Ø An individual’s immunologic risk at the time of transplant has conventionally been attributed to factors such as:
1. overall level of anti-HLA sensitization (panel reactive antibody)
2. pretransplant DSA
3. repeat transplant
4. black race, and
5. recipient age
Ø In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure. Currently in the United States, 75% of kidney recipients receive rabbit antithymocyte globulin (rATG) induction and .90% receive maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, as these regimens have historically been associated with lower rates of acute rejection
Ø Calcineurin inhibitor free maintenance immunosuppression with the newer agent belatacept has resulted in favorable, longer-term outcomes but with higher rates of T cell–mediated rejection; however, post hoc analysis has shown a significant reduction in DSA development in those receiving belatacept versus cyclosporine (1%–4% versus 12%, respectively
Ø The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy. Indications to pursue graft biopsy over concern for acute rejection include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection.
Ø Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed:
Ø T Cell–Mediated Rejection
1. Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days
2. T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for 5 to 7 doses
Ø Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
level 5
Naglaa Abdalla
2 years ago
This article is about evaluation and treatment of acute rejection in kidney allograft.
Acute rejection is one of the major causes of graft dysfunction.
Careful assessment of the recipient regarding history and clinical examination is necessary. Investigations including US, drug level, infection screen is important to rule out other differential diagnoses. Renal biopsy remain the standard investigation modality for diagnosis depending on Banff classification of rejection.
Intravenous steroids and T cell depletion remain the standard therapy for
T cell–mediated rejection and are effective in reversing most cases. Plasma exchange and intravenous Ig, with or without rituximab, are most commonly used for the treatment of antibody-mediated rejection and several newer agents have recently been investigated for severe cases.
level 5
Nazik Mahmoud
2 years ago
It is a review to diagnose kidney allograft rejection after excluding any other cause like sepsis or CNI toxicity
they are two types of rejection cellular and antibody mediated rejection
in most of cases they presented together
so ideally biopsy and PRA screening should be done but if it is not feasible we can start pulse steroid and took the PRA screening
treatment most probably depend on Histopathology it vary from ATG in vascular type of ACR to Plasmaexchange and rituxmab in ABMR
it is level 5 evidence
Rehab Fahmy
2 years ago
Acute rejection:
is either acute T cell mediated rejection or Ab mediated rejection and sometimes mixed rejection
Usually occurs in patients with high immunological risk like highly sensitized recepients ,high level of DSA ,,ABO incompatibility
1st possibility in case of delayed graft dysfunction
Diagnosed by Disney biopsy with spescific histological findings summariezed in BANFF classification
C4D staining is important in case of AMR
Prevention:
desensitization
Paired Donor exchange
Treatment:
AMR:IVIG ,plasmapheresis,Rituximab
T cell mediated rejection:ATG ,steroids
level 5 of evidence
The diagram for delayed graft function is good and informative
Hamdy Hegazy
2 years ago
Please summarize this article
Acute rejection is classified into acute T-cell mediated and Antibody mediated rejection.
Factors that trigger the immune system to develop rejection include the following: HLA mismatches, previous sensitization, PRA, repeat transplant, presence of DSAs.
Recipients with pre-transplant DSA have 30-50% chance to experience antibody mediated rejection which is determined by immunosuppression regimen as well.
Belatacept and CNI free maintenance IS resulted in higher rates of T-cell mediated rejection and significant reduction of DSA compared to cyclosporine (1-4% vs 12%).
Acute rejection is diagnosed by a renal graft biopsy which is indicated when graft function deteriorates without obvious explanation.
Histopathological interpretation of graft biopsy using Banff classification which was developed since 1990 with continuous update.
T-cell mediated rejection histological findings include tubulitis, and large vessel vasculitis.
Antibody mediated rejection feature include active tissue injury, peri-tubular capilliritis with or without C4d deposition and circulating DSA. These Criteria was updated by Banff 2017.
Treatment of acute rejection:
1- Treatment of T-cell mediated rejection: pulse methyl-prednisolone for 3-5 days, then ATG is required for 5-7 doses if Banff II and III.
2- Treatment of antibody mediated rejection: includes plasma exchange followed by IVIG +/- Rituximab. Other lines of AMR treatment include Bortezomib, Eculizumab or C1-estrase inhibitors
Subclinical Rejection is diagnosed by protocol biopsy What is the level of evidence provided by this article? Level V
Ahmed Omran
2 years ago
When unexplained graft dysfunction occurs, non-immunological causes : infection, CNI toxicity, hemodynamic disorders and fluid collection need to be ruled out .The next step would be to check for presence of rejection through renal biopsy and DSA screening. We apply BANFF criteria to delineate the type of the rejection whether antibody mediated or cellular rejection. In case of antibody mediated rejection, then implementation of plasma exchange, IV IG and rituximab are the cornerstone treatment. If it is cellular rejection, then the use steroid and r ATG is required.
In biopsy is not feasible, we can give steroid empirically and do tests for DSA. If the serum creatinine is improving with negative DSA, the management will include optimization of immune-suppressants and close monitoring. If DSA were positive, the need for a biopsy is still there. If the AKI is not resolved with positive DSA, the treatment will be as a case of AMR. If the graft dysfunction is severe, ATG is used. If the DSA were negative then rATG alone will be enough. The need for renal biopsy remains valid except for cases with improved renal function & negative DSA.
Level 5 article.
Abdullah Raoof
2 years ago
II. Evaluation and Treatment of Acute Rejection in Kidney Allografts.
1) Please summarise this article. Introduction:
With time the immunsupressive agents become effective in reducing the rejection accordingly the acute rejection rates reduced from nearly 100% in the first era of organ transplantation to approximately 10% . these rates mainly achieved by introduction of cyclosporine and T cell–depleting agents. Acute rejection broadly classified in to either T cell mediated” or antibody mediated Acute Rejection Risk:
Immunological response generally depend on the level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black race, and recipient age.
