumab is studied for treating chronic active AMR Treatment of early active AMR Consensus (≤30 days transplanation)
The combination of PLEX, IVIG with corticosteroids could be a standard treatment of care, similar to the conclusions of the FDA workshop and KDIGO guidelines.
The adjunctive therapies include complement inhibitors, rituximab, or splenectomy can be needed especially when the risk of graft loss is high and concomitant TCMR is present. Treatment of late active and chronic AMR consensus (≥30 days posttrasnplant)
For patients with preexisting DSA and active AMR without chronic features, treatment include PLEX, IVIG, and corticosteroids.
In cases of chronic active AMR optimizing immunosuppression need to be optimised with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL.
In cases with denovo DSA ,Optimizing immunosuppression and treat potential medication nonadherence and associated TCMR.
Initial assessment for anti-HLA DSA ; This should include HLA typing, anti-HLA antibody screening, history of allo-sensitization (IA).
Molecular HLA typing involves ; A, B,C, DR,DQ,DP(2B)
Antibody screening ; should be done by SAB solid phase assay(IA)
Monitoring for De Novo DSA ; Must be considered in the following condition ;
Decreased immune-suppression for any reason
Rejection
Interpreting positive DSA Results ; SAB is affected by external interference, bead
saturation, and shared epitopes. Dilution methods and ethylenediaminetetraraaetic acid can be use to detect interference
Additional DSA Testing for risk stratification ; This depend on XM test, complement binding DSA, and IgG sub-classes.
Consensus for Treatment for early active AMR(< = 30 Days Post-Transplant) ; Limited quality of evidence
Combination therapy ; PLEX, IVIG, and Corticosteroids
Adjunctive therapy ; should be considered in situation of risk of graft loss e.g. complement inhibitor, rituximab, or splenectomy depending on the availability.
Treat underlying or concomitant TCMR
Consensus for Treatment of late active and chronic active AMR ;( >=30 Days Post-Transplant)
Pre-existing DSA ; one should ;
Stabilize or reduce the rate of deterioration in GFR, proteinuria and balance it against risk of drug toxicity, infections, and cost.
Control pressure, blood sugar, and dyslipidemia
Keep tacrolimus > 5 ng/ml
De Novo DSA ; This is mainly cause by under immune-suppression e.g.Non-adherence.
Optimize immune-suppression
Address the issue of non-adherence
Treat concomitant TCMR
Conclusions
The consensus opinion at the moment based on observational studies, low level evidence, and expert opinion. The future in this area is to have new studies and large transnational trial consortia to undertake these studies
Level of evidence ; This an expert opinion and therefore, level 5 evidence
It is a meeting report and expert opinion with level 5 of evidence.
Despite modern immunosuppression, ongoing kidney injury and graft loss due to alloantibody-induced immunity remains an important issue. Driving this response are polymorphic HLA antigens.
By 10 years, after kidney transplantation, up to 25% have developed de novo DSA (dnDSA). AMR is the common cause of graft loss in different studies.
Biology of the alloimmune response
In alloimmune naive individuals, the generation of antibody-secreting cells follows a series of events that ultimately leads to T cell activation and generation of memory B cells, plasma blasts and long-lived plasma cells.
In presensitized patients, robust long-lived plasma cells constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid anamnestic antibody response.
Memory B cells are derived from B cells with receptors that are less mutated and of lower affinity than those that are destined to become plasma cells. the repertoire of plasma cells and the antibodies they produce are up to 100-fold more restricted compared with the repertoire of memory B cells. As a result, treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells. The ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of presensitized recipients. The diversity at the level of antibodies is another challenge.
Diagnostic criteria and histological features of AMR
The important findings of AMR based on Banff 2017 are: histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause; histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and the presence of circulating DSA, predominantly anti-HLA antibody.
The more important histologic findings of AMR is MVI in the form of glomerulitis or peritubular capillaritis. However, peritubular capillaritis alone in the presence of TCMR is insufficient for diagnosis.
Clinical phenotypes of AMR
AMR can present with abrupt allograft dysfunction early posttransplant but can also have an insidious or subclinical onset, presenting later posttransplant.
Considering the timing of presentation, and type of DSA (preexisting or de novo), in relation to the histological classification is recommended.
Early posttransplant (<30 days) active AMR
In case of performed DSA or immunologic amnestic response, early AMR can occur in 30-days post-transplant. This active form of AMR presents with an abrupt increase in DSA accompanied with allograft dysfunction. If untreated it can lead to cortical necrosis and graft loss within days.
Late (30 days) post-transplant AMR with preexisting AMR
Patients with performed DSA can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy. When detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present. MVI tends to persist and is later accompanied by chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering.
Late (30 days) AMR associated with dnDSA
The most common form of AMR is associated with dnDSA. dnDSA formation occur after 3 months post transplantation, and in the context of inadequate immunosuppression which can be due to patient nonadherence. This form is usually presents with allograft dysfunction and concomitant or preexisting TCMR.
AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA.
Features associated with reduced allograft survival in late AMR
Chronic histological features such as the presence of transplant glomerulopathy (Banff cg score >0) and the degree of interstitial fibrosis and tubular atrophy are predictive of allograft failure. In addition, concomitant TCMR, C4d positivity, and vascular lesions (Banff cv score >0) are associated with inferior allograft survival. Allograft dysfunction at diagnosis, proteinuria, and time of diagnosis posttransplant are also predictive of outcomes. Additionally, C1q positive and anti-class II DSA are associated with poor outcomes.
Initial assessment for anti-HLA DSA
Donor and recipient HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events (previous transplant, blood transfusion, and pregnancy) are initial assessment of renal transplant candidate.
Monitoring for de novo DSA
Monitoring for dnDSA is recommended in the setting of immunosuppression reduction by physician for any reason, known patient medication nonadherence, or at the time of rejection episode (TCM or AMR).
Interpreting positive DSA results
Although SAB test is most important test for detection of DSA but has some limitations. The positive cutoffs is different between laboratories.
SAB tests are also prone to interference from external substances, bead saturation, and “shared-epitope” phenomenon, which can lead to a falsely low MFI.
Additional DSA testing for risk stratification
Crossmatch testing can be used with SAB testing for AMR risk stratification. Testing to assess the complement binding ability of DSA (C1q or C3d) are associated with AMR. DSA IgG subclass testing has been used for research purposes.
Treatment of active and chronic active AMR
Plasma exchange and IVIG are used removing circulating DSA and reducing DSA production. They are regarded as a standard of care for acute active AMR.
Complement system is an important contributor to AMR. The main goal of using complement inhibitors is to avoid the downstream damage to the allograft from DSA. Eculizumab results in terminal complement blockade as a monoclonal antibody targeting C5. Despite prevention of early active AMR, the long-term incidence of chronic AMR and allograft survival is not affected by Eculizumab therapy.
Rituximab, a B-cell–depleting agent, was suggested as a treatment option. Rituximab as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.
Imlifidase, an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA. Although data are lacking for using IdeS in AMR, this agent has been used safely in highly sensitized individuals for desensitization. After administration of IdeS, all previously positive crossmatches became negative.
Antithymocyte globulin (ATG) or other T-cell–depleting antibodies have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. no benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
Surgical splenectomy, splenic embolization, and splenic radiation has been used as a salvage procedure for severe early AMR.
Bortezomib, a proteasome inhibitor, have no beneficial effect on treatment of AMR when it is used alone.
Tocilizumab, an IL-6 inhibitor, is suggested as an option for IVIG and rituximab unresponsive AMR.
Consensus for treatment of early active AMR
The combination of PLEX, IVIG with corticosteroids could be regarded as standard of care. The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability.
Consensus for treatment of late active and chronic active AMR
Among patients with known preexisting DSA and active AMR without chronic features, PLEX, IVIG, and corticosteroids are recommended. The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR. Optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control are recommended.
AMR in the setting of dn DSA is often initially detected with concomitant TCMR. The standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence. Treatment of concomitant TCMR is also recommended. PLEX, IVIG, and Rituximab is used in some centers.
Risk of AMR still remain problem Despite improving of immunosuppressive drug due to polymorphism of HLA antigen matching and protocol of renal biopsy may help to detect sub clinical rejection before clinical symptoms occur but still no specific guidelines help in diagnosis and prevention of AMR and specific protocol to prevent and treated AMR.
INTRODUCTION
Despite modern immunosuppression, ongoing kidney injury and graft loss due to alloantibody-induced immunity remains an important issue. By 10 years, after
kidney transplant, up to 25% have developed de novo DSA (dnDSA).5 Thus, it is not surprising that AMR was the most common cause of allograft failure in a cohort of renal transplant recipients with indication biopsies before graft failure.
Given the scope and severity of the problem, it is unfortunate that there are no commonly accepted guidelines for treatment. To date, clinical trials of AMR have been small or inconclusive, and there are no Federal Drug Administration (FDA)-approved therapies for the prevention and treatment of the condition.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
The salient features of active AMR based on the Banff 2017 classification14 are
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause;
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and
(3) the presence of circulating DSA, predominantly anti-HLA antibody
Clearly, the main histological manifestation of active AMR in renal allografts is MVI in the form of glomerulitis (g) and peritubular capillaritis (ptc). The presence of either (g + ptc > 0) satisfies criterion 1, and a (g + ptc) sum score of ≥2 also satisfies
criterion 2. The exception is that peritubular capillaritis alone is insufficient for diagnosis in the presence of T-cell–mediated rejection (TCMR), including borderline rejection.
Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the context of glomerulitis and thrombotic microangiopathy.
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR. Signs of chronic tissue injury include transplant glomerulopathy (Banff chronic glomerulitis [cg] score > 0), severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause.
CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories (including chronic AMR with transplant glomerulopathy and current or prior DSA but no MVI or C4d
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AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
As recommended by guidelines,56 most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies
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Despite the scope and severity of AMR, there is no approved therapy nor guidelines to direct the management plan. Transplantation society gathered expertise from all around the world to create a consensus to guide the Management of AMR.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR: based on the Banff 2017 classification
CONSENSUS FOR MEASURING AND MONITORING OF DSA:
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Level of evidence: expertise opinion( level 5)
AMR is a major cause of allograft failure. Antibody-mediated damage caused allograft dysfunction late post-transplant in about 60% of renal transplant patients.
there are no standard management for AMR.
Biology of the allo-immune response
The development of antibody secreting cells, starts with the initial encounter of alloantigen with B cells, which activates B-cell migration to the T- and B-cell interface in the lymph node, where it receives help from alloreactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells. Some of B cells differentiate into memory B cells or short-lived plasmablasts, while the rest enter into germinal centers to emerge as high-affinity and class switched memory B cells, plasmablasts, and long-lived plasma cells. Presensitized individuals have a robust long-lived plasma cells
constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid antibody response.
Diagnostic criteria and histological features of AMR
The salient features of active AMR based on the Banff 2017 classification are:
The main histological manifestation of active AMR in renal allografts is MVI in the form of glomerulitis (g) and peritubular capillaritis (ptc).
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR.
Clinical phenotypes of AMR
Early post-transplant (<30days) active AMR
Early post-transplant AMR occurs in up to 40% of patients with preformed DSA and
a positive flow cytometric crossmatch.
It typically presents with an abrupt increase in DSA accompanied by allograft dysfunction
If not recognized and treated quickly, it can lead to cortical necrosis and allograft loss within days.
Late (>30 days) post-transplant AMR With preexisting DSA
Indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy for mild allograft dysfunction.
Late (>30 days) AMR associated with dnDSA
dnDSA is a new DSA detected after >3 months post-transplant in the context of inadequate immunosuppression. It presents with allograft dysfunction and concomitant or preexisting TCMR.
studies suggested that AMR with dnDSA is associated with inferior allograft survival
when compared with AMR from preexisting DSA.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Treatment studies for AMR are rarely comparable,and the available evidence is generally of low quality.
Most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies)
Plasma Exchange and IVIG
This treatment regimen is most commonly used to treat active AMR, although frequency, modality, and dosing may vary
(KDIGO) in 2010 suggest that PLEX and IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy.
the studies demonstrated their ability to improve short-term outcomes , while their results on long-term effects remain variable, emphasizing the need for new alternatives or adjunctive therapy for the treatment of AMR. In addition, there is a need to better
define the amount of PLEX and dosing of IVIG.
The rationale for using PLEX and IVIG is to combine
removal of circulating DSA with immunomodulation of the antigraft immune response and in particular modulation of the B-cell response.
Complement inhibitors
The main goal of using complement inhibitors is to avoid the downstream damage to the
allograft from DSA.
Eculizumab results in terminal complement blockadeas a monoclonal antibody targeting C5.
one study showed that among patients who received positivecrossmatch HLA-incompatible transplants, the incidence of early active AMR was decreased from approximately 40% in historical controls to 7% among treated patients.Despite these promising results, long-term follow-up of eculizumab-treated positive crossmatch patients in a single-center study has shown that despite prevention of early active AMR, the long-term incidence of chronic AMR and allograft survival is comparable to historical controls.
Rituximab
Rituximab, a B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines. Despite its frequent use, the evidence is low and 3 small randomized
trials have investigated its utility without demonstrating a clear benefit
a single-center non randomized study suggests that Rituximab as an add-on therapymay prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.but the doses and number of cycles is uncertain.
Imlifidase
An IgG-degrading enzyme of Streptococcus pyogenes (IdeS) that can rapidly
reduce or even eliminate anti-HLA DSA .
unfortunately 7–10 days of administration, patients often experience a rebound in DSA and anti-IdeS antibodies develop after 1 or 2 doses, thereby preventing repeated administrations. Thus, IdeS will unlikely be an isolated treatment for active
or chronic active AMR, but rather an adjunct to other therapies aiming to reduce DSA in the long term.
Anti-thymocyte globulin
Although depleting antibodies were proposed by KDIGO guidelines as potential treatmentoptions, no benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
Splenectomy
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR. It must be performed
rapidly after the onset of early AMR to be effective.
Bortezomib
is a proteasome inhibitor that directly targets antibody-producing plasma cells making it an attractivecandidate for the treatment of active AMR. Data supporting its use are limited to case series suggesting a positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting antibodies.
Cyclophosphamide
Previous anecdotal reports describe its use within a multimodal treatment regimen for
the treatment of refractory rejections. While it is relatively inexpensive, there are no trial data to support its use.
Interleukin-6 Inhibitors
A single-center, nonrandomized trial of tocilizumab (anti-interleukin-6 receptor monoclonal antibody) was undertaken in 36 patients with chronic active AMR that had failed IVIG plus rituximab. Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function.
level of evidence 5
INTRODUCTION:
There are no commonly accepted guidelines for treatment of ABR, though the
PROBLEM IS COMMON.
By 10 years, after kidney transplant, up to 25% have developed de novo DSA.
Thus, it is not surprising that AMR was the most common cause of allograft failure
Caused allograft dysfunction late posttransplant in nearly 60% of renal transplant
recipients.
BIOLOGY OF THE ALLOIMMUNE RESPONSE:
The initial encounter of alloantigen with B cells expressing the appropriate BC
This event activates B-cell migration to the T- and B-cell interface in the lymph node,
Where it receives help from alloreactive T cells that encountered alloantigen presented
indirectly on recipient dendritic cells. Some of B cells differentiate into memory B cells or
Short-lived plasmablasts, while the rest enter into germinal centers to emerge as high-
Affinity and classe witched memory B cells, plasmablasts, and long-lived plasma cells.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR:
Based on the Banff 2017 classification are:
(1) Histologicalevidence of graft injury:
-microvascular
inflammation (MVI).
– Intimal or
transmural arteritis (v > 0).
– Acute
thrombotic microangiopathy.
-or
acute tubular injury.
2) Histological evidence of antibody-endothelial interactions either by C4d deposition or
At least
moderate MVI; and
3) The presence of circulating DSA, predominantly anti-HLA antibody.
Chronic active AMR, morphological features of chronic tissue injury are present in
Addition to criteria 2 and 3 for active AMR.
CLINICAL PHENOTYPES OF AMR:
AMR can present with abrupt allograft dysfunction early posttransplant but can also
have An insidious
or subclinical onset, presenting later posttransplant.
Early Posttransplant (<30 Days) Active
AMR> (<30 Days) Active AMR>less than 30
Days) active AMR:
OCCURE IN
40%.MORE WITH HIGH PRETRANSPKANT DSA and positive FXCM.
Typically
presents with an abrupt increase in DSA accompanied by allograft dysfunction
(Increased
creatinine and oliguria with or without proteinuria).
Late (>30 Days) Posttransplant AMR with
Preexisting DSA
Indolent .
progressive form of AMR.
Late (>30 Days) AMR Associated With
dnDSA:
The most common form of AMR is associated with dnDSA.
In general, dnDSA is a new DSA detected after >3 months posttransplant in the context
Of inadequate immunosuppression.
Often presents with allograft dysfunction and concomitant or preexisting TCMR.
Associated with inferior allograft survival when compared with AMR from preexisting
DSA.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE
AMR:
Most studies describe the use of a variable mix of interventions (egg, variable
intensity of
Plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of
Steroid pulses together with or without different T-cell–depleting and B-cell–depleting
Antibodies.
Plasma Exchange and IVIG:
Regarded as a standard of care for acute active AMR BY FDA Antibody-Mediated
Rejection Workshop in 201767 as well as KDIGO.
Low evidence.
Complement Inhibitors:
Eculizumab results in terminal complement blockade as a monoclonal antibody
Targeting C5.
Among patients who received positive crossmatch HLA-incompatible transplants, the
Incidence of early active AMR was decreased.
Long-term follow-up of Eculizumab-treated positive crossmatch patients in a single-
Center studyhas shown that despite prevention of early active AMR, the long-term
Incidence of chronic AMR and allograft survival is comparable to historical controls.
Proximal complement inhibition:
Has also been studied as a therapeutic target. The plasma C1 esterase inhibitors
Berinert (CSL Behring) and Cinryze (Takeda/Shire/ ViroPharma) have been tested in 2
Pilot studies and indicate a possible improvement in allograft function in kidney
Recipients with AMR.
Rituximab:
A B-cell–depleting agent, was suggested as a treatment option by KDIGO
guidelines.
Despite its frequent use, the evidence is low and 3 small randomized trials have
Investigated its utility without demonstrating a clear benefit. Some positive effects of
Rituximab in multimodal treatment regimens together with steroids, plasmapheresis, and
High-dose IVIG, especially on patients with vascular AMR.
Imlifidase:
An IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or
evenEliminate anti-HLA DSA. it has been used safely in highly sensitized individuals for Desensitization.