Wehmeier et al. report that pretransplant donor-specific anti bodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection .
30%–50% of patients with high pre transplant DSA titers will experience acute antibody-mediated rejection . but lower-level not associated with rejection.
Acute rejection risk is associated with immunosuppression regimen and exposure.
75% of kidney recipients receive (rATG) induction and 90% receive maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone. With very good outcome .
Strategies to reduce calcineurin inhibitor (CNI) exposure include
1) By using mammalian target of rapamycin inhibitors (mTOR’s) associated with higher rates of acute rejection and side effects .
2) Calcineurin inhibitor free maintenance immunosuppression with belatacept associated with longer-term outcomes but higher rates of T cell–mediated rejection. With significant reduction in DSA development in those receiving belatacept versus cyclosporine.
3) Adams et al. report that adding tacrolimus to the existing belatacept regimen followed by a steady taper over the firs post-transplant year lead to significant acute rejection reduction. (acute rejection rates of 51% with belatacept alone versus 16% with belatacept plus tacrolimus taper).
Also there is a correlation between overall tacrolimus exposure and acute rejection risk.
Mean tacrolimus levels, 8 ng/ml through-out the first year increased the risk of DSA development and levels of 4–6 versus .8 ng/ml were associated with a 2.3-fold higher risk of acute rejection.
Of note non immunologic causes may be most likely in an older patient who received rATG induction with consistently therapeutic tacrolimus levels .
Acute Rejection Diagnosis
The gold standard for diagnosing acute rejection is tissue biopsy. Which is indicated in acute unexplained graft dysfunction or the presence of a biomarker consistent with acute rejection.
Allograft biopsy is a safe procedure and should be done in patients with graft dysfunction that is not explained by other no immunologic causes. Allograft histology is interpreted using the Banff classification of kidney allograft pathology.
NON INVASIVE BIOMARKERS
Umerous urine and blood biomarkers studies , such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have generally shown mixed sensitivity and specificity for
1) Identifying acute rejection.
2) differentiating T cell–mediated rejection.
3) antibody-mediated rejection.
4) distinguishing immunologic injury from other forms of graft damage.
single-stranded microRNA and donor-derived cellfree DNA (cf-DNA) are another biomarker .
in one study of cf-DNA levels showed that a negative predictive value for AMR of 96%.( cut-off value 1%) and the positive predictive value was only 44%.
Tissue biopsy remains the gold standard for diagnosing acute and noninvasive biomarkers have failed tocompletely replace tissue diagnosis. The high negative predictive value, of cf-DNA, may reassure nephrologist in patients with abnormal clinical findings (DSA, graft dysfunction) in whom tissuebiopsy is either not feasible or considered too high risk.
Acute Rejection Treatment:
Early recognition and diagnosis of acute rejection is important for early initiate appropriate of treatment.
T Cell–Mediated Rejection:
Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days.
Banff class 1 lesions responding to methylprednisolone alone. Banff II and III lesions generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
One study compared rATG with horse anti-thymocyte globulin, howing superior effectiveness of rATG over horse ATG.
Cochrane Database review concluded that antibody therapy was superior to steroid therapy in reversing T cell–mediated rejection. Antibody-Mediated Rejection:
AMR treatments are directed at
· Removing antibody-producing B cells or plasma cells,
· Removing antibodies (DSA), and/or inhibiting the subsequent complement-regulated graft damage.
The a systematic review by Roberts et al. report low-quality evidence supporting antibody removal therapies (plasma exchange , immunoabsorption ), and very low-quality evidence for all other treatments.
plasma exchange and intravenous Ig (IVIG), with or without rituximab is most accepted regimen for treatment of AMR.
A typical regimen includes:
daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2. Bortezomib:
It is used because of its ability to induce apoptosis in antibody-producing plasma cells. But there is minimal effect on DSA burden when used as a sole agent with mixed results when used in combination with plasma exchange/IVIG . The humanized mAb eculizumab :
Orandi et al. severe antibody-mediated rejection by either splenectomy , eculizumab, or combination splenectomy and eculizumhab . there was high graft loss in the splenectomy and eculizumab groups, compared to combination splenectomy and eculizumab which show no graft loss and minimal transplant glomerulopathy on protocol biopsy Anti-IL six receptor antibody tocilizumab:
This agent is not studied in the treatment of acute antibody-mediated rejection. C1-esterase inhibitors (C1-INH): This agent lacks the efficacy for the treatment of AMR. Subclinical Rejection:
involves protocol biopsy or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions. The incidence of subclinical T cell–mediated is low and long term outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection.
In one study , the incidence of subclinical T cell–mediated rejection was only 5%, with no difference in graft function despite treatment.
While Subclinical antibody-mediated rejection, is an attractive therapeutic target given the attributed poor long-term outcomes.
Using DSA as a biomarker, approximately 50% of patients with stable function and de novo DSA will show evidence of subclinical AMR on biopsy . Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection, few data exist to suggest treatment intervention will alterthe clinical course. Orandi et al. in their stusy report that overall rates of graft loss were similar between those treated and untreated.
2) What is the level of evidence provided by this article?
Level of evidence is 5 .