An adjunct to other therapies aiming to reduce DSA in the long term.
The unique feature of this drug is that it permits any highly sensitized patient to
undergo
Transplantation within hours of a donor being identified regardless of the crossmatch
Status.
Antithymocyte Globulin:
No benefit has been demonstrated for treatment of pure AMR with T-cell–depleting
Therapy.
Splenectomy:
There are several case series of surgical splenectomy, splenic embolization, and
splenic Radiation being used as a salvage procedure for severe early AMR.
Proteasome Inhibitor:
Bortezomib: Data supporting its use are limited to case series suggesting a positive
Effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting
Antibodies. Side effect preclude its use.
Cyclophosphamide:
There are no trial data to support its use.
Interleukin-6 Inhibitors:
Tocilizumab (anti-interleukin-6 receptor monoclonal antibody) was undertaken in 36
Patients with chronic active AMR that had failed IVIG plus rituximab.
Patient and graft survival at 6 years (91% and 80%, respectively) were found to be
Superior to historical controls, with significant reductions in DSA and stabilization of
renal
Function.
Clazakizumab, an anti-interleukin-6 monoclonal antibody, is evaluating now for the
Treatment of chronic active AMR.
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS
POSTTRANSPLANT):
Preexisting DSA (or no immunologically naïve) Active AMR:
Plasmapheresis (daily or alternative day × 6 based on DSA titer) (1C)
IVIG 100mg/kg after each plasmapheresis treatment or IVIG 2 g/kg at end of
Plasmapheresis treatments (1C) Corticosteroid.
Consider adjunctive therapies:
Complement inhibitors (2B) Rituximab 375mg/m2 (2B) Splenectomy
Late (>30 days posttransplant) Preexisting DSA Active AMR
Plasmapheresis (daily or alternative day × 4–6 based on DSA titer) (2C)
IVIG 100mg/kg after each plasmapheresis treatment or IVIG 2 g/kg at end of
Plasmapheresis treatments (2C) Corticosteroids.
Consider adjunctive therapies:
Rituximab 375mg/m2 (2B).
De novo DSA Active AMR Optimize baseline immunosuppression (egg, add steroids if on A steroid-free regimen) (1C) Evaluate and manage nonadherence.
Consider adjunctive therapies:
Plasmapheresis and IVIG (3C) Rituximab.
Chronic AMR:
Optimize baseline immunosuppression (egg, add steroids if on a steroid-free regimen)
Consider adjunctive therapies:
IVIG
CONCLUSIONS:
The consensus opinion of those present at the meeting was based largely on
Observational studies, low-level evidence, and expert opinion. Further studies are
Needed.
Level of evidence 5.
Summary
The 2019 Transplantation Society Working Group consensus guidelines of ABMR:
• ABMR is a major cause of allograft loss.
• the advances in immunology to detect anti HLA antibodies and understanding in histopathological diagnosis made the ABMR a well-recognized problem.
• Diagnosis of acute ABMR requires:
o Evidence of tissue damage as microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic micro-angiopathy (TMA), ATN (acute tubular necrosis), after exclusion of any other causes.
o Circulating DSA.
o Positive c4d.
• Diagnosis of chronic active ABMR requires:
o Evidence of chronic tissue damage as transplant glomerulopathy (Banff chronic glomerulitis [cg] score > 0), multilayering of the peritubular capillary basement membrane on E/M, or new arterial intimal fibrosis without another obvious cause.
o Circulating DSA.
o Positive c4d.
• Clinical phenotypes of ABMR:
o Early post-transplant ABMR: during 1st month- post transplant due to pre-existing DSA, positive cross match, uncommon as those cases are not 5transplanted without desensitization. prognosis depends on the degree and strength of antibody positivity.
due to memory B cell.
Presented with increasing titer of DSA, oliguria, graft dysfunction with or without proteinuria.
Early appropriate treatment can reverse histological damage completely. However, inappropriate treatment can turn it into chronic active ABMR with worse graft outcome.
Inappropriate or delayed treatment leads to graft loss within days.
o Late ABMR with pre-existing DSA
Less aggressive form, not presented early.
due to pre-existing plasma cell response.
mild or no graft dysfunction.
Aggressive but indolent course, progressive proteinuria and GFR decline till graft loss years post transplantation.
Diagnosis by protocol biopsy.
Inappropriate or delayed treatment leads to graft loss within months to years.
o late ABMR with de novo DSA:
Occurs late (more than 1 month-post transplantation).
Most common.
Formation of de novo dsa.
Main cause is inadequate therapy and non adherence (predicted from prior non adherence to CKD medications).
Worse graft outcome than those with pre-existing DSA.
• Poor prognostic factors of late ABMR (either with pre-existing or de novo DSA):
Histological markers of chronicity as tubular atrophy, transplant glomerulopathy and interstitial fibrosis.
Presence of vascular injury, c4d positive and concomitant TCMR.
Graft dysfunction and marked proteinuria.
C1q positive DSA34,35,52 and anti class II DSA and the level or strength of DSA.
• Screening for pre-existing DSA by solid phase SAB luminex is essential, and for sensitized persons we need 4 digit or high resolution antibody screening.
• Screening for de novo DSA: done prior to reduction of therapy, at time of reduction or regular screening in highly sensitized patients.
• Positivity of DSA by SAB is variable between labs (no definite cut off point). However, general saying that MFI > 1500 may be significant.
• Positive complement-dependent cytotoxicity (CDC) crossmatch is at higher risk of rejection than positive flow cytometric crossmatch than negative crossmatch.
• Treatment of acute ABMR and chronic active ABMR;
Usually mix of pulse steroids, IVIG, PEX and B , T cell depleting agents.
Most common is PEX to remove DSA and IVIG to abolish their effects and modulate B cell response, as recommended by the KDIGO 2010. however, the number of PEX sessions and dose of IVIG are not well defined.
Ecluizimab (inhibit last step of complement activation) may be beneficial in acute ABMR, but long term effect on the incidence of chronic active ABMR and graft survival need further studies.
Rituximab may be beneficial, but low evidence exist and appropriate dose is still unknown and needs further justification.
New therapeutic options as Ides, bortezomib are still under investigations and need longitudinal follow up studies. till now used as adjuvant therapy.
Ides effectively cleave human IgG and inhibit both CDC and antibody-dependent cellular cytotoxicity, mainly used for desensitization (not in ttt of acute ABMR). the main drawbacks are the rebound in DSA and development of anti-IdeS antibodies after 1 or 2 doses, so can not be given repetitively.
ATG (T cell depleting agent) used in steroid refractory TCMR, vascular rejection and mixed rejections, but not effective in pure ABMR.
Proteasome Inhibitor: Bortezomib (directed against plasma cells), 1st described in multiple myeloma (used now combined with other thaerpies).
Cyclophosphamide (1st used in ANCA vasculitis and proliferative lupus nephritis) can be used as adjuvant in refractory rejection.
Tocilizumab (anti-interleukin-6 receptor monoclonal antibody) may be beneficial in chronic active ABMR.
Conclusion consensus guidelines for acute ABMR:
o Standard ttt of acute ABMR is combination of PLEX, IVIG with corticosteroids plus or minus other adjuvants.
o The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability.
o Concomitant TCMR should be treated.
Conclusion consensus guidelines for chronic active ABMR:
o Combined PLEX, IVIG, and corticosteroids is the standard (in absence of any evidence of chronicity).
Conclusion consensus guidelines for chronic ABMR:
o Just optimization of maintenance therapy.
o Return to steroids in steroid free regimen.
o control systemic diseases as DM and hypertension.
o The aim here is just to delay progression of graft dysfunction by conservative management.
o Avoidance of aggressive immunosuppressive therapy that can cause hazardous adverse effects without benefit.
Level of evidence
consensus or expert opinion (level Iv) , as it based on reviewing multiple case control studies.
Expert consensus: level of evidence 4/5
Measuring and Monitoring of DSA
Initial assessment for DSA should include HLA typing, anti-HLA ab screening, history of sensitization .SAB solid phase assay must be implemented.
In case of decreased immune-suppression and rejection, de novo DSA must be checked.
Interpreting positive DSA should consider that SAB is affected by factors like bead
saturation& shared epitopes. Dilution and EDTA are used to detect interference.
More DSA Testing for risk stratification depends on XM test, complement DSA binding, and IgG subclasses..
Treatment for early active AMR;< = 30 Days Post-transplantation :
Combination therapy :IVIG ,PE& steroids, adjuvant therapy ; implemented in case of risk of graft loss. and treatment of associated TCMR.
Treatment of late active and chronic active AMR ; >=30 Days Post-transplantation:
In case of previous DSA , following to be implemented
In case of de Novo DSA , the following must be implemented:
To Conclude: This is a consensus expert opinion on observational studies basis, with low level evidence. Other larger scale studies are needed.
Recommended Treatment for Antibody-mediated Rejection ( AMR ) After Kidney Transplantation: The 2019 Expert Consensus From the Transplantation Society Working Group.
Pathogenesis
Plasma cell in pre sensitized kidney transplant recipients continuously produce anti HLA antibodies. Stimulation of resting plasma B cell upon antigens exposure.
Classification Base on Duration Post Transplant as Suggested by Transplant Society Working Group.
1) Early ( Acute )
2) Late ( Chronic )
Furthermore, consensus opinion suggested management should focus on optimizing immunosuppression keep tacrolimus level at least 5 ng/mL with steroids (if on a steroid-free regimen). Regular monitor blood pressure, blood glucose, and lipid level is essential.
In conclusion, this is level 4-5 evidence articles which solely base on expert opinion. Individualization in the management of AMR is the key for better outcome.
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
Meeting was being organized by Transplantation Society, participant are international experts The aim is to develop a consensus for appropriate treatment of active and chronic active AMR.
They discussed, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes.
Despite modern immunosuppression AMR was the most common cause of allograft failure
Understanding of complexity of immune system is essential to understand the different presentations of AMR and potential treatment options.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
starts when alloantigen encounter with B cells which expressing the appropriate B-cell antigen receptor leads to the activation of B-cell migration to the T- and B-cell interface in the lymph node, where it receives help from alloreactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells. Some of B cells differentiate into memory B cells or short-lived plasma blasts, while the rest enter into germinal centers to emerge as high-affinity and class switched memory B cells, plasma blasts, and long-lived plasma cells, secreting anti-HLA antibodies.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
Based on the Banff 2017 classification are
(1) histological evidence of graft injury.
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI
(3) the presence of circulating DSA.
CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories including
1. Abrupt allograft dysfunction early post-transplant.
2.Insidious or subclinical onset.
3. late post-transplant.
Anti-HLA antibody can be present before transplant (preexisting DSA) or develop after transplant (dnDSA) in the setting of under-immunosuppression.
In some circumstances, the histological features suggestive of AMR are present, but anti-HLA antibody is not detected.
Early Post transplant (Abrupt) active AMR occurs within 30 days, preexisting measurable DSA or immunologic amnestic response due to previous exposure to allo-antigens. The risk increases with DSA (MFI), the degree of positive flow cytometry cross match, and the number or breadth of cross-reactive DSA specificities, Pathophysiology memory B cell response
the criteria for Banff active AMR, C4d is usually positive and thrombotic micro angiopathy usually present. with prompt diagnosis and treatment, patients can recover allograft function and histological features of active AMR frequently resolve.
Late (>30 Days) Post transplant AMR with Preexisting DSA
Usually There are preexisting DSA or Denovo antibodies
Banff 2017 classification of active or chronic active AMR with C4d staining may or may not be present, concomitant TCMR are often present.
Clinical presentation: allograft dysfunction and proteinuria due to pre-existing plasma response or under immunosuppression (Denovo Abs), prognosis graft loss within months to year
Features associated with reduced allograft survival in late AMR (Preexisting or Dee novo antibodies)
Chronic histological features of transplant glomerulopathy (Banff cg score >0), the degree of interstitial fibrosis and tubular atrophy, concomitant TCMR, C4d positivity, vascular lesions (Banff cv score >0), and clinical factors such as graft dysfunction at diagnosis, proteinuria, and time of diagnosis post-transplant, under-immunosuppression, medication non adherence, C1q positive DSA, titer and MFI with C1q positivity cross match and anti-class II DSA.
CONSENSUS FOR MEASURING AND MONITORING OF DSA
The essential immunological workup of recipient and donor are Molecular typing for HLA includes A; B; C; DRB1; DRB3, DQA1/DQB1; and DPA1/DPB1
Obtaining a history of allo sensitizing events, and screening for anti-HLA antibody
by high-resolution level (“4-digit” typing) screening for alloantibody would be with single-antigen bead (SAB) solid-phase assays or multi antigen beads.
Patients with no history of allo sensitizing events, negative anti HLA antibody are at low risk for AMR.
Monitoring for dnDSA is recommended in the following settings: immunosuppression reduction by physician for any reason, patient medication non adherence, or at the time of rejection (T cell or antibody mediated.
The presence of dnDSA is indicator of under-immunosuppression so reevaluation of maintenance immunosuppression is needed., close monitoring of allograft function and kidney biopsy is also recommended to detect T-cell or AMR (clinically evident or subclinical).
Interpreting Positive DSA Results
Positive cut off MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies. But false low MFI can present due to external substances, bead saturation, and “shared-epitope” phenomenon, which need serum dilution or using ethylene diamine tetra acetic acid. for Risk Stratification cross matching plus SAB are used.
Risks of AMR from highest to lowest based on cross match and SAB-positive testing are the following: positive complement-dependent cytotoxicity (CDC) cross match, positive flow cytometry cross match, and negative cross match, Importantly, hyper acute AMR is also associated with having a positive CDC cross match.
EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Challenges of treatment of AMR are due to Small and heterogeneous available studies. As recommended by guidelines the use of a variable mix of interventions (e.g., variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies treatment effects.
plasma exchange (PLEX) and IVIG
It is the most common regimen used for removing circulating DSA and reducing DSA production. Recommended by FDA 2017 in combination with low- or high-dose IVIG (immunomodulation) and by KDIGO 2010 for PE and IVIG in association with corticosteroids, its regarded as a standard of care for acute active AMR.
Complement Inhibitors
Through which we can avoid the downstream damage to the allograft from DSA.
Eculizumab is a monoclonal antibody results in terminal complement blockade as a targeting C5
Many studies confirmed the protective effect of eculizumab for preventing early active AMR in positive cross match HLA-incompatible living and deceased donor populations.
Rituximab
B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines.
Several retrospective analyses have suggested some positive effects of rituximab in combination with steroids, plasmapheresis, and high-dose IVIG, especially on patients with vascular AMR
A single-center study suggests that Rituximab as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.
In 3 small randomized trials its utility investigated without demonstrating a clear benefit.
Imlifidase
An IgG-degrading enzyme can rapidly reduce or even eliminate anti-HLA DSA and is undergoing clinical trials in AMR.
Anti thymocyte Globulin
T-cell–depleting antibodies used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. proposed by KDIGO guidelines as potential treatment options no benefit has been demonstrated for treatment of pure AMR, Side effects (higher risk of infectious-associated death), particularly when its combined with B-cell depletion.
Splenectomy
It must be performed rapidly after the onset of early AMR
Proteasome Inhibitor: Bortezomib
It has positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting antibodies.
Cyclophosphamide
Its use within a multimodal treatment regimen for the treatment of refractory rejections. While there are no trial data to support its use.
Interleukin-6 Inhibitors
Tocilizumab (monoclonal antibody) traid in patient with chronic active AMR.
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
The combination of PLEX, IVIG with corticosteroids regarded as standard of care, with adjunctive therapy with other agents such as complement inhibitors, Rituximab 375mg/m2 and Splenectomy depending on availability, where concomitant TCMR is present, it should be treated
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT) Preexisting DSA.
With preexisting DSA and active AMR, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids plus adjuvant (Rituximab 375mg/m2)
chronic active AMR or chronic transplant vasculopathy,
Goals of therapy should be to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, and titer of DSA while minimizing drug toxicity. The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR
De Novo DSA
AMR in this setting is initially detected with concomitant TCMR. the standard management is to optimize baseline immunosuppression and manage potential medication non adherence. Treatment of concomitant TCMR is recommended treatment with PLEX, IVIG, and Rituximab is used in some centers, although the evidence level is low.
CONCLUSIONS
There were no clear treatment regimens to recommend and there are no approved treatments. The consensus opinion of those present at the meeting was based largely on observational studies, low-level evidence, and expert opinion.
level of evidence 4/5 , based on expert opinion
This publication is a summary of that meeting and includes up-to-date information about the pathogenesis of the condition, the criteria for diagnosis, prognosis, and long-term outcome.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
In alloimmune naive individuals, the generation of antibody-secreting cells follows a scripted series of checkpoint events involving T- and B-cell interface. And in the context of transplantation, presensitized individuals have a robust long-lived plasma cells constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid anamnestic antibody response. For this second the differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells. Likewise, the absence of DSA does not imply the lack of memory B cells and the potential for an anamnestic response. Thus, the ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of presensitized recipients susceptible for an active AMR early posttransplant.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
The salient features of active AMR based on the Banff 2017 classification are: (1) histological evidence of graft injury via microvascular inflammation (MVI); (2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and (3) the presence of circulating DSA, predominantly anti-HLA antibody.
Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the context of glomerulitis and thrombotic microangiopathy. To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR.
CLINICAL PHENOTYPES OF AMR
Further complicating the diagnosis and management of AMR are various clinical phenotypes:
– abrupt allograft dysfunction early posttransplant
– insidious or subclinical onset, presenting later posttransplant
– Anti-HLA antibody can also be present before transplant (preexisting DSA)
– Anti-HLA develop after transplant (dnDSA) in the setting of under-immunosuppression
– histological features suggestive of AMR are present, but anti-HLA antibody is not detected.
Incorporating these clinical features of AMR into the current Banff classification while considering the likely underlying immunologic mechanisms is critical to appropriately guide therapeutic decisions and ultimately design efficient and effective therapeutic clinical trials.
A – Early Posttransplant ( < 30 days) active AMR
This aggressive form of active AMR typically presents with an abrupt increase in DSA accompanied by allograft dysfunction (increased creatinine and oliguria with or without proteinuria). If not recognized and treated quickly, it can lead to cortical necrosis and allograft loss within days.
From a histological perspective, the criteria for Banff active AMR are met and C4d is usually positive. There is often interstitial hemorrhage, glomerular fibrin thrombi, and microvascular coagulative necrosis. With prompt diagnosis and treatment, patients can recover allograft function and histological features of active AMR frequently resolve completely.
B – Late ( > 30 days) Posttransplant AMR With Preexisting DAS
While many patients with preexisting DSA do not develop an aggressive early AMR as described above, they can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy (in the setting of stable function) or on a for-cause biopsy for mild allograft dysfunction. Histological findings are dependent on the timing of the biopsy.
C- Late (>30 Days) AMR Associated With dnDSA
In the current era of sensitive DSA testing and a general avoidance of preexisting DSA, the most common form of AMR is associated with dnDSA. In general, dnDSA is a new DSA detected after >3 months posttransplant in the context of inadequate immunosuppression which is either due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs. This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR. In patients who have routine surveillance DSA testing or surveillance biopsies, the presentation can be more indolent and is similar to that of late posttransplant AMR in patients with preexisting DAS. Results from 2 recent studies have suggested that AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA after adjusting for clinical, histological, and immunologic characteristics.
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
The histological, clinical, and alloantibody features associated with reduced allograft survival are similar between them. Allograft histology is key to document the chronicity and extent of injury.
A – Are predictive of allograft failure:
– Chronic histological features such as the presence of transplant glomerulopathy (Banff cg score >0)
– the degree of interstitial fibrosis
– tubular atrophy
– concomitant TCMR
-C4d positivity;
– Vascular lesions (Banff cv score >0)
Not surprisingly, clinical factors are also predictive of outcome including allograft dysfunction at diagnosis:
-Proteinuria;
– Time of diagnosis posttransplant;
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Initial Assessment for Anti-HLA DSA
The first-line screening for alloantibody would be with single-antigen bead (SAB) solid-phase assays (LABScreen [one Lambda] or LifeScreen [LifeCodes-Immucor]), but multiantigen beads can also be used . Patients with no history of allosensitizing events and with negative anti-HLA antibody testing using single-antigen or multiantigen bead solid-phase assays are at low risk for AMR.
Molecular HLA typing ideally includes A; B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; and DPA1/DPB1.
Monitoring for De Novo DAS
Monitoring for dnDSA is recommended in the following settings: immunosuppression reduction by physician for any reason, known patient medication nonadherence, or at the time of rejection episode (T cell or antibody mediated).The presence of dnDSA is a general indicator of under-immunosuppression and signals the need to reevaluate maintenance immunosuppression.
Based on the strong relationship between dnDSA, AMR, and graft loss, transplant patients with dnDSA should undergo close monitoring of allograft function. A kidney biopsy is also recommended to detect T-cell or AMR (clinically evident or subclinical).
Interpreting Positive DSA Results
The SAB test detecting DSA has been an important advancement to the field; however, the test has limitations that must be identified for correct interpretation. Methods to identify interference and bead saturation include performing serum dilution or using ethylenediaminetetraacetic acid. We recommend the routine use of these methods in the following situations: transplant candidates/recipients who are not immunologically naive, unexpected positive crossmatch, or AMR with unexpectedly low DSA MFI.
Additional DSA Testing for Risk Stratification.
Remains unclear whether complement binding assays outperform antibody titers for AMR risk stratification. For this reason, we do not recommend routine use of complement binding assays unless it is used as a means of predicting high strength DAS.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
As recommended by guidelines, most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of intravenous immune globulins [IVIG], variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting antibodies). Obviously, these different interventions create a challenge in the interpretation of treatment effects. As a consequence, treatment studies for AMR are rarely comparable, and the available evidence is generally of low quality.
Plasma Exchange and IVIG
PLEX and IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy. The rationale for using PLEX and IVIG is to combine removal of circulating DSA with immunomodulation of the antigraft imune response and in particular modulation of the B-cell response.
Complement Inhibitors
Several studies have been undertaken to evaluate the ability of various complement inhibitors to prevent and treat AMR. The main goal of using complement inhibitors is to avoid the downstream damage to the allograft from DSA.
Eculizumab has protective effect for preventing early active AMR in positive crossmatch HLA-incompatible living and deceased donor populations.
Rituximab
Despite its frequent use, the evidence is low and 3 small randomized trials have investigated its utility without demonstrating a clear benefit in B-cell–rich rejections. Despite this, any trials and prospectives studies there were no differences between treatment and control groups in estimated glomerular filtration rate decline, level of proteinuria, Banff score on biopsy, or MFI of the immunodominant DAS. In contrast, several retrospective analyses have suggested some positive effects of rituximab in multimodal treatment regimens together with steroids, plasmapheresis, and high-dose IVIG, especially on patients with vascular AMR.
Imlifidase
It´s an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA and is undergoing clinical trials in AMR. Although data are lacking for using IdeS in AMR, this agent has been used safely in highly sensitized individuals for desensitization. After administration of IdeS, all previously positive crossmatches became negative and all studied patients received a transplant.
Antithymocyte Globulin
It´s a T-cell–depleting antibodies and have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. Side effects are well described with a higher risk of infectious-associated death, particularly when ATG was combined with B-cell depletion.
Splenectomy
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR. Most of these AMR cases occur in the first week after transplantation and result in profound graft dysfunction and a sudden rise in DSA strength, usually from an anamnestic response.
Proteasome Inhibitor: Bortezomib
It´s directly targets antibody-producing plasma cells making it an attractive candidate for the treatment of active AMR. Data supporting its use are limited to case series suggesting a positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, and depleting antibodies, although the only prospective randomized, double-blind, placebo-controlled trial was in “late” AMR and did not demonstrate any beneficial effect of bortezomib alone.
Cyclophosphamide:
There are no trial data to support its use. It is is used for the treatment of antibody mediated diseases such as anti-neutrophil cytoplasmic antibody vasculitis or lupus nephritis.
Interleukin-6 Inhibitors
Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function.
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
The current evidence for treatment options in active AMR is of limited quality. The consensus view was that the combination of PLEX, IVIG with corticosteroids could be regarded as standard of care. The trials had many limitations, and most evidence comes from small retrospective studies with different combination therapies using different AMR definitions in different populations.40,55,62,83 Thus, the available evidence supporting the use of any adjunctive agents is of low quality with the best evidence relating to drug toxicity and costs.
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Preexisting DSA
Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids. Although, has not been shown to improve outcomes in patients with chronic active AMR (as distinct from acute active AMR) and has to be balanced against increased risk of adverse events such as infection and cost.
De Novo DSA
dnDSA generally occurs in the context of reduced immunosuppression whether from patient nonadherence or a physician-directed change in immunosuppression. AMR in this setting is also often initially detected with concomitant TCMR. Therefore, the standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases. Similar to patients with chronic active AMR in the context of preexisting antibodies, treatment with PLEX, IVIG, and Rituximab is used in some centers, although the evidence level (3C) is low
CONCLUSIONS
Despite the severity of the problem and poor outcomes for patients who develop AMR, there is very little highlevel evidence to support the use of any therapy.
The consensus opinion of those present at the meeting was based largely on observational studies, low-level evidence, and expert opinion. Despite the clear lack of evidence, it was considered important to define a standard of care for AMR, which could be used as a benchmark for future studies and prospective trials.
This consensus has level 05, because is a expert opinion consensus.
This paper is recommendations from the Transplantation Society Working Group to seek uniformity in the treatment of antibody-mediated rejection after kidney transplantation. After ten years, 25% of patients had de novo DSA, with antibody rejection the leading cause of graft rejection in biopsies collected before its failure.
The histological criteria described by the international Banff classification, separate the diagnosis of chronic active AMR with signs of chronic tissue injury such as transplant glomerulopathy, electron microscopy showing basement membrane with severe peritubular capillaritis, or intima arterial fibrosis with no obvious cause. These findings are predictive of allograft failure.
Acute AMR will not necessarily become chronic, as histologic findings typical of transplant glomerulopathy develop renal dysfunction, proteinuria, and eventually graft loss. Allograft survival at 8 years post-transplant was only 56%, compared with 88% subclinical TCMR and 90% if the biopsy was normal.
Anti-HLA antibodies may occur before transplantation or after (de novo DSA) due to inadequate immunosuppression. de novo DSA is a general indicator of under-immunosuppression and signals the need to reevaluate its maintenance. We should routine dosing at transplant candidates who are not immunologically naive, unexpected positive crossmatch or AMR with unexpectedly low DSA MFI.
There is no specific protocol for chronic active AMR, but there is a need for some immunosuppressive strategy. Classically, rituximab associated with plasma exchange and immunoglobulin has been used, with specific situations including bortezomib, eculizumab, IdeS, rATG, cyclophosphamide, and IL6 inhibitors, and the use of each of these drugs should be individualized.
Despite the lack of evidence, immunosuppressive treatment is superior to observational strategies.
Summary:
AMR continued the key cause of graft loss despite the improvement in the immunosuppressive medication and the new advances in molecular genetic testing, still 25% of the kidney transplant recipient developed denovo- DSA over times and increased the risk of acute and chronic ABMR with progressive graft loss.
Till date no FDA approved prevention and treatment therapy for the AMR, yet no standardized guideline for the treatment of AMR due to lack of evidence most of the studies are limited to small observation with inconclusive results that hampered the introduction of novel new immunosuppression, so this review give summary of the recommendation from the expert meeting based on the best available evidence for treatment and prevention of active and chronic ABMR.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
The production of the antibodies in immunologically naïve or presensitized candidate undergo a complex immunological process including T and B cells activation prefiltration in peripheral lymphoid Tissues following sequences of checkpoints events with T and B cells crosstalk with alloantigen recognition by APC like B cells dendritic cells which some will be short-lived plasma blast cells or memory B cells and rest enter the GC to further differentiated to high affinity plasmablast and long live B memory cells with low affinity receptors compared to plasma cells ,in presensitized kidney transplant candidate will have robust high affinity anti -HLA- antibody production upon re-exposure to antigens and lead to antibody antigen immune response .
Quantification of the donor specific memory B cells may help in risk stratification and aid in treatment for those at risk of AMR.
DSAs level another limiting factor with different FC receptors binding capacity with heterogenicity in expression, Public and private cross reactivity and specificities considered other challenges in the diagnosis and treatment of AMR.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
International clinicopathological Banff CLASSIFICATION evolved over years since 1997, AMR classification entered in 2003, in 2017 addition of the salient features of Active AMR criteria which includes: Microvascular inflammation (MVI, g, pct >0), intimal endarteritis(V>0 ), ATN and ,or TMA in the absence of other cause , C4D staining and Positive DSA anti HLA antibodies .
Chronic active antibody mediated rejection (CABMR)
In addition to the criteria 2,3 of AMR need the addition of chronic histological injuries like chronic transplant glomerulopathy Cg with PCTGB multilayering in EM and new arteriolar intimal hyalinosis in the absence of other causes.
AMR is very complex and started from the time of DSA formation but not all DSA s leads to active AMR some tend to be subclinical and progressive overtime lead to chronic active AMR This adds to the challenges for the diagnosis and treatment of AMR
Also, the AMR phenotypes.
Early AMR < 30 days usually acute aggressive within days post-transplant ,due to performed DSA rebound and the memory B cells recalls with positive XCM and high MFI, CPRA %,associated with C4D staining and characterized by sudden oliguric acute graft dysfunction, positive DSA with or without proteinuria, can lead to immediate graft loss if not treated.
Late AMR > 30 days still could be due to preformed DSA with Banff classification 2017 of active and chronic ABMR, c4d +VE with preformed DSA positive, proteinuria with progressive graft dysfunction within months to years Late > 30 days due to denovo DSA with subclinical or progressive chronic allograft injuries with negative C4D or positive sometimes with TCMR, with proteinuria, triggers by nonadherence to immunosuppression in > 40% with class 11 denovo DSA. Associated with progressive graft loss over months – years. Less responsive to treatments.
Predictors for inferior graft survival
Histological degree of chronic transplant glomerulopathy C g>0 and IFTA, combination with TCMR, C4D +ve , chronic vascular injury VC >0 .
Clinical proteinuria and allograft dysfunction
Time of the diagnosis, C1q positive DSAs and class 11 Denovo DSA
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Donor and recipient HLA typing with historic sensitization for the recipient (1A).
The Standard molecular genetic HLA typing for class 1HLA-A, B-C, class11 DRB1, DR3,4,5, DQA1, DQB1, DPA1, DPB1, (B2).
In HLA sensitized Patients preferred to do high resolution molecular HLA typing for 4digit HLA typing with ALLEL specificity.
Preferred using single antigen bead (SAB) solid phase assay (Lab screen, one lambda).Both C1q DSA monitoring based on center policy and IgG subclasses assay are not yet recommended only for research level.
However, the risk stratification for AMR still based on the crossmatch results (CDC, FXCM) and the level of DSA.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
We know that so many factors that impact the graft outcome and survival like type and time of the rejection, type of DSA so not only the treatment, that’s why most of the available treatments based on evidence from small studies with heterogenous population selections and not taken in consideration the above-mentioned important factors that can impact the response to treatments.
Till date we have low quality of evidence regarding the treatment of AMR, mixed rejection, Chronic active AMR. different protocols different combinations with different dosing which is challenging to conclude a specific guideline or protocol
Standard of care for treatment of active AMR < 30 days with performed DSAs is the use of combination of plasmapheresis and IVIG (KDIGO2010, expert consensus updated work shop in 2017).as it was shows good efficacy to improve short term outcome based on weak evidence studies as the combination of plasma therapy with IVIG help in removal of the antibodies and immunomodulation of the B cell response but such treatment loose its efficacy overtime due to the rebound effect.
So, using multiple adjunctive treatments that inactivate the complement like using eculizumab monoclonal AB ant c5 complement its use limited as salvage therapy to refractory AMR, its use limited due to the cost and also the duration of treatment not yet determined. B cell depleting agents again the evidence is limited to the use of rituximab, BORTOEZMAB as adjuvants therapy to prevent the rebound effects with safety concern due to the increased risk pf infections, hematological side effects.
Chronic Active ABMR > 30 days with performed DSA preferred optimization of the maintenance immunosuppression (add steroid in case of steroid free protocol), consider IVIG (3c) Deno DSA and Chronic active ABMR again address the nonadherence and optimization of the maintenance IS, may consider trial of PLSAMAPHERSIS, IVIG with or without rituximab (case by case )3C. Concomitant TCMR with CABMR with preexistent DSA standard of care as per the expert consensus to go for plasmapheresis, IVIG, steroid +/- rituximab
Chronic AMR optimization of IS will focus on control of BP, proteinuria, stabilize the GFR, aviod nephrotoxic drugs, treat infections and may consider trial of IVIG alone (3C).
to conclude: that treatment of Acute and chronic AMBR not yet standardized and its based on weak evidence from limited studies and its a call for more clinical trials and research with better designs adding a newer agents and better characterization of the AMR.
Summary
This article is about the diagnostic features of AMR and the recommended expert guided evidence based treatment for active AMR and chronic active AMR.
AMR can be identified through the following features
AMR timing
Within 30 days post transplant : Previously sensitized patient with measurable DSA. There can be sudden increase in serum creatinine and oliguria with or without proteinuria. Without intervention, graft loss can occur in a matter of days.
Histological features seen :
After 30 days post transplant with pre-existing DSA : Detected on surveillance biopsy.
Features :
Microvascular inflammation in glomeruli and peritubular capillaries
Positive C4d staining possibly but not necessary for diagnosis
Transplant glomerulopathy
peritubular basement membrane multilayering.
After 30 days post transplant with dnDSA : dnDSA is a new DSA detected after 3 months of post transplant when there is inadequate immunosuppression.
The causes for these could be :
AMR in this category would present as allograft dysfunction with TCMR. Increased proteinuria is a key feature.
Prognosis is poor.
Treatment of active and chronic active AMR
Level of evidence :
4/5 since this article is a consensus based on observational studies, low level evidence and expert opinion.
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
25 % of patients will develop denovo DSA after a decade of kidney transplantation, so AMR was the most common cause of allograft failure. Sadly, there is no standard protocol of treatment of AMR.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
AMR is diagnosed based on:
CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories:
Early Post-transplant (<30 Days) Active AMR
Increasing DSA strength or breadth at the time of transplant (DSA mean fluorescence intensity (MFI)), the degree of flow cytometric crossmatch positivity, and the number or breadth of cross-reactive DSA specificities has been risk for developing AMR, however it is an uncommon form.
Late (>30 Days) Post-transplant AMR with Preexisting DSA
Late (>30 Days) AMR Associated With dnDSA
This is the most common form of AMR
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
Allograft histology has been important in the chronicity and extent of injury.
Chronic histological features – presence of transplant glomerulopathy and the degree of interstitial fibrosis and tubular atrophy are predictive of allograft failure.
Under-immunosuppression is a major risk factor for dnDSA, medication nonadherence is independently associated with inferior allograft survival among patients with dnDSA.
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Plasma Exchange and IVIG:
Complement Inhibitors
Rituximab
Imlifidase
Antithymocyte Globulin
Proteasome Inhibitor: Bortezomib
Directly targets antibody-producing plasma cells
Interleukin-6 Inhibitors Toclizumab and Clazakizumab
Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids.
Those who has chronic active AMR or chronic transplant vasculopathy, goals of therapy should be to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, and titer of DSA while minimizing drug toxicity.
Treatment should focus on optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control.
dnDSA: standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence.
.– Antibody-mediated damage caused allograft dysfunction late posttransplant in nearly 60% of renal transplant recipients.
-The features of active AMR based on the Banff 2017 classification are:
(1) histological evidence of graft injury .
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
(3) the presence of circulating DSA, predominantly anti-HLA antibody
-To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to criteria 2 and 3 for active AMR. Signs of chronic tissue injury include transplant glomerulopathy (Banff chronic glomerulitis [cg] score > 0), severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause.
CONSENSUS FOR MEASURING AND MONITORING OF DSA
-The initial assessment of a renal transplant candidate involves donor and recipient HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events (previous transplant, blood transfusion, and
pregnancy) ( 1A).
-Molecular HLA typing ideally includes A; B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; and DPA1/DPB1 (2B).
-The first-line screening for alloantibody would be with single-antigen bead (SAB) solid-phase assays (LABScreen [one Lambda] or LifeScreen [LifeCodes-Immucor]), butmultiantigen beads can also be used (1A).
-Monitoring for dnDSA is recommended in the following settings: immunosuppressionm reduction by physician for any reason, known patient
medication nonadherence, or at the time of rejection episode
(T cell or antibody mediated) (2B).
-Based on the strong relationship between dnDSA, AMR, and graft loss, transplant patients with dnDSA should undergo close monitoring of allograft function
(1B).
-The SAB test has a high coefficient of variation, and thus, the positive
cutoff varies among and within laboratories but a positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies.
. We recommend the routine use of these methods in the following situations: transplant candidates/recipients who are not immunologically naive, unexpected positive crossmatch, or AMR with unexpectedly low DSA MFI (2B).