Dalia Ali
2 years ago
Acute Rejection Risk
An individual’s immunologic risk at the time of transplant has conventionally been attributed to factors such as overall level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black race, and recipient age. Wehmeier et al.recently examined traditional risk factors in 527 kidney recipients, showing pretransplant donor-specificantibodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation had no predictive effect. With this in mind, it is worth noting the degree of immunologic risk conferred by pretransplant DSA will depend on characteristics of the antibodies detected. Approximately 30%–50% of patients with pretransplant DSA at titers strong enough to warrant desensitization before transplant will experience acute antibody-mediated rejection (8), whereas lower-level antibodies do not appear to increase acute rejection risk or graft survival in the intermediate term
Acute Rejection Diagnosis
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy. Indications to pursue graft biopsy over concern for acute rejection include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection. As described in the preceding section, assessment of a patient’s immunologic risk at the time of and after transplant can help further define pretest probability of acute rejection when contemplating the utility of biopsy; however, allograft biopsy is generally considered a safe procedure and should be pursued without delay in patients with graft dysfunction that is not explained by other nonimmunologic causes. Allograft histology is interpreted using the Banff classification of kidney allograft pathology, which has undergone extensive updating and revision since its development in the 1990s The diagnostic criteria for T cell–mediated rejection have undergone little change in recent years, and include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field
Acute Rejection Treatment
The approach to treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology. Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed. Graft prognosis after treated acute rejection also depends on type and severity . however, any untreated clinical acute rejection episode will ultimately result in accelerated graft loss. Thus timely recognition and diagnosis of acute rejection is crucial to promptly initiate appropriate treatment.
T Cell–Mediated Rejection
The treatment of T cell–mediated rejection has changed little over time and few data exist comparing one strategy to another. Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5days,as recommended by international guidelines ). Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylprednisolone alone. T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses
Antibody-Mediated Rejection Similar to T cell–mediated rejection, few high-quality, randomized trials exist comparing treatment regimens for antibody-mediated rejection. In contrast to T cell–mediated rejection, however, several new therapeutic treatment options have been studied in recent years. Antibodymediated rejection treatments are directed at removing antibody-producing B cells or plasma cells, removing antibodies (DSA), and/or inhibiting the subsequent complement-regulated graft damage
Subclinical Rejection
The identification and treatment of alloimmune responses before the onset of clinical graft dysfunction may theoretically minimize the development of chronic lesions that ultimately lead to graft loss (47,48). This approach involves protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions. The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low and longterm outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection
Orandi et al.published a retrospective analysis of 77 patients with subclinical antibodymediated rejection diagnosed by protocol biopsy, 54% of which received treatment with various combinations of plasma exchange, IVIG, rituximab, and eculizumab. With a mean follow-up of 5.2 years, overall rates of graft loss were similar between those treated and untreated. However, when compared with matched controls, treated patients experienced a lower risk of graft loss versus untreated patients (hazard ratio, 1.73 [P50.21] versus 3.34 [P50.01], respectively). Thus, although the prospect of identifying subclinical antibody-mediated rejection before clinical dysfunction remains attractive
Conclusions
Despite historically low acute rejection rates thanks to increasingly effective immunosuppressive protocols, acute rejection episodes continue to affect graft survival and prompt recognition and treatment is crucial. When feasible tissue biopsy should be performed in any patient with unexplained acute graft dysfunction, and accurate assessment of immunologic risk can assist in determining the need for tissue diagnosis. The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA andC4ddeposition, with several new agents under investigation for treatment. Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
Level 5
Asmaa Khudhur
2 years ago
Evaluation and treatment of Acute Rejection in kidney allograft.
Acute rejection previously classified as steroid responsive and steroid non responsive .now is characterized as either T cell mediated or antibody mediated acute rejection.
Each one has distinct separate mechanistic pathways, different histologic findings and prognosis with distinct approaches to treatment.
Acute rejection immunological risk assessment:
Pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch are the main predictors at AMR and T cell mediated rejection whereas PRA and repeat transplantation has no predictive effect. And the degree of immunological risk conferred by pretransplant DSA depends on antibodies characteristics.
High level antibodies warrant desensitization before transplantation will experience acute antibody mediated rejection, whereas low level antibodies do not appear to increase acute rejection risk or graft survival.
In post-transplant period , risk of acute rejection is determined by IS regimen and exposure.
Diagnosis of acute rejection:
Tissue biopsy is the gold standard for diagnosing acute rejection.
Banff classification of kidney allograft pathology used to interpreted allograft histology.
Histologic criteria for diagnosing acute allograft rejection according to Banff 2017 guidelines :
Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
Acute antibody-mediated rejection (AMR): all three criteria below required
Histologic evidence of tissue injury including one or more of the following:
Microvascular inflammation (g.0 and/or ptc.0) Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc $2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Noninvasive biomarkers have failed to replace tissue diagnosis, so it is remains the gold standard for diagnosing Acute rejection.
Acute Rejection Treatment:
Treatment options for acute allograft rejection
Acute Rejection Treatment
The approach to treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology. Treatment strategies differ between T cell–mediated rejection and antibody mediated rejection.
In case of unexplained graft dysfunction we must rule out non immunological causes of graft dysfunction like infection, drug toxicity, hemodynamics causes, anatomical/fluid collection or obstruction.
If all are normal, we proceed for tissue biopsy and assessment for de novo DSA.
If the biopsy not safe or feasible, we treat by solumedrol for 3-5 days . If AKI resolved , we assess DSA , if it’s negative, we continue by monitoring graft function with optimizing IS .
If the DSA’s positive, we monitor graft function and optimize IS, then obtain graft biopsy when feasible.
If the AKI not resolved after solumedrol , we assess DSA , if it’s positive, we do empiric PEX plus IVIG , and consider ATG if it’s severe and obtain biopsy if feasible.
If the DSA’s negative, we give ATG and obtain biopsy if feasible.
If we can obtain biopsy and diagnosed the dysfunction as immunological cause either T cell mediated or AMR.
T cell mediated rejection treated by steroid and ATG
AMR treated by PEX and zIVIG followed by RTx after the last session.