-C1q and C3d binding positivity is associated with a high DSA titer.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Plasma Exchange and IVIG
-The strongholds for contemporary treatment of AMR are represented by plasma exchange (PLEX) and IVIG, although neither of these have FDA approval
-The expert consensus at the FDA Antibody-Mediated Rejection
Workshop in 201767 as well as Kidney Disease and KDIGO in 201068 was that PLEX and IVIG could be regarded as a standard of care for acute active
AMR, despite the weakness of evidence in support of efficacy.
-It improve short-term outcomes has been demonstrated by several studies while their results on long-term effects remain variable .
Complement Inhibitors
-The main goal of using complement inhibitors is to avoid the downstream damage to the allograft from DSA.
-when Eculizumab used in patients who received positive crossmatch HLA-incompatible transplants, the incidence of early active AMR was decreased from approximately 40% in historical controls to 7% among treated patients.
Rituximab
-several retrospective analyses have suggested some positive effects of rituximab in multimodal treatment regimens together with steroids, plasmapheresis,
and high-dose IVIG, especially on patients with vascular AMR.
-A single-center nonrandomized study suggests that Rituximab as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly
sensitized patients.
Imlifidase
-Imlifidase (Hansa Biopharma AB), an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA and is undergoing clinical trials in AMR.
-It has been used safely in highly sensitized individuals for desensitization. After administration of IdeS, all previously positive crossmatches became negative and all studied patients received a transplant.
Antithymocyte Globulin
-It has been used for treatment of refractory rejection, vascular rejection, mixed
rejections, and AMR.
– A large retrospective series suggests that T-cell depletion in combination with steroids has no effect on the outcome in vascular AMR.
Splenectomy
– It must be performed rapidly after the onset of early AMR to be effective.
– Some patients who recover develop transplant glomerulopathy and premature graft loss.
Proteasome Inhibitor: Bortezomib
Bortezomib is a proteasome inhibitor approved for the treatment of multiple myeloma that directly targets antibody-producing plasma cells making it an attractive candidate for the treatment of active AMR.
-The drug has well-documented side effects, and at the present time, there
are no trial data to support its use.
Cyclophosphamide
-It is used within a multimodal treatment regimen for the treatment of refractory rejections.
– While it is relatively inexpensive, there are no trial data to support its use.
Interleukin-6 Inhibitors
-Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function.
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
-The consensus view was that the combination of PLEX, IVIG with corticosteroids could be regarded as standard of care, consistent with the conclusions
of the FDA workshop and KDIGO guideline.
– The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability .
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Preexisting DSA
-Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids.
-The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR (as distinct from acute active AMR) and has to be balanced against increased risk of adverse
events such as infection and cost.
-The consensus opinion was that treatment should focus on optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control.
De Novo DSA
-AMR in this setting is also often initially detected with concomitant
TCMR.
-The standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication
nonadherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases.
-Treatment with PLEX, IVIG, and Rituximab is used in some centers,
although the evidence level (3C) .
-level of evidence :5
There is no consensus on treatment of antibody mediated rejection either acute or chronic. Transplantation society held a meeting to review the available literature in this regard and have given their expert opinion published in the form of this paper.
The fact that by 10 years 25% of transplant patients develop DSA simply signifies the importance of acting early.
In the context of transplantation, presensitized individuals have a robust long-lived plasma cells constitutively secreting anti-HLA antibodies and resting memory B cells primed to secrete large amounts of antibody upon antigen reexposure leading to a rapid anamnestic antibody response.
The differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells.
The diversity at the level of antibodies presents an additional challenge. Alternatively, cross-reactive alloantibodies may be donor reactive but not donor specific, and some may bind multiple HLA molecules.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
The salient features of active AMR based on the Banff 2017 classification14 are
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute throm- botic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other appar- ent cause;
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and
(3) the presence of circulating DSA, predomi- nantly anti-HLA antibody .
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to crite- ria 2 and 3 for active AMR.
Signs of chronic tissue injury include transplant glomerulopathy (Banff chronic glomer- ulitis [cg] score > 0),
severe peritubular capillary basement membrane multilayering on electron microscopy,
or new arterial intimal fibrosis without another obvious cause.
Phenotype of AMR should be considered alongside Histo pathological interpretation for guiding any kind of therapy.
Early Posttransplant (30 Days) Posttransplant AMR With Preexisting DSA
While many patients with preexisting DSA do not develop an aggressive early AMR as described above, they can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy (in the setting of stable function) or on a for-cause biopsy for mild allograft dysfunction.
Histological findings are depend- ent on the timing of the biopsy.
Overtime, however, the GFR declines and the patient becomes proteinuric with graft failure often occurring several years after transplant.
Late (>30 Days) AMR Associated With dnDSA
In general, dnDSA is a new DSA detected after >3 months posttransplant in the context of inadequate immunosuppression which is either due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs.
This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR.
Recent studies have suggested that AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA after adjusting for clinical, histological, and immunologic characteristics. Despite these find- ings, it remains unclear whether it is the dnDSA itself that is associated with inferior allograft survival or a delay in AMR diagnosis.
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
Transplant glomerulopathy
Degree of IFTA
Concomitant TCMR
Vascular leison
C4d positivity
Allograft dysfunction
Proteinuria
Time of diagnosis post transplant
Class 2 DSA
C1 q binding
Level of DSA
Monitoring for De Novo DSA
immunosuppression reduction by physician for any reason
known patient medication non-adherence
the time of rejection episode (T cell or antibody mediated)
Interpreting Positive DSA Results
In general, a positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies.
SAB tests are also prone to interference from external substances
bead saturation
and “shared-epitope” phenomenon, which can lead to a falsely low MFI.
Methods to identify interference and bead saturation include performing serum dilution or using ethylenediaminetetraacetic acid.
We recommend the routine use of these methods in the following situations: transplant candidates/recipients who are not immunologically naive
unexpected positive crossmatch
or AMR with unexpectedly low DSA MFI
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
Plasma Exchange and IVIG
expert consensus at the FDA Antibody-Mediated Rejection Workshop in 2017as well as Kidney Disease: Improving Global Outcomes (KDIGO) in 2010 was that
PLEX and IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy.
Complement Inhibitors
Despite prevention of early active AMR, the long-term incidence of chronic AMR and allograft survival is comparable to historical controls.
Rituximab
Rituximab, a B-cell–depleting agent, was suggested as a treatment option by KDIGO guidelines.Despite its frequent use, the evidence is low and 3 small randomized trials have investigated its utility without demonstrating a clear benefit.
Antithymocyte Globulin
Although depleting antibodies were proposed by KDIGO guidelines as potential treatment options,no benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
Splenectomy
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR. However in modern practice it’s role is questionable
Proteasome Inhibitor: Bortezomib
The drug has well-documented side effects, and at the present time, there are no trial data to support its use
Cyclophosphamide
No data to support it’s role
Interleukin-6 Inhibitors
A single-center, nonrandomized trial of tocilizumab (anti-interleukin-6 receptor monoclonal antibody) was undertaken in 36 patients with chronic active AMR that had failed IVIG plus rituximab. Patient and graft survival at 6 years (91% and 80%, respectively) were found to be superior to historical controls, with significant reductions in DSA and stabilization of renal function. Further trials are underway
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
PLEX
IVIG with corticosteroids could be regarded as standard of care, consistent with the conclusions of the FDA workshop and KDIGO guidelines
adjunctive therapy may be warranted especially when the risk of graft loss is considered high. The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Preexisting DSA
. Among patients with known preexisting DSA and active AMR without chronic features, the con- sensus treatment recommendations include PLEX, IVIG, and corticosteroids.
The use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in patients with chronic active AMR (as distinct from acute active AMR) and has to be balanced against increased risk of adverse events such as infection and cost.
De Novo DSA
AMR in this setting is also often initially detected with concomitant TCMR. Therefore, the standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence. Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases.
PLEX, IVIG, and Rituximab is used in some centers, although the evidence level (3C) is low.
Conclusion
It is expert opinion only on the basis of
Observational studies and low level evidence
By 10 years, after kidney transplant, up to 25% have developed de novo DSA (dnDSA) so AMR was the most common cause of allograft failure. Yet, there are no commonly accepted guidelines for treatment.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
The generation of antibody-secreting cells follows series of checkpoint events; alloantigen with B cells expressing the appropriate B-cell antigen receptor, B-cell migration to the T- and B-cell interface in the lymph node and alloreactive T cells present alloantigen indirectly on recipient dendritic cells.
Some of B cells differentiate into memory B cells or short-lived plasma blasts, while the rest enter into germinal centers to result in high-affinity class switched memory B cells, plasma blasts, and long-lived plasma cells which secrete large amounts of antibody upon antigen reexposure.
Differences between memory B cells and plasma cell generation predict that treatment aiming to prevent plasma cell generation and subsequent DSA production. Thus, the ability to quantify donor-specific memory B cells may aid in risk stratification and treatment of presensitized recipients susceptible for an active AMR early post-transplant.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
AMR is a clinicopathological diagnosis;
(1) histological evidence of graft injury via microvascular inflammation(MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause.
(2) Histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
(3) The presence of circulating DSA, predominantly anti-HLA antibody.
The exception is that peritubular capillaritis alone is insufficient for diagnosis in the presence of T-cell–mediated rejection (TCMR).
Recurrent or de novo glomerulonephritis must be considered as a differential diagnosis, especially in the presence of glomerulitis and thrombotic microangiopathy.
Signs of chronic tissue injury include transplant glomerulopathy, severe peritubular capillary basement membrane multilayering on electron microscopy, or new arterial intimal fibrosis without another obvious cause.
To diagnose chronic active AMR, morphological features of chronic tissue injury are present in addition to active AMR criteria.
CLINICAL PHENOTYPES OF AMR
The Banff classification has 3 AMR diagnostic categories:
Early Post-transplant (<30 Days) Active AMR
The risk is indicated by increasing DSA strength or breadth at the time of transplant (DSA mean fluorescence intensity (MFI)), the degree of flow cytometric crossmatch positivity, and the number or breadth of cross-reactive DSA specificities. It is uncommon form.
Late (>30 Days) Post-transplant AMR with Preexisting DSA
Patients with preexisting DSA who don’t develop an aggressive early AMR can develop an indolent and progressive form of AMR that is usually initially detected on a surveillance biopsy or on a for-cause biopsy for mild allograft dysfunction. If detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present. MVI may persist and is later accompanied by chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering.
Late (>30 Days) AMR Associated With dnDSA
The most common form of AMR is associated with dnDSA (due to sensitive DSA testing and a general avoidance of preexisting DSA). DnDSA is a new DSA detected after >3 months post-transplant owing to inadequate immunosuppression (patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs).
Allograft survival was 63% in patients with preexisting DSA and only 34% in patients with dnDSA 8 years after the rejection diagnosis.
Compared with patients with preexisting DSA, those with dnDSA tend to have increased proteinuria and increased expression of interferon-γ–inducible, natural killer cell, and T-cell transcripts at presentation.
FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
Allograft histology is key to the chronicity and extent of injury. Chronic histological features such as the presence of transplant glomerulopathy and the degree of interstitial fibrosis and tubular atrophy are predictive of allograft failure. Under-immunosuppression is a major risk factor for dnDSA, medication nonadherence is independently associated with inferior allograft survival among patients with dnDSA.
CONSENSUS FOR MEASURING AND MONITORING OF DSA
Initial Assessment for Anti-HLA DSA (history of allosensitizing events as previous transplant, blood transfusion, and pregnancy).
Monitoring for De Novo DSA (Immunosuppression reduction either as a result of nonadherence or under physician direction is associated with development of dnDSA)
The presence of dnDSA is a general indicator of under-immunosuppression.
Interpreting Positive DSA Results (a positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies).
Shared-epitope phenomenon, which can lead to a falsely low MFI.
Additional DSA Testing for Risk Stratification (All patients with DSA are at some risk for AMR: Crossmatch testing, complement-dependent cytotoxicity, testing to assess the complement binding ability of DSA (C1q or C3d)).
Available evidence for the treatment of active and chronic active AMR.
Plasma Exchange and IVIG:
It removes circulating DSA and reducing their production along with immunomodulation of the antigraft immune response and in particular modulation of the B-cell response.
In experimental models, IVIG has been shown to inhibit B-cell responses by the Fc portion of the Ig binding the Fc fragment of IgG2b receptor on B cells, and sialylated IVIG binds CD22, inducing apoptosis of mature B cells. It also functions as a scavenger of activated complement.
Complement Inhibitors
Eculizumab a monoclonal antibody targeting C5.it has a protective effect of eculizumab for preventing early active AMR in positive crossmatch HLA-incompatible in living and deceased donor populations.it also has effectiveness in treating early active AMR that occurs within the first month posttransplant.
Rituximab
B-cell–depleting agent, used as an add-on therapy may prevent DSA rebound as part of a desensitization protocol in highly sensitized patients.
Imlifidase
An IgG-degrading enzyme of Streptococcus pyogenes (IdeS), can rapidly reduce or even eliminate anti-HLA DSA. IdeS cleaves human IgG at a highly specific amino acid sequence within the hinge region producing Fc and F (ab) 2 fragments and effectively blocking CDC and antibody-dependent cellular cytotoxicity.
It is used as an adjunct to other therapies aiming to reduce DSA in the long term.
The unique feature of this drug is that it permits any highly sensitized patient to undergo transplantation within hours of a donor being identified regardless of the crossmatch status.
Antithymocyte Globulin
T-cell–depleting antibodies have been used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR. Side effects are higher risk of infectious-associated with death.
Proteasome Inhibitor: Bortezomib
Directly targets antibody-producing plasma cells.
Interleukin-6 Inhibitors Clazakizumab
Among patients with known preexisting DSA and active AMR without chronic features, the consensus treatment recommendations include PLEX, IVIG, and corticosteroids. In cases of chronic active AMR or chronic transplant vasculopathy, goals of therapy should be to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, and titer of DSA while minimizing drug toxicity.
Treatment should focus on optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, and optimizing medical management with focus on blood pressure, blood glucose, and lipid control.
De Novo DSA: standard for managing AMR in this setting (active or chronic active) is to optimize baseline immunosuppression and manage potential medication nonadherence.
CONCLUSIONS
It is obvious that new agents and clinical trials are needed urgently.
In addition, better characterization of the different forms of AMR based on pathophysiology, histology, as well as clinical and genetic phenotypes is needed.
Level of evidence (4 – 5)
Despite the newly discovered IS medications, Graft loss due to alloimmunity is still a problem. It is well known that around 25% of kidney transplant recipients develop de novo DSA 10 years post-transplantation; this will lead to the development of ABMR, and because of this fact, ABMR is considered the most common cause of allograft failure.
There are no accepted guidelines for the treatment of ABMR, and to date, clinical trials of ABMR are either small or inconclusive, and there is no FDA approved therapy for prevention or treatment of ABMR.
Diagnostic criteria and histological features of ABMR:
ABMR is a clinicopathological diagnosis that was first described in 2003 in addition to the 1997 international Banff classification of kidney allograft rejection.
The salient features of active ABMR in Banff 2017 classification are:
The main histological manifestations are glomerulitis and peritubular capillaritis.
Clinical phenotypes of ABMR:
Features associated with reduced allograft survival in late ABMR:
Consensus for measuring and monitoring of DSA
Initial assessment of DSA:
Monitoring for de novo DSA:
Recommended in:
Interpreting positive DSA results:
SAB testing has limitations that may interfere with the results such as:
Additional DSA testing for risk stratification:
The risk of ABMR from highest to lowest based on XM and SAB-positive testing are:
positive CDC XM, positive FCXM, and negative XM.
Positive complement-binding DSA is associated with ABMR and graft loss.
The available evidence for the treatment of active and chronic ABMR:
Level 4/5
Despite the fact that Antibody mediated rejection is the most common advrse related to poor allograft outcome, there is no consunsus about the best management and treatment thereof.The transplantation society host an expert meeting to discuss and stratify the treatment strategy based on best available evidence.This article is a summary that meeting…
An important points to consider in Allosensitization:
After the encounter of B lymphocytes with an allo antigens in the transplanted kidney,B cells differentiate to memery cells or Plasma cells.The repertoir of memory cells is much different from that of plsma cells.therefore, treatment of plasma cell will not prevent the memory cell formation. similarly,absence of DSAs is not synonymous with absence of memory cells or the lack of potential amnestic reaction towards an allograft antigens.
Diagnostic criteria of AMR:
1]Histologic evidence of allograft injury in the form of MVI, Microangiophaic thrombosis, intimal or transmural arteritis.Or acute tubular injury in the absence of any other detectible reason.
2]Antibody -endothelial interaction evidence based on C4d or MVI.
3] DSAs
The presence of gloerulitis and PTC of more than 0 satisfy criterion 1 and g+ptc of equal or more than 2 is satisfing criterion 2.
Chronic active AMR:
include the presence of criteria 2 and 3 , in addition to features of chrinisity which are basically transplant glomerulopathy TG and peri-tubular multilayring PTCM.Or new arterial intimal fibrosis with no othe causes.
Phenotype of AMR:
DSAs anti HLA can often be associated with acute AMR ,but sometimes its not causing acute AMR. AMR is commonly a long term progressive disease, however , its not always progressing to chrinic active AMR after an episode of acute AMR.
DSAs cause active AMR ,which is commonly [but not limited to] MVI.
Chronic AMR, is the presence of TG with current or prior DSAs without C4d or MVI.
Overtime, histological features of chronic AMR in the form of TG and PTCM with IFTA is becoming increasingly evident with clinical features of allograft dysfunction and proteinuria with eventual allograft loss.
The course of the disease.its stage and histological features,are dependent entirely, on when the allograft biopsy is contemplated, So its basically the timing of biopsy reflecting the stage of disease ,rather than having different types of AMR.
DSAs:
Early [less than 30 days]:
Active AMR can occur in the first 30 days ,if there is detectable DSAs at time of transplantation or if there is an amnestic response.
depending on DSAs MFI and positivity on FCXM up to 40 % risk ratio.
Late [more than 30 days]posttransplant AMR with preexisting DSAs:
An indolent and progressive form of AMR can develop secondary to preexisting DSAs.
its associated with pooor allograft outcome.
Late more than 30 days, AMR associated with dn DSAs.:
DSAs developed after 3 months , due to noadherence to medication or physician directed.
The presentation of AMR in the context of dnDSAs is often present with concomitent TCMR, with clinically, indolent allograft dysfunction.
Two recent studies showd inferior graft survival with dnDSA associated AMR than AMR associated with pre existing DSAs.it could be relatred to delayed diagnosis of AMR.
Features associated with reduced allograft survival in late AMR [preexisting or dnDSAs]:
1}TG and IFTA.
2}Concomitant TCMR
3}C4d positivity.
4}Vascular lesion.
5}Allograft dysfunction at diagnosis.
6}Proteinuria.
7}TIME OF DIAGNOSIS POST TRANSPLANT.
8}C1q positive antibodies.
9}level of DSAs by MFI and FCXM.
10}anti class II HLA DSAs.
Monitoring of dnDSAs:
1- Immunosuppresion reduction.
2- nonadherence.
3-Rejection episode TCMR or AMR.
There is a strong correlation between dnDSAs, AMR and graft loss.therfore close follow up of DSAs are of prime significance.Similarly,renal function and kidney biopsy to be perforemd whenever needed.
Interpretation of positive DSAs:
SAB test was an important test for detection of DSAs.
A cut off of 1000 -1500 is associated with detection of specific HLA antibodies.
SAb isprone to interference with external substances, bead saturation and shared epitop phenomina which can lead to a falsely low MFI.
Treatment of Active AMR:
PP and IVIG are the main steps in the managment.:
to remove the DSAs and modulate the production of DSAs by inhibiting Blymphocytes.
Eculizumab is a monoclonal antibody targeting C5. To inhibit the complement system, as its involved in the AMR events.result in terminal complement blockade.
Bortizomib its a proteasome inhibitor targetting antibody producing Plasma cells.
Chronic Active AMR:
The aim of therapy is to stabilize or reduce the rate of decline of GFR,proteinuria,histological injury score,and titer of DSAs while minimizing drug toxicity.
IVIG, RITUXIMAB,PP were shown to be ineffective in improving the allograft outcome in chronic active AMR
Consus opinion was:
optimization of immunosuppresion.
reintroduction of steroid therapy.
to keep Tac.trough level more than 5 ng/ml.
blood pressure , glucose and lipid control.
In conclusion:
Despite the vast knowledge obtained about the immunology and pathogenesis of AMR , its still associated with worse prognosis and limited high level evidence studies to stratify its management .
Its narrative review with level of evidence 4
☆The Transplantation Society brought together a group of experts from around the globe with the aim of producing a consensus document that outlined recommended treatments for active and chronic active AMR, based on the best available evidence.
◇BIOLOGY OF THE ALLOIMMUNE RESPONSE:
▪︎Presensitized individuals have a long-lived plasma cells which secrete anti-HLA Abs & resting memory B cells.
▪︎The repertoire of plasma cells and memory B cells are not identical. So, treatment aiming to prevent plasma cell generation and subsequent DSA production may not stop the generation of memory B cells.
▪︎Absence of DSA does not mean the lack of memory B cells.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR:
▪︎AMR is a clinicopathological diagnosis.
▪︎Features of active AMR based on the
Banff 2017 classifcation are:
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute TMA in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
(2) histological evidence of antibody endothelial interactions either by C4d deposition or at least moderate MVI
(3) the presence of circulating DSA, predominantly anti-HLA antibody.
▪︎Glomerulitis (g) and peritubular capillaritis (ptc) are the main forms of MVI
▪︎Histological manifestation of active AMR:
Criterion 1, (g + ptc > 0)
Criterion 2, (g + ptc) sum score of ≥2 ▪︎ptc alone is insufficient for diagnosis in the presence of TCMR. Recurrent or de novo GN must be considered as a DD.
▪︎Diagnosis of chronic active AMR: Morphological features of chronic tissue injury + criteria 2 and 3 for active AMR.
▪︎Signs of chronic tissue injury:
Transplant glomerulopathy (TG) (Banff chronic glomerulitis [cg] score > 0), severe peritubular capillary basement membrane multilayering on EM, or new arterial intimal fibrosis without another obvious cause.
◇CLINICAL PHENOTYPES OF AMR:
The Banff classifcation has 3 AMR diagnostic categories (including chronic AMR with TG & current or prior DSA but no MVI or C4d).
▪︎There are many clinical phenotypes of AMR (early and late) which complicate it’s diagnosis and management .
◇To design effcient and effective therapeutic clinical trials, the authors recommended:
1) considering the timing of presentation
2) Type of DSA (pre-existing or de novo), in relation to the histological classifcation.
◇Phenotypes:
1. Early posttransplant (30 Days) posttransplant AMR With Preexisting DSA
3. Late (>30 Days) AMR Associated With denovo DSA dnDSA
◇FEATURES ASSOCIATED WITH REDUCED ALLOGRAFT SURVIVAL IN LATE AMR (PREEXISTING OR DNDSA)
▪︎In late AMR (preexisting or dnDSA), the histological, clinical, and alloantibody features associated with reduced allograft survival are similar .
▪︎Chronicity and extent of injury depend on allograft histology
▪︎Graft outcomes is associated with:
1. Chronic histological features such as the presence of TG (Banff cg score >0) and the degree of IFTA,
2. Presence of TCMR
3. C4d positivity
4. Vascular lesions (Banff cv score >0)
5. Clinical factors including allograft dysfunction at diagnosis, proteinuria, and time of diagnosis.
6. History of medication nonadherence (is associated with inferior allograft survival among patients with dnDSA).
7. Alloantibody characteristics.
◇AVAILABLE EVIDENCE FOR THE TTT OF ACTIVE AND CHRONIC ACTIVE AMR:
▪︎Most studies describe the use of a variable mix of interventions (eg, variable intensity of plasmapheresis, different doses of IVIG, variable use of steroid pulses together with or without different T-cell–depleting and B-cell–depleting Abs).
1- Plasma Exchange and IVIG
▪︎Most commonly used to treat active AMR and regarded as standard care by FDA AMR-Workshop in 2017 as well as KDIGO in 2010.
▪︎Can improve short-term outcomes. But, their results on long-term effects remain variable, so there is a need for other
2- Complement Inhibitors
▪︎Are used avoid allograft damage
produced by DSA.
3- Rituximab: a B-cell–depleting agent
▪︎ Was suggested as a treatment option by KDIGO guidelines.
4- Imlifdase: an IgG-degrading
enzyme of Streptococcus pyogenes (IdeS), ▪︎Can rapidly reduce anti-HLA DSA
▪︎Is undergoing clinical trials in AMR.
5- Antithymocyte Globulin
▪︎Depletingantibodies
▪︎Proposed by KDIGO guidelines as a potential treatment options. But, no beneft has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
▪︎Side effects are well described with a higher risk of infectious-associated death 6- 6- Splenectomy: Used as a salvage procedure for severe early AMR.
7- Proteasome Inhibitor: Bortezomib
▪︎Data supporting its use are limited
8- Cyclophosphamide:
▪︎No trial data to support its use.
9- Interleukin-6 Inhibitors
▪︎A few numbers of study, in patients with chronic active AMR
◇CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)
▪︎The combination of PLEX, IVIG with corticosteroids could be regarded as standard of care.
▪︎The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability. ▪︎Where concomitant TCMR is present, it should be treated.
◇CONSENSUS FOR TREATMENT OF LATE
ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
▪︎Preexisting DSA and active AMR without chronic features: PLEX, IVIG, and corticosteroids.
▪︎Chronic active AMR or chronic transplant
vasculopathy: treatment must focus on optimizing IS and supportive care, with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, & optimizing medical management with focus on BP, blood glucose & lipid control.
▪︎De Novo DSA (active or chronic active):
– Optimize baseline IS and manage potential medication nonadherence.
– Treatment of concomitant TCMR is recommended in all cases.
– Similar to patients with chronic active AMR in the context of preexisting antibodies, treatment with PLEX, IVIG, and Rituximab is used in some centers.
◇CONCLUSIONS:
▪︎There is very little high level evidence to support the use of any therapy, no clear treatment regimens to recommend and no approved treatments for AMR.
▪︎The consensus opinion was based largely on observational studies, low-level evidence, and expert opinion.
▪︎New agents and clinical trials for treatment of AMR are needed urgently. ▪︎Better characterization of the different types of AMR based on pathophysiology, histology, as well as clinical and genetic phenotypes is needed.
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantation Society Working Group.
INTRODUCTION:
Delayed graft dysfunction is an obstacle for kidney recipients which has multifactorial causes but ABMR still one of the most common causes of graft failure specially with more laboratory evolution in DSA detection and BANFF criteria update.
Still no strong based evidence guidelines or recommendation for treatment.
BIOLOGY OF THE ALLOIMMUNE RESPONSE:
Initial encounter of alloantigen with B cells , activates B-cell migration to the T- and B-cell interface in the lymph node, where it receives help from allo-reactive T cells that encountered alloantigen presented indirectly on recipient dendritic cells then B cells differentiate into memory B cells or plasma cells, while the rest enter into a germinal center to emerge as high-affinity and class-switched memory B cells and plasma cell.
Pre-sensitized patients produce large amount of antibodies against HLA with strong response.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause.
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
(3) the presence of circulating DSA.
With the above three criteria if there is chronic changes e.g arterial multi-layering or arterial intimal fibrosis to be considered chronic active ABMR.
CLINICAL PHENOTYPES OF AMR:
A-Early Post-transplant (30 Days) Active AMR.
Occur in patient with performed DSA with high MFI and its clinically uncommon as those patient mostly avoided.
Need aggressive treatment as it may led to cortical necrosis.
B-Late (>30 Days) Post-transplant AMR With Preexisting DSA.
Some patients have pre-exciting DSA but not devolped early AMR and may discovered by protocol biopsy if delayed in diagnosis it may progress to chronic changes.
C-Late (>30 Days) AMR Associated With dnDSA
De novo DSA is the most common cause of AMR at time being which detected mainly after 3 months due to many causes like patient non-adherence, physician directed , under-immunosuppression is a major risk factor for dnDSA .
Some studies showed that AMR with dnDSA is associated with inferior allograft survival when compared with AMR from preexisting DSA.
CONSENSUS FOR MEASURING AND MONITORING OF DSA:
1-Initial Assessment for Anti-HLA DSA
History of allo-sensitizing events (previous transplant, blood transfusion, and pregnancy).
Donor and recipient HLA typing.
Anti-HLA antibody screening.
2-Monitoring for De Novo DSA.
Recommended in the following settings: immunosuppression reduction by physician , medication non-adherence, or at the time of rejection episode .
3-Interpreting Positive DSA Results
Positive cutoff for SAB is variant from laboratories because high coefficient of variation, also interference from external substances, bead saturation, and “shared-epitope” phenomenon can lead to a falsely low MFI so in transplant candidates/recipients who are not immunologically naive, unexpected positive cross-match, or AMR with unexpectedly low DSA MFI we should routinely do serum dilution or using ethylenediaminetetraacetic acid.
Additional DSA Testing for Risk Stratification
Hyper acute AMR is also associated with having a positive CDC crossmatch, complement binding ability of DSA are associated with AMR and allograft loss.
AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
The aim of treatment overall to remove circulating DSA and reducing DSA production.
1-Plasma Exchange and IVIG.
Both considered the mainstay of treatment for acute active AMR but the evidence consists largely of case series and poorly controlled randomized trials.
2-Complement Inhibitors.
Two multicenter randomized phase 2 trials confirmed the protective effect of eculizumab for preventing early active AMR in positive crossmatch HLA-incompatible living73 and deceased74 donor populations.
3-Rituximab.
It is suggested by KDIGO but still no clear evidence regarding optimal doses, number of treatment cycles.
4-Imlifidase/(IdeS).
Used in desensitization and all patients shifted from CM positive to negative but rebound in DSA and anti-IdeS antibodies develop after 1 or 2 doses but still not evident as a single treatment of ABMR.
5-Antithymocyte Globulin.
No benefit has been demonstrated for treatment of pure AMR with T-cell–depleting therapy.
6-Splenectomy.
7-Proteasome Inhibitor: Bortezomib.
8-Cyclophosphamide.
9-Interleukin-6 Inhibitors.
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT)(table)
Plasmapheresis (daily or alternative day × 6 based on DSA titer) (1C).
IVIG 100mg/kg after each plasmapheresis treatment or IVIG 2 g/kg at end of plasmapheresis treatments (1C)
Corticosteroids (EO).
Adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability with high risk graft failure.
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT)
Preexisting DSA
Active AMR: same as acute ABMR less than 30 days.
Chronic AMR: Optimize baseline immunosuppression (eg, add steroids if on a steroid-free regimen) (1C).
De novo DSA:
Optimize baseline immunosuppression (eg, add steroids if on a steroid-free regimen) (1C) Evaluate and manage nonadherence.
CONCLUSIONS:
AMR is considered the most common cause of graft dysfunction and still no strong based evidence for treatment and depending on expert consensus hence we need more randomized control trials looking for a powerful guidelines recommendation for improving patients and graft survival.
LEVEL OF EVIDENCE 4/5.
*** Summarise this article
AMR is major cause of kidney graft loss.
*HLA molecular typing and solid phase assays to detect DSA and a more advancing histological classification, the diagnosis of (AMR) has become more common.
* Transplantation Society developed recommendation for appropriate treatment of active and chronic active AMR.
*The aim is to help consensus in evaluation the standard care, treatment with new therapies, the underlying biology of AMR, criteria for diagnosis, clinical phenotypes and outcomes.
# DIAGNOSTIC CRITERIA AND HISTOLOGICAL FEATURES OF AMR
* Banff 2017 classification ofAMR are
(1) Histological evidence of graft injury
* microvascular inflammation (MVI)
* intimal or transmural arteritis (v > 0)
* acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
(2) Histological evidence of antibody-endothelial
interactions either by C4d deposition or at least moderate MVI
(3) The presence of circulating DSA, predominantly anti-HLA antibody.
# All 3 criteria for diagnosis of CAMR
1)Evidence of chronic tissue injury
2)Evidence of current/recent antibody interaction with vascular endothelium
3) Serologic evidence of (DSA, to HLA or other antigens).
.
# CLINICAL PHENOTYPES OF AMR
Early Posttransplant (30 Days) Posttransplant AMR With Preexisting DSA
* Itis indolent and progressive form of AMR that detected on biopsy.
* When detected early, MVI in glomeruli and peritubular capillaries is the predominant finding and C4d staining may or may not be present.
*MVI tends to persist and is later accompanied by chronic histological
features including transplant glomerulopathy and peritubular basement membrane multilayering.
* Itis minimal if any reduction in (GFR)or proteinuria even when mild chronic features are present.
# Late (>30 Days) AMR Associated With dnDSA.
* Most common form of AMR associated with dnDSA.
* DnDSA detected after >3 months posttransplant due to Inadequate immunosuppression.
*This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR.
* Subclinical, associated with inferior allograft survival or a delay in AMR diagnosis compared with preexisting DSA.
# FEATURES ASSOCIATED WITH REDUCED
ALLOGRAFT SURVIVAL IN LATE AMR
(PREEXISTING OR DNDSA)
* Chronic histological features such as the presence of transplant glomerulopathy, degree of interstitial fibrosis and tubular atrophy, concomitant TCMR, C4d positivity
Vascular lesions , proteinuria, time of diagnosis posttransplant, history of medication and nonadherence ,
the presence of C1q , positive DSA and anti class II DSA, he level or strength of DSA all are independently associated with inferior allograft out come
#CONSENSUS FOR MEASURING AND MONITORING OF DSA
* Initial Assessment for Anti-HLA DSA
*The initial assessment involve HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events.
* Molecular HLA typing ideally includes A;
B; C; DRB1; DRB3; DQA1/DQB1; and DPA1/DPB1.
* The first-line screening for alloantibody with single antigen bead (SAB) solid phase assays, but multiantigen beads can also be used.
* Patients with no history of allosensitizing, negative DSA are at low risk for AMR.
* Monitoring for De Novo DSA is recommended in the following conditions: immunosuppression reduction by physician for any reason, patient nonadherence and at the time of rejection episode.
* The SAB test detecting DSA has limitations due it’s variation between laboratories.
* Positive cutoff MFI of 1000–1500 is associated with the detection of specific anti-HLA antibodies.
* Falsely low MFIresult from external substances, bead saturation and“shared-epitope”.
# Additional DSA Testing for Risk Stratification
* Crossmatch testing can be used with SAB testing for AMR risk stratification.
* Hyperacute AMR is associated with having a positive CDC crossmatch, (C1q or C3d) positive results associated with AMR and allograft loss.
*C1q and C3d binding positivity is associated with a high DSA titer.
# AVAILABLE EVIDENCE FOR THE TREATMENT OF ACTIVE AND CHRONIC ACTIVE AMR
* Most studies recommended the use of plasmapheresis & [IVIG], variable use of steroid pulses together with or without different Tcell depleting and Bcell depleting antibodies).
# Plasma Exchange and IVIG
* It removing circulating DSA and reducing DSA production.
*(PLEX) and IVIG Most commonly used to treat active AMR recommended by the expert consensus at the FDA Antibody-Mediated Rejection Workshop in 2017, Kidney Disease, (KDIGO) in 2010 despite the weakness of evidence supporting itis efficacy.
#Complement Inhibitors
* It use to avoid the downstream damage to the allograft from DSA.
* Eculizumab results in terminal complement blockade as a monoclonal antibody targeting C5.
* Study showed that patients with positive crossmatch HLA i the incidence of early active AMR was decreased from approximately 40% to 7%.
# Rituximab
*Is B cell depleting agent, was suggested by KDIGO guidelines.
* Studies suggested the use of rituximab together with steroids, plasmapheresis,
and high dose IVIG, in vascular AMR had some positive effects.
# Imlifidase
* An IgG degrading enzyme of Streptococcus pyogenes (IdeS), rapidly
reduce or eliminate DSA and is undergoing clinical trials in AMR.
* Safely used in highly sensitized patients for desensitization and after administration historic positive crossmatches became negative, within 7–10 days
* Rebound in DSA and anti-IdeS antibodies develop after 1 or 2 doses.
# Antithymocyte Globulin
(ATG) or other Tcell depleting antibodies have been used for
treatment of refractory rejection, vascular rejection, mixed rejections, and AMR.
* No benefit has been showed for treatment of pure AMR with Tcell depleting therapy.
* Rretrospective study suggests the use of ATG in combination with steroids has no effect on the outcome of vascular AMR.
* Side effects is higher risk of infectious & death if it combined with B cell depletion.
# Splenectomy
*In several case it used as a salvage procedure for severe early AMR.
* Must be performed rapidly after the onset of early AMR to be effective.
* Patients had splenectomy are historic sensitized, or recived desensitization therapy.
#Proteasome Inhibitor: *Bortezomib directly targets plasma cells
* Limited data for Its use suggesting a positive effect within treatment regimen of PLEX, IVIG, steroids, and depleting antibodies.