If mixed rejection add T cell mediated rejection treatment according to banff category.
Level of evidence 5
Mu'taz Saleh
2 years ago
Introduction :
Despite the development in the immunosuppression medication rejection still in the top of differential diagnosis of any renal impairment post renal transplantation .
because of its effect in long term graft survival early diagnosis and optimal management is mandatory in this cases .
Tissue biopsy remains the gold standard for evaluating immunologic graft damage, and the histologic definition of acute rejection .
Two types of rejection T cell mediated and AMR are founded each one needs specific management .
Risk factor for rejection :
pretransplant risk factor
High PRA ( anti HLA )
Pre transplant DSA
previous transplantation
black race
recipient age
Post transplant risk factor : immunosuppression regimen and level of these medication ( till now induction with rATG and triple maintenance therapy ( CNI , mycophenolate , prednisolone giving good results and low risk of rejection )
Diagnosis :
tissue biopsy remains the gold standard for diagnosing acute rejection in transplant recipients and noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies .
Acute T cell–mediated rejection (TCR)
lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field
Acute antibody-mediated rejection (AMR):
All three criteria below required :
Histologic evidence of tissue injury including one or more of the following: Microvascular inflammation (g.0 and/or ptc.0)
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA) Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Despite advances in immunosuppression in recent decades, acute rejection is still an event of great importance, as it has the potential to significantly affect graft survival. And understanding the pre and post-transplant risk factors for acute rejection can help estimate the probability of immunologic graft damage, and accurate identification of the type and severity of acute rejection will guide appropriate investigate and treatment.
Today acute rejection is classificated in: T cell mediated or antibody mediated. Normally, acute rejection has been attributed to pre-transplant factors such as overall level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black race, and recipient age, but recent studies has showing that panel reactive antibody and repeat transplantation had no predictive effect. And pretransplant donor-specific antibodies (DSA) for antibody-mediated rejection and HLA A/B/DR mismatch to T cell–mediated rejection, are main predictors .
Post-transplant factors largely determined by immunosuppression regimen and exposure and encompasses immunosuppressants used from induction to maintenance. Regimens with induction through rabbit antithymocyte globulin (rATG) and maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, seem to be associated with lower rates of acute rejection. The control of Tacrolimus concentration is the biggest challenge of these regimens, due to its adverse effects. Regimens that attempt to spare the calcineurin inhibitor appear to have higher rates of acute rejection and side effects.
ACUTE REJECTION DIAGNOSIS
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy, so, in cases of unexplained deterioration in graft function, the performance of biopsy should be evaluated. Banff classification contains the criteria for the diagnosis of T cell–mediated and antibody rejection, which involve the presence of: lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate, active tissue injury, immunohistologic evidence of peritubular capillary complement split-product C4d deposition, and circulating DSA.
ACUTE REJECTION TREATMENT
Differentiating diagnoses is essential for defining treatment. Among the most used possibilities we have:
A)T-cell mediated rejection: has changed little treatment over the years. There are few data evaluating the two types of treatment.
– Methylprednisolone: Banff class 1 lesions
– rATG: Banff II and III lesions
B)Antibody-mediated rejection: there is also little comparative evidence between treatments, however new proposals have emerged recently.
– Plasma Exchange: remove antibodies DSA
-IVIG: is the most commonly used treatment, with or without Rituximab.
– Rituximab: known to have good effects associated with IVIG, but ongoing studies on rituximab as rescue therapy for treatment insufficient efficacy
– Bortezomib: initially approved proteasome inhibitor for treatment of multiple myeloma, has better effect when used in association with Plasma Exchange or IVIG
– Eculizumab: possibility of replacing the effect of splenectomy
– C1-INH: inhibits proximal enzymes in the classic complement pathway
The possibility of subclinical rejection still exists, but its incidence has been decreasing since the new therapies.
What is the level of evidence provided by this article?
Your evidence is 05 – narrative review
Manal Malik
2 years ago
Evaluation and Treatment of Acute Rejection in Kidney Allografts
Transplantation of donor organs to non-HLA identical recipients introduces stimulants for an alloimmune response. Any graft dysfunction in the transplant recipient still may need to rule out acute rejection. Acute rejection is either T-cell-mediated or antibody-mediated rejection. This review summarize the recent approach to M3K assessment, diagnosis, and treatment of acute rejection. Acute rejection risk:
Risk factors at the time of transplant:
Ø PRA
Ø Recipient transplant
Ø Black race
Ø Recipient age
Ø In the post-transplant period, acute rejection risk is based on the immunosuppression regimen and exposure
In the united states, 75% of kidney recipients receive rATG induction and >90% receive tacrolimus and mycophenolate mofetil, with or without prednisolone, this regimen is associated with loa were rate of acute rejection.
mTOR is associated with high rate of acute rejection and maintenance
CNI-free maintenance immunosuppression with the result gent belatacept has result in a few recommendations come.
recommendation for appropriate dose and exposure of tacrolimus to prevent acute rejection have not been established.
In cohort 53 transplant recipient on TAC based therapythe level <8ng/ml throughout first year increased the risk of DSA development and 4-6ng/ml
Serum <8ng/ml 2-3 folder higher risk of acute rejection. Acute rejection diagnosis:
Gold slandered to diagnose acute rejection is kidney biopsy. Indication for kidney biopsy:
1. Acute or unexplained deterioration of graft function
2. Presence of biomarker consistent with acute rejection
Allograft histology is interoperated using the Banff classification of kidney allograft pathology.
Diagnostic criteria for T-cell mediated rejection depend on the degree of lymphocyte infiltrate per high-powered field which can involve tubules and large vessels.