# Cyclophosphamide
* Used for the treatment of antibodymediated diseases( anti neutrophil cytoplasmic antibody vasculitis or lupus nephritis), but there are no trial data to support its use.
# Interleukin-6 Inhibitors
*Tocilizumab suggested to be used in patients with chronic active AMR that
had failed IVIG plus rituximab.
# CONSENSUS FOR TREATMENT OF EARLY ACTIVE
AMR (≤30 DAYS POSTTRANSPLANT)
*The consensus was suggested that the combination of PLEX, IVIG with corticosteroids may regarded as standard of care, while in some centers corticosteroids is reserved for patients with concompetant TCMR.
* They recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy depending on availability and may be indicated only when the risk of graft loss is high.
# CONSENSUS FOR TREATMENT OF LATE
ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS
POSTTRANSPLANT)
* Preexisting DSA
* Patients with preexisting DSA and active AMR without chronic features, recommended to use PLEX, IVIG and corticosteroids.
* In chronic active AMR or chronic transplant vasculopathy, the aim of therapy to stabilize the GFR, proteinuria, histological injury score, DSA titer and to prevent drug toxicity.
* Un like acute active AMR the use of IVIG and PLEX, with or without Rituximab, has not been shown to improve outcomes in chronic active AMR.
* The consensus focus on optimizing immunosuppression
and supportive care, with reintroduction of
steroids when free regimen is used, maintaining trough tac levels >5 ng/mL, blood pressure, blood glucose, and lipid control.
# De Novo DSA
*The standard for managing AMR in case of denovo DSA in case of active or chronic active is to optimize baseline immunosuppression and manage nonadherence.
*Treatment of concomitant TCMR is recommended in all cases .
* As in chronic active AMR with preexisting antibodies, treatment Included PLEX, IVIG, and Rituximab.
*** What is the level of evidence?
Level of evidence 4/5
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
Introduction:
AMR was the most common cause allograft failure in what of renal transplant recipients with indicated biopsies before graft failure
No guideline for treatment of AMR
The transplant society brought together a group of expert from around the globe for 1-5 days meeting that outlined recommended treatment for active and chronic active AMR
BIOLOGY OF THE ALLOIMMUNE RESPONSE:
Generation of antibody secreting cells follow a series events:
1) Alloantigen with B cells expressing the appropriate B cell antigen receptor
2) This event activate B cell migration to the B and T cell interface in the lymph node
3) Where it receive help from alloreactive T cells encountered alloantigen presented indirectly on recipient dendritic cells
4) Some of B cells differentiate into:
a) Memory B cells
b) Short-lived plasmablast
c) Long-lived plasma cells
In presensitized patients have long-lived plasma cells, secreting anti-HLA antibodies and memory B cells secrete large amount of antibody upon antigen expressive leading to rapid antibody response
Receptors of plasma cells and memory B cells are not identical so this difference predict that treatment to prevent plasma cell generating and subsequent DSA production may not stop
The generation of memory B cells
Diagnostic criteria and histological features of AMR:
Features of active AMR based on the Banff 2017 classification are:
1) Evidence of grafting via microvascular inflammation acute TMA in the absence of another apparent cause ATN =of any other cause
2) Antibody-endothelial interaction either by c4d deposition or moderate MVI
3) Presence of circulating DSA
Chronic AMR (transplant glomerulopathy)(Banff chronic GN)
1) TG
2) Severe peritubular capillary basement membrane multilayering on electron microscopy
3) New arterial intimal fibrosis without another obvious cause
Clinical phenotypes of AMR:
The Banff classification has 3 AMR diagnostic categories:
1) Chronic AMR with TG and current or prior DSA without MVI or c4d AMR
2) Acute sudden allograft =early post renal transplant or subclinical or sublate
3) Anti-HLA antibody can also be pre-existing DSA or develop after transplant(dn DSA) in the setting of under immunosuppression
Early post transplant(<30 days) active AMR:
Active AMR can occur in the first 30 days post renal transplant
This form of AMR is uncommon as can be available (pretransplant)
Factors increase the risk of early post transplant AMR:
1) Presence of DSA at time of transplant
2) Crossmatching positive
3) Presence of cross-relative DSA
Speciality presenting:
1) Sudden =and oliguria with or without proteinuria
2) If untreated quickly can lead to graft loss within days
If treated properly and in time graft can received completely
Late (>30 days) post -transplant AMR with pre-existing DSA:
This type of AMR is subclinical and progressive form inspite of pre-existing DSA diagnosis on surveillance biopsy
Graft factors it can be stable or mild dysfunction
Histological finding are dependant on the timing of the biopsy
1-=MVI in the glomeruli and PTC +- c4d standering
2-if late include
i)TG
ii ) multilayering
late >30 days AMR associated with dn DSA:
de novo DSA detected after 3 months due to inadequate =
it present with allograft dysfunction with pre-existing TCMR
It has subclinical presentation
Graft survival is inferior to AMR with dn DSA compared with AMR from pre-existing DSA
Features associated with reduced allograft survival in late AMR(pre-existing or dn DSA):
Predictive of graft failure are:
1) TG
2) Intestinal fibrosis and tubular atrophy
Histological features associated with inferior allograft survival:
1) Concomitant TCMR
2) C4d positive
3) Vascular lesion
Clinical factors associated poor graft outcome:
1) Allograft dysfunction at diagnosis
2) Proteinuria
3) Time of diagnosis post renal transplant
Non adherence and under immunosuppression is major risk factor for dn DSA
Alloantibody characterized associated with graft outcome:
1. CIq positive DSA and anti class2DSA
2. DSA level
3. Flowcytometry cross-match positive
Consensus for measuring and maintain of DSA:
Initial assessment for anti-HLA DSA
The initial assessment of renal transplant candidate involve donor and recipient
1. HLA typing
2. Anti-HLA antibody screening
3. History of allo sensitizing event
Anti-HLA-sensitized recipient, high level of typing called 4 digit typing (allelic level)
First line for alloantibody is single antigen head SAB
Maintain for de novo DSA:
Development of dn DSA is result from immunosuppression reduction (Non adherence or under==
Maintaining for dn DSA in recommended in the following :
1. Immunosuppression reduction by physician for reason
2. Patients Non adherence to medication
3. At the time of rejection(T cell antibody mediated)
To early predict AMR and avoid graft loss dn DSA close monitoring and kidney biopsy can be done
Interpretating positive DSA result:
Positive SAB test detecting DSA varies among laboratory
Positive cut off MFI of 1000-1500
Showed epitope phenomena can lead to falsely low MFI
Additional DSA testing for MSK stratification:
The MSKs of AMR from highest to lowest based on crossmatch and SAB-positive testing the following:
1. Positive CDC crossmatch
2. Positive flowcytometric crossmatch and -ve crossmatch
Hyperacute AMR associated with having appositive CDC crossmatch
C1q and C3d banding positivity is associated with a high DSA titre but not applicable for clinical use
Available evidence for the treatment of active and chronic active AMR:
Plasma exchange and IVIG:
Different intervention create a challenge in the interpretation of treatment effects
Treatment studies for AMR are rarely compatible and the available evidence low quality plasma exchange and IVIG
Aim of plasma exchange to remove circulating DSA
PLEX and IVIG never have FDA approach
The effect of PLEX short term outcome but long term effects remain variable
IVIG combined with PLEX to modulate B cells response
Complement inhibitors:
Goal complement inhibitors to avoid graft injury from DSA
A single =small case series has also shows eculizumab effective in the first month post transplantation Active AMR treatment
But still long term or include a clear AMR and allograft survival remain variable
Plasma C1 esterase (-) for treatment of AMR evaluating reassement to FLEX and IVIG in renal transplant recipient is on goining
Rituximab:
B cell depleting agents suggest treatment by KDIGO guidelines
Several retrospectives analysis have suggested some positive effects of rituximab in multi-model treatment regimens together with steroids, plasmapheresis, and high dose IVIG especially patients with vascular AMR
Imlifidase:
IgG-degrading enzymes of streptococcus pyogens (Ides)
Can rapidly reduce or even eliminate anti-HLA-DSA
Under goining clinical trial in AMR
It has been used safely in highly sensitized patients for desensitization but still clinical trial ongoing in AMR
Disadvantages:
1. Rebound DSA of 7-10 days
2. Anti-Ides antibodies left 1 or 2 days
Advantages:
Highly sensitized patients undergo transplantation within hours of donor regardless of crossmatch status
Antithymocyte Globulin:
T cell depleting antibodies
Indications:
1. Refractory rejection
2. Vascular rejection
3. Mixed rejection and AMR
No benefit for treatment of pure AMR have been demonstrated
Splenectomy:
Splenectomy used as salvage procedure for some early AMR
It must be performed rapidly after the onset of early AMR to be effective
Proteasome Inhibitor: Bortezomib:
Bortezomib is a protease inhibitor approval for the treatment targeting antibodies
Producing plasma cells
No trial data to support it use
Cyclophosphamide:
No trial data to support it use
nterleukin-6 Inhibitors:
large multicentre randomized control trial for tocilizumab has been started to evaluate it
clazakizumab:
Is an anti-interleukin-6 monoclonal antibody for the treatment of chronic active AMR
CONSENSUS FOR TREATMENT OF EARLY ACTIVE AMR (≤30 DAYS POSTTRANSPLANT):
Limited data and quality for treatment option of active AMR
Standard of care for treatment of AMR are combination of PLEX ,IVIG with corticosteroid
Because of limitation of trials of different combination therapies for AMR
No available drug evidence to support its use as adjunct
Adjunctive agents in treatment of AMR:
The recommended adjunctive therapy include complement inhibitors , rituximab or splenectomy depend on availability
Concomitant TCMR should be treated
CONSENSUS FOR TREATMENT OF LATE ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS POSTTRANSPLANT):
preexisting DSA:
Active AMR without chronic features and no preexisting DSA the treatment recommendation include : PLEX,IVIG and corticosteroids
Chronic active AMR or chronic transplant vasculopathy stabilized the eGFR ,proteinuria by:
1. Optimizing immunosuppression
2. Reduction of steroids (if steroids-free regimens)
3. TAC trash level>5 ng/ml
4. Optimize the Bp, blood glucose and lipid control
De Novo DSA:
dnDSA occurs of reduction of immunosuppression
AMR usually associated with TCMR
Treatment of concomitant TCMR is recommended in all cases of AMR
Conclusion:
AMR usually has poor outcome low high level of evidence to support the use of any therapy
There were no clear treatment regimens to recommend and there is no approved treatment
Level4/5
Thank You, you need to shorten your summary Dr Manal
II. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group
Summarise this article
Introduction
This expert group produced these consensus recommendations to overcome the lack of evidence-based guidelines for the treatment of active & chronic active AMR.
Diagnostic features of AMR
Banff 2017 features of active AMR:
(1) histological evidence of graft injury:
– MVI,
– intimal or transmural arteritis (v > 0),
– acute TMA in the absence of any other cause, or – acute tubular injury in the absence of any other
apparent cause
(2) histological evidence of antibody-endothelial
interactions either by C4d deposition or at least
moderate MVI; and
(3) the presence of circulating DSA, predominantly
anti-HLA antibody.
To diagnose CA-AMR, morphological features of chronic tissue injury are present in addition to criteria 2 & 3 for active AMR.
Signs of chronic tissue injury include:
– TG (Banff cg score > 0),
– Severe PTC BM multi-layering on EM, or
– New arterial intimal fibrosis with no other cause.
AMR is frequently a chronic progressive process that starts with the formation of DSA.
DSA may or may not lead to active AMR, & not all active AMR will progress to CAMR.
Over time, chronic histological features such as TG become evident, & eventually, the patient develops allograft dysfunction, proteinuria, & may be graft loss.
Early posttransplant (<30 Days) active AMR
DSA present at the time of transplant or there is an immunologic amnestic response due to previous exposure to allo-HLA.
The risk increases with growing DSA strength (mean MFI), the degree of FCM-XM positivity, & the number or breadth of cross-reactive DSA specificities.
This form of AMR is uncommon, as transplant is usually avoided if preformed DSA is found.
Late (>30 Days) posttransplant AMR with preexisting DSA
A more indolent & progressive form of AMR
Detected on a protocol biopsy or on biopsy for mild graft dysfunction.
MVI in glomeruli & PTCs is the predominant finding
C4d staining may or may not be present.
MVI persists & later chronic histological features , including TG & PTC BM multi-layering occurs.
Late (>30 Days) AMR associated with dnDSA
It the most common form of AMR.
dnDSA usually appear after >3 months post-transplant in the context of inadequate IS(non-adherence, iatrogenic, or genetically determined variability in metabolism of IS drugs).
Presents with allograft dysfunction & concomitant or preexisting TCMR.
Inferior allograft survival when compared with AMR from preexisting DSA.
There is tendency to increased proteinuria, increased expression of interferon-γ–inducible, NK cell, & T-cell transcripts at presentation compared with patients with preexisting DSA.
Features associated with reduced allograft survival in late AMR (preexisting or dnDSA)
– Presence of TG & the degree of IF/TA
– Concomitant TCMR
– C4d positivity
– Vascular lesions (Banff cv score >0)
– Proteinuria
– Time of diagnosis post-transplant.
– Non-adherence
– The presence of C1q positive DSA
– Anti-class II DSA
– The level or strength of DSA
Initial Assessment for Anti-HLA DSA
HLA typing
Anti-HLA antibody screening
H/O previous transplant, blood transfusion, & pregnancy.
Molecular HLA typing ideally includes A; B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; & DPA1/DPB1
SAB is the 1st-line screening method for alloantibodies
Multiantigen beads can also be used.
Monitoring for dnDSAis recommended in the following:
IS reduction by physician for any reason.
Known patient non-adherence.
At the time of any rejection episode.
Interpreting positive DSA results
A positive cutoff MFI of 1000–1500 is associated with the
detection of specific anti-HLA antibodies.
Falsely low MFI SAB can result from interference from external substances, bead saturation, & “shared-epitope” phenomenon.
==========================================
Available evidence for the treatment of active & chronic active AMR:
Plasma Exchange & IVIG
Remove circulating DSA & reduce DSA production.
Are the most commonly used treatments(not FDA approved).
Expert consensus at the FDA AMR Workshop in 2017 as well as KDIGO in 2010 state that PLEX & IVIG could be regarded as a standard of care for acute active AMR, despite the weakness of evidence in support of efficacy, especially on long-term outcomes.
Complement Inhibitors
Eculizumab is a monoclonal antibody that targets C5 & blocks the terminal complement system.
Decreased early active AMR in positive XM HLA-i transplants (single center study).
Two multicenter randomized phase 2 trials confirmed
its protective effect for preventing early active AMR in positive XM HLA-i living & deceased donor transplants.
Long-term effect was comparable to controls(single-center study).
C1 esterase inhibitors indicate a possible improvement in graft function in AMR (2 pilot studies).
An ongoing trial (NCT03221842) is evaluating a C1 esterase inhibitor for the treatment of AMR that is resistant to PLEX & IVIG.
Rituximab (B-cell–depleting agent)
Suggested as a treatment option by KDIGO guidelines.
No clear benefit was seen in 3 small randomized trials.
A reasonable safety profile.
Other studies showed no difference between rituximab & control groups or standard of care populations.
Several retrospective studies suggested some positive effects of rituximab in multimodal treatment regimens together with steroids, PP, & high-dose IVIG, especially on patients with vascular AMR.
Imlifidase (an IgG-degrading, IdeS):
Reduces or even eliminate anti-HLA DSA
Is undergoing clinical trials in AMR.
IdeS cleaves human IgG at a highly specific amino acid sequence & effectively blocking CDC & antibody dependent cellular cytotoxicity.
Was safely for desensitization in highly sensitized patients.
Rebound DSA & anti-Ides antibodies develop within 7-10 days, thus preventing repeated administrations.
Unlikely to be used alone as treatment for active or chronic active AMR.
It can allow highly sensitized patient to transplanted within hours of a donor being identified irrespective of the XM status.
Antithymocyte Globulin
Proposed by KDIGO as potential treatment option.
No benefit has been shown for treatment of pure AMR.
No prospective trial for use in AMR.
A large retrospective trial showed no effect on outcome in vascular AMR when used combined with steroids.
Higher risk of infectious-associated death.
Splenectomy
Used as a salvage procedure for severe early AMR (several case series)
It must be performed rapidly after the onset of early AMR to be effective.
Proteasome Inhibitor: Bortezomib
Limited data (case series) suggest a positive effect within a multimodal treatment regimen of PLEX, IVIG, steroids, & depleting antibodies.
A single prospective randomized trial in “late” AMR did not show any beneficial effect.
Interleukin-6 Inhibitors
Tocilizumab was superior to historical controls in the treatment of CA-AMR that had failed IVIG plus rituximab (a single-center, nonrandomized trial).
Consensus for treatment
1. Early active AMR (≤30 days posttransplant)
Combination of PP, IVIG & steroids could be regarded as standard of care (consistent with the conclusions of the FDA workshop & KDIGO guidelines).
Some centers use steroids only when there is concomitant TCMR.
In the absence of trial data, adjunctive therapy may be used only when the risk of graft loss is considered high.
The recommended adjunctive therapies include complement inhibitors, rituximab, or splenectomy.
1. Late active & CA-AMR (≥30 days posttransplant)
Preexisting DSA
The consensus treatment recommendations include PP, IVIG, & steroids.
The aim is to stabilize or reduce the rate of decline in GFR, proteinuria, histological injury score, & titer of DSA while minimizing drug toxicity.
The consensus also focuses on optimizing IS & supportive care, reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL, & optimizing control of BP, blood glucose, & lipid.
De Novo DSA
The standard in this setting (active or chronic active) is to optimize baseline IS & manage potential non-adherence.
Treatment of concomitant TCMR is recommended in all cases of AMR but is particularly relevant in these cases. Similar to patients with CA-AMR in the context of pre-existing antibodies, treatment with PP, IVIG, & Rituximab is used in some centers, though the evidence level is low.
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What is the level of evidence?
Level IV, expert opinion
Thank You, try to make it shorter Dr Mohamed
Despite advances in transplant immunology, implementation of high resolution single antigen bead in antibody screening, and standardization of immunosuppression, AMR remains the most common cause of allograft failure.
The current recommendation on immunosuppression lack prospective studies and strong evidence, and most of the recommendation and suggestion are based on low evidence and retrospective studies.