Antibody-mediated rejection required 3 features:
1. Acute tissue injury
2. Evidence of current/recurrent antibody interaction with endothelium
3. Serological evidence of DSA or positive c4d or AMR-associated transcripts.
As tissue biopsy is a potential risk for the patient with possible sample error. Other biomarkers recently emerged to aid in the diagnosis of acute rejection:
1. miR-210 level associated with T cell-mediated rejection
2. cf-DNA donor-derived cell-free DNA in blood for diagnosis of active kidney transplant recipients
tissue biopsy remains the gold standard for diagnosis of acute rejection and biomarker failed completely replace tissue diagnosis. Acute rejection treatment:
Treatment approach of the transplant recipient with acute rejection relies on accurate diagnosis. Classification of immunological pathology. and type of acute rejection. T cell-mediated rejection:
Initial treatment phase methylprednisolone at 250—500mg daily for 3-5 days.
T cell-mediated rejection. Banff II and III less as to treat by rATG 1.5mg/kg for 5-7 days. Antibody-mediated rejection:
Plasma exchange and intravenous Ig with or without a single dose of rituximab limited data in this field
Although there are different approaches. In this type of therapy that no difference in the primary outcome.
Bortezomib and eculizumab CI-Inff medication this role in treatment of AMR still needed more studies. Subclinical rejection:
Use potential biopsy of stable graft or serum for DSA are used to identify alloimmune response before the onset of clinical graft dysfunction to minimize chronic losses and subsequent graft loss.
Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection for data exist to suggest treatment intervention will affect the clinical cause. Conclusion:
Treatment of acute rejection episode and effective immunosuppression therapy is mandatory as to preserve graft survival
Tissue biopsy still remaining the gold standard to evaluate acute graft dysfunction.
The Banff criteria for diagnosing antibody-mediated rejection not require the confirmation of DSA and c4d deposition
Several new agents under investigation for treatment.
Further clinical data are needed to determine if the treatment for AMR
Transplantation of donor organs to non-HLA identical recipients introduces stimulants for an alloimmune response. Any graft dysfunction in the transplant recipient still may need to rule out acute rejection. Acute rejection is either T-cell-mediated or antibody-mediated rejection. This review summarize the recent approach to M3K assessment, diagnosis, and treatment of acute rejection. Acute rejection risk:
Risk factors at the time of transplant:
Ø PRA
Ø Recipient transplant
Ø Black race
Ø Recipient age
Ø In the post-transplant period, acute rejection risk is based on the immunosuppression regimen and exposure
In the united states, 75% of kidney recipients receive rATG induction and >90% receive tacrolimus and mycophenolate mofetil, with or without prednisolone, this regimen is associated with loa were rate of acute rejection.
mTOR is associated with high rate of acute rejection and maintenance
CNI-free maintenance immunosuppression with the result gent belatacept has result in a few recommendations come.
recommendation for appropriate dose and exposure of tacrolimus to prevent acute rejection have not been established.
In cohort 53 transplant recipient on TAC based therapythe level <8ng/ml throughout first year increased the risk of DSA development and 4-6ng/ml
Serum <8ng/ml 2-3 folder higher risk of acute rejection. Acute rejection diagnosis:
Gold slandered to diagnose acute rejection is kidney biopsy. Indication for kidney biopsy:
1. Acute or unexplained deterioration of graft function
2. Presence of biomarker consistent with acute rejection
Allograft histology is interoperated using the Banff classification of kidney allograft pathology.
Diagnostic criteria for T-cell mediated rejection depend on the degree of lymphocyte infiltrate per high-powered field which can involve tubules and large vessels.
Antibody-mediated rejection required 3 features:
1. Acute tissue injury
2. Evidence of current/recurrent antibody interaction with endothelium
3. Serological evidence of DSA or positive c4d or AMR-associated transcripts.
As tissue biopsy is a potential risk for the patient with possible sample error. Other biomarkers recently emerged to aid in the diagnosis of acute rejection:
1. miR-210 level associated with T cell-mediated rejection
2. cf-DNA donor-derived cell-free DNA in blood for diagnosis of active kidney transplant recipients
tissue biopsy remains the gold standard for diagnosis of acute rejection and biomarker failed completely replace tissue diagnosis. Acute rejection treatment:
Treatment approach of the transplant recipient with acute rejection relies on accurate diagnosis. Classification of immunological pathology. and type of acute rejection. T cell-mediated rejection:
Initial treatment phase methylprednisolone at 250—500mg daily for 3-5 days.
T cell-mediated rejection. Banff II and III less as to treat by rATG 1.5mg/kg for 5-7 days. Antibody-mediated rejection:
Plasma exchange and intravenous Ig with or without a single dose of rituximab limited data in this field
Although there are different approaches. In this type of therapy that no difference in the primary outcome.
Bortezomib and eculizumab CI-Inff medication this role in treatment of AMR still needed more studies. Subclinical rejection:
Use potential biopsy of stable graft or serum for DSA are used to identify alloimmune response before the onset of clinical graft dysfunction to minimize chronic losses and subsequent graft loss.
Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection for data exist to suggest treatment intervention will affect the clinical cause. Conclusion:
Treatment of acute rejection episode and effective immunosuppression therapy is mandatory as to preserve graft survival
Tissue biopsy still remaining the gold standard to evaluate acute graft dysfunction.
The Banff criteria for diagnosing antibody-mediated rejection not require the confirmation of DSA and c4d deposition
Several new agents under investigation for treatment.
Further clinical data are needed to determine if the treatment for AMR
subclinical will alter outcome, so more studies needed
evidence 5
rindhabibgmail-com
2 years ago
The rejection could be T cell mediated, Antibody mediated.
The diagnosis is confirmed by gold standard method like graft biopsy. The biopsy is assessed and treatment started according to BENIFF. However, it should confirmed that the level is not high enough causing MAHA/ vasoconstriction/ CNI toxicity, non immunological causes like infection.
After confirming treatment is given accordingly.
Level of evidence V
Hinda Hassan
2 years ago
Please summarise this article
In cases of unexplained graft dysfunction, non-immunological cause such as infection, CNI toxicity, hemodynamic causes and fluid collection need to be excluded. If these are not present, then the next step would be to assess for presence of rejection through renal biopsy and DSA screening. We could apply BANFF criteria to define the type of the rejection whether antibody mediated or cellular rejection. If it is antibody mediated rejection, then provision of plasma exchange, IV IG and rituximab are the mainstay treatment. If the rejection is cellular then the use steroid and rATG is mandatory.
In cases where the biopsy is not feasible, we need to give steroid empirically and do tests for DSA. If the serum creatinine is better in the presence of negative DSA, the management will include optimization of immune-suppressants and follow up. If DSA were positive, then the need for a biopsy is still there once it is feasible. In cases where the AKI is not resolved with positive DSA, then the treatment will be as cases of AMR. If the dysfunction of the graft is severe, ATG is used. If the DSA were negative then rATG alone will be used. The need for renal biopsy is still there except for cases with improved renal function with negative DSA. What is the level of evidence provided by this article? Level 5
MICHAEL Farag
2 years ago
What is the level of evidence provided by this article? Level V (review article) Acute Rejection Risk An individual’s immunologic risk at the time of transplant has conventionally been attributed to
– overall level of anti-HLA sensitization (panel reactive antibody).
– repeat transplant
– Black race, and
– recipient age.
NB: recently examined traditional risk factors in 527 kidney recipients, showing pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation had no predictive effect. In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure
Acute Rejection Diagnosis The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy. Allograft histology is interpreted using the Banff classification of kidney allograft pathology. Many biomarkers have undergone investigations to be used as indicator for acute rejection but still graft biopsy is the gold diagnostic tool
Acute Rejection Treatment Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
A) T Cell–Mediated Rejection
– Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days for most of Banff class I
– T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses. B) Antibody-Mediated Rejection
– A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2 This combination regimen between IVIG& PE is relatively superior to using IVIG /PE alone
– alternative agents for antibody-mediated rejection refractory to “standard” treatment regimens e.g. Bortezomib, The humanized mAb eculizumab, the anti-IL six receptor antibody tocilizumab, C1-esterase inhibitors (C1-INH)
Farah Roujouleh
2 years ago
Types of acute graft rejection :
T cell mediated rejection
Antibody mediated rejection
Each one is associated with unique histologic findings and prognoses, and require distinct approaches to treatment. Risk factors :
anti-HLA sensitization (PRA), repeat transplant, black race, and recipient age.
Pretransplant DSA and HLA mismatch Diagnosis of AR:
tissue biopsy is the gold standard for diagnosing and is indicated when there is an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with AR.
Banff classification of kidney allograft pathology help to determind the level of rejection and type of management
TCMR include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis)
AMR (1)Active tissue injury.(2) Immunohistologic evidence of peritubular capillary complement split-product C4d deposition. (3) Circulating DSA. Treatment :
Treatment strategies differ between TCMR and AMR.
Any untreated clinical AR episode will ultimately result in accelerated graft loss. TCMR treatment: pulse methylpred at 250–500 mg daily for 3–5 days.
In addittion toT cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses. AMR treatment:
Plasma exchange and IVIG, with or without rituximab, was the most commonly used strategy.
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 375 mg/m2.
A recent case series describes successful reduction in plasma cell infiltrate and stabilization of graft function after treatment with bortezomib in patients with plasma cell-rich AR.,
level of evidence: V
Huda Saadeddin
2 years ago
Despite historically low acute rejection rates thanks to increasingly effective immunosuppressive protocols, acute rejection episodes continue to affect graft survival and prompt recognition and treatment is crucial. When feasible tissue biopsy should be performed in any patient with unexplained acute graft dysfunction, and accurate assessment of immunologic risk can assist in determining the need for tissue diagnosis. The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition, with several new agents under investigation for treatment. Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
level V
Tahani Ashmaig
2 years ago
Evaluation and Treatment of Acute Rejection in Kidney Allografts: ___________________________ ▪︎The aim of this review is to provide the general nephrologist caring for transplant recipients with an approach to immunologic risk assessment & a summary of recent advances in the diagnosis and treatment of acute graft rejection. ♧Introduction Initially acute rejection (AR) episodes was known as “steroid responsive” and “steroid nonresponsive,” but now it is broadly characterized as either “T cell mediated (TCMR)” or “antibody mediated (AMR),” respectively. ▪︎These two forms of AR result from separate mechanistic PWs, are associated with unique histologic findings and prognoses, and require distinct approaches to treatment. ♧ Acute Rejection Risk Immunologic risks at the time of transplant: overall level of anti-HLA sensitization (PRA), repeat transplant, black race, and recipient age. ▪︎Pretransplant DSA and HLA A/B/DR mismatch are the main predictors of AMR and TCMR, respectively, ▪︎The degree of immunologic risk conferred by pretransplant DSA depends on characteristics of the antibodies detected. ▪︎Lower-level antibodies do not appear to increase AR risk or graft survival in the intermediate term. ▪︎ In the post-transplant period, AR risk is largely determined by immunosuppression regimen and exposure. ♧Diagnosis of AR: ▪︎Assessment of a patient’s immunologic risk at the time of & after transplant. ▪︎A tissue biopsy is the gold standard for diagnosing and is indicated when there is an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with AR. ▪︎Allograft histology is interpreted using the Banff classification of kidney allograft pathology. ▪︎The diagnostic criteria for TCMR include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field. ▪︎ Banff classification of acute AMR continues to evolve first was recognized in the early and mid-2000s and required three features for diagnosis: (1)Active tissue injury. (2) Immunohistologic evidence of peritubular capillary complement split-product C4d deposition. (3) Circulating DSA.