AMR diagnosis according to Banff 2017 classification:
Active AMR features:
1-Histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis , acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
2- Histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI
3- The presence of circulating DSA, predominantly anti-HLA antibody
AMR clinical phenotypes
Early Posttransplant (<30 days ) Active AMR
Early AMR occurs in patients who are presensitized. The risk increases with increasing DSA level at the time of transplant (high MFI), the degree of flowcytometry crossmatch positivity, and other factors.
This type of AMR became uncommon because of advances in detection of preformed DSA, desensitization protocols and prescription of aggressive induction and maintenance therapies.
Late (>30 Days) Posttransplant AMR With Preexisting DSA
It is an indolent form and commonly subclinical detected in a protocol biopsy. When detected early, MVI in glomeruli and peritubular capillaries is predominant and C4d staining may or may not be present. MVI tends to persist and is associated with chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering. There is minimal if any reduction in GFR or proteinuria even when mild chronic features are present
Late (>30 Days) AMR Associated With dnDSA
This is the most common form of AMR which leads to chronic allograft failure.new Detection of de nove DSA >3 months posttransplant due to inadequate immunosuppression ether due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs.
The presentation is subclinical and slowly progressive. AMR with de novo DSA is associated with inferior allograft survival compared with AMR from preexisting DSA.
Consensus for DSA monitoring
Initial Assessment for Anti-HLA DSA
HLA typing an antibodies screening
For anti-HLA–sensitized recipients, a high-resolution level of typing.
Patients with no history of sensitization and negative antibody testing using solid-phase assays are at low risk for AMR.
Monitoring of De Novo DSA is preferable in cases, requiring immunosuppression reduction for specific reasons, nonadherence, or at the time of rejection episode.
Positive DSA Results assessment
SAB test has limitations, because it is liable to interference from external effectors
Positive cut off MFI of 1000–1500 is associated with anti-HLA antibodies presence.
DSA Testing for Risk Stratification
Hyperacute AMR is associated with positive CDC crossmatch.
C1q and C3d binding positivity is associated with a high DSA titer
Evidence for treatment of active and chronic active AMR
Multiple studies addressed different mix of therapies as plasmapheresis, intravenous immune globulins , steroid pulses with or without different T-cell–depleting and B-cell–depleting antibodies.
Plasma Exchange and IVIG
First line treatment in active AMR.
PLEX and IVIG could be a standard treatment for acute active AMR according to the FDA Antibody-Mediated Rejection Workshop in 2017 and KDIGO.
Complement Inhibitors
Ecluzimab a monoclonal antibody targeting C5
Multiple trials revealed the preventive role of eculizumab for early active AMR in positive crossmatch HLA-incompatible living and deceased donor recipients.
C1 esterase inhibitors Berinert and Cinryze showed a possible improvement in allograft function in kidney recipients with AMR.
Rituximab
anti CD20 is used in combination with other therapies, as complementary effect. Some studies did not demonstrate any positive effect in combination with other modalities while other studies revealed some positive effect when used with IVGV high dose, plasma exchange and steroids particularly with vascular AMR.
Imlifidase
IgG-degrading enzyme of Streptococcus pyogenes (IdeS is used for desensitization in highly sensitized cases and also used in the treatment of resistant AMR.
ATG
Used in induction therapy for high risk patients, and also for the treatment of refractory rejection, vascular rejection, mixed rejections and AMR. If combined with B cell depleting agent it has high life threatening infection risk .
Splenectomy
it is no more used, and replaced by B cell depleting agent, Rituximab.
Proteasome Inhibitor: Bortezomib
bortezomib is effective as inhibitor of plasma cells, but does not have effect on produced antibodies. It is a candidate for the treatment of active AMR in a multimodal treating regimen.
IL6 inhibitors
Toclizumab revealed acceptable results in treating chronic active AMR after failure of IVIG and rituximab.Clazakizumab is studied for treating chronic active AMR
Treatment of early active AMR Consensus (≤30 days transplanation)
Standard treatment of care includes the combination of PLEX, IVIG with corticosteroids in agreement with KDIGO guidelines.
The adjunctive therapies include complement inhibitors, rituximab, or splenectomy can be needed especially when the risk of graft loss is high and concomitant TCMR is present.
Treatment of late active and chronic AMR consensus (≥30 days posttrasnplant)
For patients with chronic active AMR maintenance immunosuppression should be optimized with reintroduction of steroids (if on a steroid-free regimen), targeting higher trough tacrolimus levels >5 ng/mL.
Thank You
INTRODUCTION
Despite current immunosuppression, alloantibody-induced kidney damage and transplant loss persist.
HLA antigens drive this response. The impact of HLA antibodies on kidney allograft survival has been known for some time, but the size of the problem has only recently been realized with the advent of sensitive solid-phase assays to detect donor-specific anti HLA antibodies (DSA) and the Banff diagnostic criteria for antibody-mediated rejection (AMR). Following 10 years, 25% had de novo DSA after a kidney transplant (dn DSA).
AMR was the leading cause of transplant failure in a Review Abstract group. With new solid-phase techniques to identify anti-HLA antibodies and a more exact histology categorization, antibody-mediated rejection (AMR) is a prominent cause of kidney transplant failure. No medicines are licensed, and treatment recommendations are based on low-quality research.
clinical manifestations of AMR
There are three different AMR diagnostic categories in the Banff classification, one of which is chronic AMR with transplant glomerulopathy and another is present or previous DSA without MVI or C4d.
AMR may manifest itself via acute allograft malfunction early on in the recovery process after a transplant, or it can have a subclinical beginning and manifest itself later on in the recovery process. Anti-HLA antibodies may be a preexisting DSA or develop after transplant (dn DSA) in the context of inadequate immunosuppression. Both of these scenarios are possible.
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Early posttransplantation (less than 30 days after) AMR in use
Increased DSA levels at the time of transplant, as measured by DSA mean fluorescence intensity (MFI), the degree of flow cytometric crossmatch positive, and the number or breadth of cross-reactive DSA specificities are all factors that contribute to an increased risk of this condition.
This condition is very rare and is characterized by a sudden rise in DSA levels that is followed by allograft malfunction.
AMR after more than 30 days after the transplant with preexisting DSA
It was discovered via a surveillance biopsy that this forum is rather harmless.
When the disease is identified in its early stages, MVI predominates in the glomeruli and peritubular capillaries, and C4d staining may or may not be present. MVI has a tendency to persist and is linked with chronic histological characteristics such as peritubular basement membrane multilayering and transplant glomerulopathy.
Even in cases where only minor chronic characteristics are present, there is only a little, if any, drop in GFR or proteinuria.
AMR Associated With dn DSA That Is Late (Greater Than 30 Days)
Which of the following is the most prevalent type of antimicrobial resistance: new DSA detected after more than three months post-transplant as a result of inadequate immunosuppression brought on by either patient nonadherence, physician direction, or genetically determined variability in the metabolism of immunosuppressive drugs?
It manifests itself with allograft malfunction in addition to concurrent or previous TCMR.
Subclinical manifestations are seen, which are comparable to those of late posttransplant AMR in individuals with preexisting DSA.
When compared to AMR caused by preexisting DSA, AMR caused by dn DSA is linked with a worse rate of transplant survival.
The following characteristics, present in late-stage AMR (pre-existing or dn DSA), are associated with a worse allograft survival rate:
Chronic histological aspects such as transplant glomerulopathy, the degree of interstitial fibrosis, tubular atrophy, TCMR positive, and vascular lesions. Other chronic histological findings include C4d positivity.
-Patients who have no history of sensitization and who have anti-HLA antibody testing results that are negative utilizing single-antigen or multiantigen bead solid-phase tests are at minimal risk for AMR.
Monitoring of the newly developed DSA
Particularly during periods of immunosuppression decrease, known instances of patient medication nonadherence, or during episodes of rejection.
There is evidence for the treatment of active and chronic active AMR.
Multiple trials looked at various combinations of treatments, such as plasmapheresis, intravenous immune globulins (IVIG), and steroid pulses, with or without certain antibodies that deplete T cells and B cells.
Plasma Swap and Intravenous Immunoglobulin are routinely used in the treatment of active AMR.
-Both the FDA Antibody-Mediated Rejection Workshop in 2017 and the KDIGO in 2010 noted that PLEX and IVIG might become a routine therapy for acute active AMR; nevertheless, the effects that these treatments have over the long term are varied.
-Ecluzimab is a monoclonal antibody that targets the protein C5.
-Multiple clinical tests demonstrated that administering eculizumab before the onset of early active AMR in positive crossmatch HLA-incompatible live and dead donor recipients were effective.
-Imlifidase
an IgG-degrading enzyme found in Streptococcus pyogenes called IdeS, which may reduce anti-HLA DSA levels and is now being studied as a potential therapy for AMR but has been shown to cause a rebound rise in DSA levels.
In the most severe instances of hypersensitivities, it is used as a desensitizer.
The use of this medicine in highly sensitized patients enables transplantation to take place within hours of a donor being available, regardless of the crossmatch status. This is one of the drug’s many benefits.
-ATG
used as a therapy for AMR, refractory rejection, vascular rejection, and mixed rejections.
-Splenectomy
In order for it to be successful, it must be carried out promptly following the first signs of early AMR.
-Inhibitor of Proteasome Activity: Bortezomib
Is a candidate for the treatment of active AMR in a therapeutic regimen that utilizes several methods.
-IL6 inhibitors
In the treatment of chronic active AMR, tocilizumab showed outcomes that were tolerable after IVIG and rituximab were unsuccessful.
-Rituximab
Some studies did not find any evidence of a good benefit when IVGV was combined with other treatment modalities, whereas other studies did find some evidence of a favourable effect when IVGV was combined with high-dose IVGV, plasma exchange, and steroids, especially in the case of vascular AMR.
-The treatment of early active AMR Consensus (less than thirty days after transplantation)
In a manner analogous to the findings of the FDA workshop and the KDIGO recommendations, the combination of PLEX, IVIG, and corticosteroids may one day become the standard therapy of care.
-Treatment of late-stage active and chronic AMR consensus (less than 30 days post-transplant).
Treatment options include PLEX, IVIG, and corticosteroids for individuals who have preexisting DSA as well as current AMR that does not have chronic characteristics.
In situations with chronic active AMR, optimal immunosuppression requires the return of steroids (if the patient was previously following a steroid-free regimen), while also maintaining trough tacrolimus levels of more than 5 ng/mL.
Optimizing immunosuppression and treating probable drug nonadherence and concomitant TCMR is also important in situations with de novo DSA.
Thank You
Diagnosis of ABMR according to Banff 2017
Three components are required for the diagnosis of acute ABMR:
1-Histologic evidence of acute tissue injury (capillaritis and/or glomerulitis) or unexplained TMA or ATN
2-Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs]) or at least moderate MVI
3-Serologic evidence of circulating DSAs
Three components are required for the diagnosis of chronic active ABMR :
1-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
2-Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs] or At least moderate microvascular inflammation (g + ptc >2)
3-Serologic evidence of circulating DSAs
CLINICAL PHENOTYPES OF AMR:
Early Posttransplant (<30 Days) Active AMR
Preexisting DSA (or nonimmunologically naive), Usually C4d+,Thrombotic microangiopathy often present
Abrupt allograft dysfunction correlating with increased DSA MFI or titer usually 7–10 days post transplant
Late (>30 Days) Posttransplant AMR With Preexisting DSA
Preexisting DSA, May be C4d± Allograft dysfunction and proteinuria,
Late (>30 Days) AMR Associated With dnDSA
De novo DSA, May be C4d± Concomitant TCMR often present
Consensus for measuring and Monitoring of DSA ;
DSA should be monitored once in early post-transplant period (first 3 month) in all patients. Includes donor and recipient HLA typing, anti HLA antibody screening with SAB. For sensitized patients, high resolution typing.
Monitoring for dnDSA: whenever there is reduction of immunosuppression, suspected non adherence or at time of rejection episode.Interpretation of positive DSA results: SAB test has several limitations as positive cutoff values varies between labs, may lead to falsely low MFI due to “shared epitope phenomenon” and bead saturation. Hyperacute AMR is associated with positive CDC crossmatch.C1q and C3d binding positivity is associated with a high DSA titer .Routine use of complement binding assays is not recommended. DSA IgG subclass is not clinically validated.
Initial assessment for anti-HLA DSA ; This should include HLA typing, anti-HLA antibody screening, history of allo-sensitization (IA).
Treatment of active & chronic active rejection:
PLEX & IVIG
Complement inhibitors
rituximab
Imlifidase
ATG
Splenectomy
Proteosome inhibitors( bortezumib)
Cyclophosphamide
IL-6 inhibitors
1) For Early active AMR: Standard of care includes plasmapheresis with IVIG and corticosteroids Other adjunct therapies include Complement inhibitors, Rituximab and Splenectomy.
2) For Late active AMR with pre-existing DSA: Standard of care includes plasmapheresis with IVIG and corticosteroids while Rituximab can be used as adjunct therapy.
3) For Late active AMR with de novo DSA: Standard of care includes optimization of immunosuppression and strict compliance in case of non-adherence, if any. Plasmapheresis, IVIG and Rituximab are useful as adjunct therapies.
4) For Late chronic AMR with pre-existing or de novo DSA: Standard of care includes optimization of immunosuppression while IVIG can be used as adjunct therapy
Level of evidence 4/5
Thank You
Despite advances in renal transplant management , antibody mediated injury to graft is a significant factor of graft loss. With the development of SAB and Banff system, the magnitude of problem has been realized. There no well agreed guideline of management to antibody mediated rejection. This publication is the outcome of transplant society meeting inviting people from around the globe.
Diagnostic criteria and Histological feature of Acute AMR
As per Banff 2017
1- Histological evidence of injury via microvascular injury- MV1, intimal or transmural arteritis,, acute TMA, in the absence of any other cause.
2- Antibody endothelial interaction -C4d deposition or at least MV1
3- Presence of circulating DSA
Diagnosis of Chronic AMR
1- TG or multilayering of PTC basement membrane, or Chronic arteriopathy, no acute inflammation.
2- C4d staining in PTC or M
3- Presence of DSA
Phenotypes of AMR
Early post transplant active AMR – < 30 days
Presents as early graft dysfunction. Usually DSA present before transplant. Occurs < 30 days, Related with mean channel shift and MFI. C4d positive.
Late AMR with pre existing DSA- >30 days
It is progressive and can diagnosed clinically of by protocol biopsy. C4d may be positive. It has poor outcome
Late AMR with denovo DSA- >30 days
It is most common and can be due to non adherence or improper immune suppression . C4d may be positive. Diagnosis can be clinical or by protocol biopsy.
Consensus for monitoring of DSA
It should include –
HLA typing -A,B,C,DR, DQ, DP (2B)
Anti HLA antibody check by SAB ( it cab be affected by shared epitope, bead saturation or external factors)
Check for denovo DSA in suspected rejection or less immune response.
Further testing for Risk stratification will depend on cross match result IgG subclasses and Compliment binding DSA
Consensus for treatment of early active AMR (≤30 days post transplant)
Consensus was combination of PLEX, IVIG and steroid in line with KIDGO guidelines. Use adjuvant therapy if risk of graft loss is high(complement inhibitors, Rituximab, or Splenectomy). Concomitant TCMR should be treated
Consensus for treatment of late active and chronic active AMR (≥30 days post transplant)
Pre Existing DSA
Control medical conditions and Optimize immunosuppression
Keep tacrolimus trough levels more than 5 ng/ml
Denovo DSA
Optimize immunosuppression
Control medical conditions and treat concomitant TCMR
Conclusion.
AMR is a significant challenge in renal transplantation , there is lack of high level of evidence to support therapies available. This Conesus statement is based on observational studies, low level evidence, but still it was necessary to establish a benchmark for future research. New agents and clinical trials are required
Level of Evidence -4/5
The Transplantation Society Working Group recommended expert consensus treatment for active and chronic active antibody-mediated rejection (AMR) in kidney transplant recipients after evaluating the underlying biology of AMR, diagnostic criteria, clinical phenotypes and their outcomes as well as the evidence of different treatments.
By 10 years post-transplant, 25% of patients develop de novo DSA. AMR is one of the most common etiology of graft failure.
Biology of AMR:
The alloantigen presents to B cell antigen receptor on B cell which migrates to T/B cell interface in lymph node giving rise to memory B cells and short-lived plasma cells. The B cell enters germinal centre of lymph node producing high affinity and class switched memory B cells, plasmablasts and long-lived plasma cells giving rise to antibodies. In an immunologically naïve individual, this is how antibody secreting formed. In a pre-sensitized individual, the presence of preformed long-lived plasma cells (secreting anti-HLA antibodies) and resting memory B cells (which can secrete large number of antibodies on exposure to antigen) can lead to rapid anamnestic antibody response.
Diagnostic criteria of AMR:
The diagnostic criteria for AMR (active, chronic active and chronic AMR) are as per the Banff 2017 classification.
Clinical phenotypes of AMR:
The clinical phenotypes of AMR include either an early post-transplant AMR having an abrupt, rapid graft dysfunction or a late post-transplant AMR with slow, subclinical onset having.
a) Early onset (<30 days) active AMR: It is due to pre-existing DSA (response to memory B cells) and is seen in up to 40% of patients with preformed DSA and a positive flowcytometry crossmatch. Biopsy usually reveals C4d positivity and interstitial hemorrhage, glomerular fibrin thrombi and microvascular coagulative necrosis. Prompt treatment can reverse these changes, but if urgent action not taken, it can lead to cortical necrosis and graft loss within days.
b) Late (>30 days) posttransplant AMR with pre-existing DSA: It is in response to pre-existing plasma cells, presenting with progressive and indolent graft dysfunction having microvascular inflammation with or without C4d positivity leading to chronic changes later on and graft loss within months to years.
c) Late (>30 days) posttransplant AMR with de novo DSA: It is the most common form of AMR, usually caused by underimmunosuppression, leading to graft loss within months to years.
AMR with de novo DSA has poorer outcomes as compared to pre-existing DSA. Features associated with decreased graft survival include positive pretransplant crossmatch (T cell CDC positive or high flowcytometry crossmatch); biopsy features of Banff cg>0, higher degree of IFTA, concomitant T cell mediated rejection, Banff cv score >0 and C4d positivity; proteinuria, underimmunosuppression, high DSA MFI, anti-class II DSA and C1q positive DSA.
Measuring and monitoring DSA:
Initial evaluation should include history of prior sensitization, donor and recipient HLA typing (including A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1/DQB1 and DPA1/DPB1) and anti-HLA screening using single antigen bead (SAB) solid phase assay. Patients with DSA are at some risk for AMR; hence crossmatch testing can be used for risk stratification with a positive CDC crossmatch having higher risk than a positive flow cytometry crossmatch. Monitoring for de novo DSA is recommended in setting of rejection, non-adherence or immunosuppression reduction.