▪︎The revised 2013 Banff criteria for AMR diagnosis removed the requirement for C4d detection and broadened this category to include “evidence of current/recent antibody interaction with vascular endothelium,” which may include either (1) positive C4d staining, (2) at least moderate microvascular inflammation, or (3) increased expression of endothelial gene transcripts. ▪︎The most recent Banff consensus notes studies showing a lack of DSA in patients with biopsy specimensdemonstrating significant microvascular inflammation as well as a low false +ve rate of C4d staining, & has now removed the requirement for documented circulating DSA in the setting of positive C4d staining and microvascular inflammation. ▪︎Numerous studies of urine & blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, & Fas ligand, have generally shown mixed sensitivity and specificity for identifying AR, differentiating TCMR from AMR, and distinguishing immunologic injury from other forms of graft damage. ▪︎Short noncoding single-stranded microRNA have improved stability in urine compared with mRNA & decreased urinary miR-210 levels have been associated with TCMR and subsequent 1-year GFR decline. Recently, donor-derived cell free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of AMR, with results from the multicenter “Circulating Despite the tissue biopsy downfalls, it remains the gold standard for diagnosing AR in transplant recipients and noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies. ♧Acute Rejection Treatment ▪︎The approach to treatment of the AR relies on accurate diagnosis and classification of the immunologic pathology. ▪︎Treatment strategies differ between TCMR and AMR. ▪︎Any untreated clinical AR episode will ultimately result in accelerated graft loss. ♧ TCMR treatment: ▪︎ The treatment of T cell–mediated rejection has changed little over time. ▪︎ Initial treatment conventionally includes pulse methylpred at 250–500 mg daily for 3–5 days. ▪︎Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylpred alone. ▪︎TCMR involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
♧ AMR treatment: ▪︎ Is directed at removing antibody-producing B cells or plasma cells, removing DSA (by plasma exchange,immunoabsorption) , and/or inhibiting the subsequent complement-regulated graft damage. ▪︎Plasma exchange and IVIG, with or without rituximab, was the most commonly used strategy. ▪︎A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2. Or to recieve; ▪︎Monotherapy with IVIG at 2 gm/kg every 3 weeks four doses or a more intensive regime consisting of plasma exchange, IVIG, and 2 doses of rituximab. ▪︎A recent case series describes successful reduction in plasma cell infiltrate and stabilization of graft function after treatment with bortezomib in patients with plasma cell-rich AR., ▪︎ The humanized eculizumab has been targeted in the prevention and treatment of AMR. ▪︎Severe AMR are treated with either splenectomy, eculizumab or combination splenectomy& eculizumab. ▪︎A pilot study of the anti-IL six receptor antibody tocilizumab has shown promising results for patients with chronic AMR. ▪︎C1-esterase inhibitors (C1-INH) have recently been studied for the treatment of acute AMR in patients with AMR deemed non-responsive to conventional treatment.
♧Level of evidence: V
Theepa Mariamutu
2 years ago
AR has the potential to significantly affect graft survival. Advances IS therapy have improved incidence of AR to approximately 10% and improvements in graft survival.
AR is classified as:
T cell-mediated rejection
Antibody-mediated rejection
Risk Factors for AR:
Overall level of anti-HLA sensitization
DSA level predicts ABMR, and HLA A/B/DR mismatch predicts TCR
Repeat transplant
Black race
Recipient age
Diagnosis:
Tissue biopsy is the gold standard and should be done even in graft dysfunction that is not explained by other nonimmunologic causes.
The diagnostic criteria for TCMR; tubulities and vasculitis
The diagnostic criteria of ABMR include active tissue injury, evidence for C4d deposition, and circulating DSA.
Donor-derived cell-free DNA (cf-DNA) positive predictive value for ABMR of 69% with negative predictive value of 100%, but could not discriminate TCMR
Treatment:
TCMR
methylprednisolone at 250–500 mg daily for 3–5 days
rATG dosed at 1.5 mg/kg for 5-7 doses.
ABMR
PLEX and IVIG, with or without rituximab
PLEX consisting of 1.5 plasma volume removal
IVIG at 100–200 mg/kg
+/- a single dose of rituximab at 375 mg/m2.
Newer drugs:
Bortezomib
Eculizumab
Tocilizumab used for chronic antibody-mediated rejection.
C1-INH
Level of evidence: 5 narrative review.
Assafi Mohammed
2 years ago
Summary of the article “Evaluation and Treatment of Acute Rejection in Kidney Allografts”
This is a review article, aims to provide an approach to immunologic risk assessment and a summary of recent advances in the diagnosis and treatment of acute graft rejection. Acute Rejection Risk
1) Immunologic risk at the time of transplant has conventionally been attributed to:
a) overall level of anti-HLA sensitization (panel reactive antibody).
b) repeat transplant.
c) black race.
d) recipient age.
2) Wehmeier et al. recently examined traditional risk factorsin KTRs:
a) pretransplant DSA and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively.
b) PRA and repeat transplantation had no predictive effect.
3) In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure.
a) Induction with rATG and maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, have historically been associated with lower rates of acute rejection.
b) Strategies to reduce CNI exposure; using mTOR’s have generally been met with higher rates of acute rejection and side effects.
c) CNI- free maintenance immunosuppression with the newer agent belatacept has resulted in favorable, longer-term outcomes but with higher rates of TCMR.
d) Belatacept (versus cyclosporine) has shown a significant reduction in DSA development.
e) Adams et al.; center’s experience showing significant reduction in acute rejection in patients treated with belatacept by adding tacrolimus to the existing belataept regimen followed by a steady taper over the first post-transplant year (acute rejection rates of 51% with belatacept alone versus 16% with belatacept plus tacrolimus taper).