Evidence for treatment of active and chronic active AMR:
a) Plasma exchange and IVIG: Anti-HLA antibody removal has been shown to be associated with better graft outcomes and IVIG has pleiotropic effects, although the evidence is largely involving case series and poorly controlled randomized trials
b) Complement inhibitors: Eculizumab use has been shown to decrease early active AMR incidence, but no change in long-term incidence of chronic AMR or graft survival.
c) Rituximab: Randomized trials have not shown benefit although retrospective studies have shown a positive effect especially in patients with vascular AMR.
d) Imlifidase/ Ides: Can be an adjunct to other therapies to decrease DSA in long term.
e) ATG: No benefit in pure AMR.
f) Splenectomy: Used as a salvage procedure, but must be done early to be effective.
g) Proteasome inhibitor: Bortezomib use has not been supported by trail results.
h) Cyclophosphamide: No trial data to support its use.
i) Interleukin-6 inhibitors: Tocilizumab in AMR refractory to IVIG and rituximab has been shown to have marked decrease in DSA and stabilization of graft function.
Consensus treatment: There is very little high level evidence to support any treatment modality.
1) For Early active AMR: Standard of care includes plasmapheresis with IVIG with corticosteroids and adjunct therapies include Complement inhibitors, Rituximab and Splenectomy
2) For Late active AMR with pre-existing DSA: Standard of care includes plasmapheresis with IVIG and corticosteroids while Rituximab can be used as adjunct therapy.
3) For Late active AMR with de novo DSA: Standard of care includes optimization of immunosuppression and managing nonadherence, if any. Plasmapheresis, IVIG and Rituximab are useful as adjunct therapies.
4) For Late chronic AMR with pre-existing or de novo DSA: Standard of care includes optimization of immunosuppression while IVIG can be used as adjunct therapy.
The level of evidence is Level 5: Expert opinion
Thank You
AMR is a major cause of graft dysfunction with no evidence based guidelines for prevention and treatment, so a consensus was developed to recommend treatment for active and chronic active AMR.
Diagnostic criteria of AMR:
According to Banff 2017 classification (all 3 criteria must be present)
Active AMR: 1-Histological evidence of acute tissue injury, 2-evidence of current/recent antibody interaction with vascular endothelium and 3-serological evidence of DSA which can be substituted by C4d staining or expression of validated transcripts.
Chronic active AMR: Histological evidence of chronic tissue injury with criteria 2 and 3 of active AMR
Clinical phenotypes of AMR:
Early active AMR:
<30 days post transplant, present with acute dysfunction and rising MFI of DSA within 7-10 days post transplant, usually C4d positive.
mediated by memory B cell response
With prompt diagnosis and treatment, kidney functions may be restored and the histological features resolve.
Cortical necrosis and graft loss may occur within days if not well treated.
Late AMR with preexisting DSA:
After 30 days post transplant, present with indolent progressive course with mild decline in GFR and proteinuria.
Histological findings show MVI in glomeruli and PTC, C4d may be positive.
Leads to graft loss over years.
Late AMR associated with dnDSA:
The most common form, dnDSA are DSA detected after 3 months post transplant mostly due to inadequate immunosuppression and present with graft dysfunction and proteinuria
Associated with concomitant or pre-existing TCMR
Leads to poorer graft survival than late AMR with preexisting DSA.
Features associated with decreased allograft survival in late AMR:
Allograft histology determine the chronicity and extent of injury
TG, degree of IF/TA, concomitant TCMR, C4d positivity and vascular lesions
Graft dysfunction at diagnosis, proteinuria and timing of diagnosis
Underimmunosuppression and nonadherence.
Consensus for measuring and monitoring of DSA:
Initial assessment for anti-HLA DSA:
Includes donor and recipient HLA typing, anti HLA antibody screening with SAB
For sensitized patients, high resolution typing.
Monitoring for dnDSA:
Recommended when there is decrease in immunosuppression, suspected non adherence or at time of rejection episode.
Interpretation of positive DSA results:
SAB test has several limitations as positive cutoff values varies between labs, may lead to falsely low MFI due to “shared epitope phenomenon” and bead saturation.
Additional DSA testing for risk stratification:
Crossmatching and SAB tests are used with highest risk with positive CDC crossmatch, moderate risk in positive FCXM and the lowest risk in negative crossmatch.
Routine use of complement binding assays is not recommended.
DSA IgG subclass is not clinically validated.
Available evidence for the treatment of active and chronic active AMR:
Available evidence is of low quality.
Plasma exchange (PLEX) and IVIG:
Considered as a standard of care for acute active AMR, however, not FDA approved.
They remove circulating DSA with immunomodulation.
The amount of PLEX and doses of IVIG are not well defined.
Complement inhibitors, Eculizumab, cause terminal complement blockade with promising results but with no studies on long-term graft and patient survival.
Rituximab, B cell depleting agent, evidence for its use is low, the optimal dose and effect on patient is still unclear.
Imflidase, an IgG degrading enzyme, still under clinical trial with no available data about its use in AMR.
Anti-thymocyte globulin (ATG) used for treatment of refractory rejection, vascular rejection, mixed rejections and AMR. However, its use in treatment of pure AMR showed no benefit.
Splenectomy was used as salvage procedure for severe early AMR.
Poteasome inhibitor, Bortezomib, target antibody producing plasma cells, no available trial data to support its use in AMR.
Cyclophosphamide, used for treatment of antibody mediated disease but no trial data to support its use
IL-6 inhibitors, Tocilizumab, still under trial for use in treatment of chronic active AMR.
Consensus for treatment of early active AMR:
The consensus considered PLEX, IVIG and steroids as standard of care.
Adjunctive therapy (including complement inhibitors, rituximab or splenectomy) is recommended when there is high risk of graft loss
Concomitant TCMR should be treated.
Consensus for treatment of late active and chronic active AMR:
Preexisting DSA:
No chronic features: PLEX, IVIG and steroids are recommended.
Chronic active AMR: optimizing immunosuppression, supporting care, reintroduction of steroids, maintaining Tac level>5ng/mL and optimizing medical management as control of BP and lipid profile aiming to decrease proteinuria and the decline in GFR with decreasing drug toxicity
De novo DSA:
Optimization of baseline immunosuppression and management of potential non-adherence
Treatment of concomitant TCMR
Evidence of using PLEX, IVIG or rituximab is low.
Level of evidence 4/5
Thank You
Expert opinion, level 4
Summary:
AMR is a leading cause of graft loss ( acute & chronic). No accepted guidelines for treatment of AMR & there are no FDA approved therapy for prevention & treatment.
The Transplantation Society produce recommendation for treatment of active & chronic active AMR ( based on beast available evidence).
In immune naive individual, activation of antibody-secreted cells follow series of check point events:
In presensitized patients, they have long lived plasma cells that secret anti-HLA Abs & resting memory B cells which can release large amount of Abs where re-exposed to Ags.
Memory B cells have less mutation & lower affinity than plasma cells, plasma cells & Abs they produce are more restricted ( up to 100 fold) than memory B cells. These differences predict that treatment to prevent plasma cells activation & subsequent Abs production not affect memory B cells activation.
Histological diagnosis of acute rejection according Banff classification:
Diagnosis of chronic active AMR had same criteria 1 & 2 of acute AMR in addition to TG, capillary basement membrane multilayering or new intimal fibrosis.
Clinical phenotypes of AMR:
Inferior graft outcome associated with:
Measuring & monitoring of DSA:
Treatment of active & chronic active rejection:
Treatment of early active AMR (<30 days) by PLEX, IVIG with corticosteroids regarded standard
Treatment of late active & chronic active (>30 days):
Thank You Ban
This is guidelines, level of evidence 4/5
Diagnosis of ABMR according to Banff 2017
3 components are required for the diagnosis of acute ABMR:
3 components are required for the diagnosis of chronic active ABMR :
If the patient has the first criteria and only one of the other 2 criteria, the patient is considered to have ABMR
Phenotypes
ABMR is classified according to timing and type of DSA into 3 categories
Category 1 : Early ABMR (<30 days)
· Uncommon
· Occur due to the presence of preexisting DSA and is closely related to related to the DSA MFI and MCS (the degree of positivity of FCM)
· Presented by acute graft dysfunction which is associated with rapid increase in DSA
· Usually C4d positive
Category 2 : Late ABMR (>30 Days) associated with preexisting DSA
Category 3 : Late ABMR (>30 Days) associated With denovo DSA
Risk factors for developing ABMR
1. HLA mismatches especially class II
2. Presence of preformed DSA before transplantation
3. Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
4. Noncompliance on immunosuppressive medication ( very significant risk factor)
Poor prognostic factors in late ABMR
DSA monitoring
DSA should be monitored once in early post-transplant period (first 3 month) in all patients
After the first 3 month, no further testing is required except in the following situations
All patients with detectable DSA should undergo renal biopsy
C1q assay is a new assay that is capable of detecting only complement fixing IgG DSA , maybe usd to predict graft survival since complement fixing DSA are associated with poor graft survival
Treatment of acute and chronic ABMR
Standard of care treatment
The combination of plasmapheresis and IVIG represents the main therapy for treatment of acute ABMR, no rule of plasmapharesis in chronic ABMR
The combined use of Rituximab and ATG is associated with life-threatening infections
Salvage treatment
Conclusion
Treatment of early active AMR (≤30 days transplanation)
Treatment of late active ABMR (≥30 days posttrasnplant)
Treatment of chronic ABMR
Very nicely summarized. Why do you think that it is level 4/5 evidence and not 5? It is expert opinion consensus guidelines. I would still accept your answer as level 4/5 evidence.
Thank You Sherif
Review article, level 4
Summery:
50% of renal graft lost by 10 years post transplantation. Chronic graft loss can result from immune or non immune cause. TG is the most common finding of protocol biopsy( in glomerular disease). IFTA can be a sequel of :
Immunological causes:
Chronic injury commonly involve Ab-mediated endothelial injury go glomeruli, PTC & small- medium size vessels. persistent endothelial injury lead to duplication of PT basement membrane to give TG.
TG is non specific finding can occur in: AMR, TMA, recurrent autoimmune GN, & hepatitis-C related GN.
Recurrence of glomerular disease is a common cause of graft loss 10 years post transplant ( 3rd cause). FSGS can recur in early post transplant period with graft loss in 50-80% of cases, aHUS recurrence differ according to complaint abnormality ( 15% in MCP mutation, & 80% in circulatory protein mutation). But IGA nephropathy can recur in 40% of transplant but rarely lead to early graft loss. So through protocol biopsy early diagnosis & treatment can improve long term graft survival.
Infections can can cause chronic injury to the graft due to directly or indirectly through activation of innate immune response. CMV infection can cause rejection.
Non immunological causes:
Diagnosis of AMR:
Prevention of AMR:
Management of AMR:
Sorry this summary of journal club III
-Summary
Introduction
AMR was the most common cause of allograft failure in a cohort of renal transplant recipients with biopsies taken before graft failure.
There isn’t an accepted standard for treatment of AMR so it is difficult for industry to initiate phase 2 and 3 clinical trials for novel treatments or prevention of AMR.
Alloimmune response biology
Activated B cells migrate to the T- and B-cell interface and receive T-cell help. Some of the helped B cells differentiate into memory B cells or plasma cells,the rest enter into a germinal center to emerge as high-affinity and classswitched memory B cells and plasma cells. Memory B cells have lower B-cell receptor (BCR) affinity compared with plasma cells, and cells generated pre-GC tend to be of lower affinity than cells generated post-GC.
AMR histological feautres
The active AMR features based on the Banff 2017 classification are
1-histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis , acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause;
2- histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI; and
3- the presence of circulating DSA, predominantly anti-HLA antibody .
Chronic active AMR diagnosis include chronic tissue injury in addition to criteria 2 and 3 for active AMR.
AMR clinical phenotypes
The Banff classification has 3 AMR diagnostic categories including chronic AMR with transplant glomerulopathy and current or prior DSA without MVI or C4d.
AMR can present by sudden allograft dysfunction early posttransplant also it can have a subclinical onset, presenting later posttransplant. Anti-HLA antibody can also be preexisting DSA or develop after transplant (dnDSA) in the setting of under-immunosuppression.
Early Posttransplant (<30 days ) Active AMR
It’s risk increases with increasing DSA level at the time of transplant as detected by DSA mean fluorescence intensity (MFI), the degree of flow cytometric crossmatch positivity, and the number or breadth of cross-reactive DSA specificities.
It is uncommon, it is manifested by an abrupt increase in DSA accompanied by allograft dysfunction.
Late (>30 Days) Posttransplant AMR With Preexisting DSA
It is an indolent forum , detected on a surveillance biopsy.
When detected early, MVI in glomeruli and peritubular capillaries is predominant and C4d staining may or may not be present. MVI tends to persist and is associated with chronic histological features including transplant glomerulopathy and peritubular basement membrane multilayering.
There is minimal if any reduction in GFR or proteinuria even when mild chronic features are present
Late (>30 Days) AMR Associated With dnDSA
Which is the most common form of AMR,new DSA detected after >3 months posttransplant due to inadequate immunosuppression ether due to patient nonadherence, physician directed, or genetically determined variability in metabolism of immunosuppressive drugs.
It presents with allograft dysfunction and concomitant or preexisting TCMR
The presentation is subclinical , similar to that of late posttransplant AMR in patients with preexisting DSA
AMR with dnDSA is associated with inferior allograft survival compared with AMR from preexisting DSA.
Features accompanied by reduced allograft survival in late AMR( pre existing or dnDSA) are
Chronic histological features as transplant glomerulopathy , the degree of interstitial fibrosis ,tubular atrophy , TCMR ,C4d positivity and vascular lesions.
clinical factors are proteinuria and time of diagnosis posttransplant
other major risk factors are underimmunosuppression and medication nonadherence
Consensus for DSA monitoring
Initial Assessment for Anti-HLA DSA
By HLA typing and HLA screening
For anti-HLA–sensitized recipients, a high-resolution level of typing.
Patients with no sensitisation history and with negative antiHLA antibody testing using single-antigen or multiantigen bead solid-phase assays are at low risk for AMR.
Monitoring of De Novo DSA
Specially with immunosuppression reduction, known patient medication nonadherence, or at the time of rejection episode.
Positive DSA Results assessment
SAB test has it’s limitations , liable to interference from external effectors
Positive cut off MFI of 1000–1500 is associated with anti-HLA antibodies presence.
DSA Testing for Risk Stratification
Hyperacute AMR is associated with positive CDC crossmatch.
C1q and C3d binding positivity is associated with a high DSA titer
Evidence for treatment of active and chronic active AMR
Multiple studies addressed different mix of therapies as plasmapheresis, intravenous immune globulins [IVIG], steroid pulses with or without different T-cell–depleting and B-cell–depleting antibodies.
Plasma Exchange and IVIG
commonly used to treat active AMR.
The FDA Antibody-Mediated Rejection Workshop in 2017 and KDIGO in 2010 mentioned that PLEX and IVIG could be a standard treatment for acute active AMR, meanwhile their long-term effects are variable.
PLEX and IVIG removes circulating DSA with immunomodulation of the antigraft immune response
Complement Inhibitors
Ecluzimab a monoclonal antibody targeting C5
Multiple trials revealed the preventive role of eculizumab for early active AMR in positive crossmatch HLA-incompatible living and deceased donor recipients.
C1 esterase inhibitors Berinert and Cinryze showed a possible improvement in allograft function in kidney recipients with AMR.
Rituximab
Some studies did not demonstrate any positive effect in combination with other modalities while other studies revealed some positive effect when used with IVGV high dose, plasma exchange and steroids particularly with vascular AMR.
Imlifidase
an IgG-degrading enzyme of Streptococcus pyogenes (IdeS), which can lower anti-HLA DSA levl and is studies in AMR treatment but rebound increase in DSA level is noted .
It is used for desensitisation in highly sensitised cases.
The benefit of this drug is that it allows highly sensitized cases to undergo transplantation within hours of a donor being available regardless of the crossmatch status.
ATG
used for treatment of refractory rejection, vascular rejection, mixed rejections, and AMR.
If combined with B cell depleting agent it has high life threatening infection risk .
Splenectomy
It need to be done rapidly after the onset of early AMR to be effective.
Proteasome Inhibitor: Bortezomib
Is a candidate for the treatment of active AMR in a multimodal treating regimen.
Cyclophosphamide
It was mentioned anecdotaly its use with multimodal treatment regimen for the treatment of refractory rejections.
IL6 inhibitors
Toclizumab revealed acceptable results in treating chronic active AMR after failure of IVIG and rituximab.
Clazakizumab is studied for treating chronic active AMR
Treatment of early active AMR Consensus (≤30 days transplanation)
The combination of PLEX, IVIG with corticosteroids could be a standard treatment of care, similar to the conclusions of the FDA workshop and KDIGO guidelines.
The adjunctive therapies include complement inhibitors, rituximab, or splenectomy can be needed especially when the risk of graft loss is high and concomitant TCMR is present.
Treatment of late active and chronic AMR consensus (≥30 days posttrasnplant)
For patients with preexisting DSA and active AMR without chronic features, treatment include PLEX, IVIG, and corticosteroids.
In cases of chronic active AMR optimizing immunosuppression need to be optimised with reintroduction of steroids (if on a steroid-free regimen), maintaining trough tacrolimus levels >5 ng/mL.
In cases with denovo DSA ,Optimizing immunosuppression and treat potential medication nonadherence and associated TCMR.
– Level of evidence is 5
Thank you
Level of evidence of guidelines is 4/5
Consensus for measuring and Monitoring of DSA ;
Initial assessment for anti-HLA DSA ; This should include HLA typing, anti-HLA antibody screening, history of allo-sensitization (IA).
Monitoring for De Novo DSA ; Must be considered in the following condition ;
Interpreting positive DSA Results ; SAB is affected by external interference, bead
saturation, and shared epitopes. Dilution methods and ethylenediaminetetraraaetic acid can be use to detect interference
Additional DSA Testing for risk stratification ; This depend on XM test, complement binding DSA, and IgG sub-classes.
Consensus for Treatment for early active AMR(< = 30 Days Post-Transplant) ; Limited quality of evidence
Consensus for Treatment of late active and chronic active AMR ;( >=30 Days Post-Transplant)
Pre-existing DSA ; one should ;
De Novo DSA ; This is mainly cause by under immune-suppression e.g.Non-adherence.
Conclusions
Level of evidence ; This an expert opinion and therefore, level 5 evidence
Excellent
Level of evidence of guidelines is 4/5
Thnxs prof