Acute Rejection Diagnosis
1. Tissue biopsy is the gold standard for diagnosing acute rejection in kidney transplant recipient. Allograft histology is interpreted using the Banff classification of kidney allograft pathology. Indications for graft biopsy:
a) unexplained deterioration in graft function.
b) the presence of a biomarker consistent with acute rejection.
2. AMR; features for diagnosis:
a) Active tissue injury.
b) Immunohistologic evidence of peritubular capillary complement split-product C4d deposition.
c) Circulating DSA.
3. TCMR; diagnostic criteria include:
a) Lymphocytic infiltrate of tubules (tubulitis) and larger vessels(vasculitis).
b) With the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field.
4. Histologic criteria for diagnosing acute allograft rejection(according to Banff 2017 guidelines) A. Acute T cell–mediated rejection (TCR)
Ia: >25% Interstitial inflammation with moderate tubulitis (t2).
Ib: >25% Interstitial inflammation with severe tubulitis (t3).
IIa: Mild-to-moderate intimal arteritis (v1).
Iib: Severe intimal arteritis (v2).
III: Transmural arteritis and/or fibrinoid necrosis. B. Acute antibody-mediated rejection (AMR): all three criteria below required 1) Histologic evidence of tissue injury including one or more of the following:
a) Microvascular inflammation (g.0 and/or ptc.0) Arteritis (v>0).
b) Thrombotic microangiopathy.
c) Acute tubular injury 2) Evidence of current/recent antibody interaction with endothelium including one or more of the following:
a) Positive C4d staining of peritubular capillaries.
b) Moderate microvascular inflammation (g+ptc³2).
c) Increased expression of gene transcripts in biopsy tissue strongly associated with AMR.
5. Noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies.
3) Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA Acute Rejection Treatment
1. Management relies on:
· Timely recognition and accurate diagnosis.
· Classification of the immunologic pathology.
2. Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
3. T Cell–Mediated Rejection:
a) Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days.
b) T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
4. Antibody-Mediated Rejection:
a) Antibody- mediated rejection treatments are directed at:
· removing antibody-producing B cells or plasma cells.
· removing antibodies (DSA).
· inhibiting the subsequent complement-regulated graft damage.
b) Standard of care for AMR(“standard” treatment regimens): plasma exchange and intravenous Ig (IVIG), with or without rituximab, was the most commonly used strategy.
· A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
· Lefaucheur et al. randomized 24 patients with antibody-mediated rejection to receive either monotherapy with IVIG at 2 gm/kg every 3 weeks(four doses) or a more intensive regimen consisting of plasma exchange, IVIG, and two doses of rituximab.Patients receiving more intensive therapy experienced greater reduction in DSA with 92% graft survival at 3 years compared with 50% in those receiving IVIG alone.
· Sautenet et al. (34) attempted to clarify the utility of rituximab in combination with standard plasma exchange/IVIG therapy with the multicenter, blinded, randomized, placebo-controlled “Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Trans- plantation” (RITUX-ERAH) trial. There was no difference in the composite primary outcome of graft loss or improvement in graft function at day 12; however, a large crossover between groups limits accurate interpretation of these data.
5. Alternative agents for AMR refractory to “standard” treatment regimens:
· Bortezomib, an approved proteasome inhibitor for treatment of multiple myeloma; there is minimal effect on DSA burden when used as a sole agent , with mixed results when used in combination with plasma exchange/IVIG.
· Eculizumab, the humanized mAb (C5 inhibitor) has been targeted in the prevention and treatment of antibody-mediated injury.
· Tocilizumab, anti-IL-6 receptor antibody has shown promising results for patients with chronic antibody-mediated rejection. (43), a disease for which there is currently no proven treatment; however, this agent has not been studied in the treatment of acute AMR.
· C1-esterase inhibitors (C1-INH) have recently been studied in two small studies for the treatment of acute AMR. C1-INH inhibits proximal enzymes in the classic complement pathway including C1q, and reports of poor outcomes after detection of C1q-binding DSA provide further rational for its use in AMR.
6. Subclinical Rejection:
a) to identify and treat alloimmune responses before the onset of clinical graft dysfunction, this approach involves:
· Protocol biopsy of stable grafts.
· Screening biomarkers such as DSA.
b) The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low, and long- term outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection.
· In 121 patients treated with tacrolimus, mycophenolate mofetil, and prednisone and randomized to protocol versus indication-only biopsies, the incidence of subclinical T cell–mediated rejection was only 5%, with no difference in graft function at 6 months despite those with subclinical rejection receiving treatment.
c) Subclinical antibody-mediated rejection, in contrast, represents an attractive therapeutic target given the attributed poor long-term outcomes, likely via progression to chronic antibody-mediated rejection over time.
· Using DSA as a biomarker, studies have shown approximately 50% of patients with stable function and de novo DSA will show evidence of subclinical antibody-mediated rejection on biopsy.
· Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection, few data exist to suggest treatment intervention will alter the clinical course.
· Orandi et al. published a retrospective analysis of 77 patients with subclinical antibody- mediated rejection diagnosed by protocol biopsy, 54% of which received treatment with various combinations of plasma exchange, IVIG, rituximab, and eculizumab. With a mean follow-up of 5.2 years, overall rates of graft loss were similar between those treated and untreated. However, when compared with matched controls, treated patients experienced a lower risk of graft loss versus untreated patients. Thus, although the prospect of identifying subclinical antibody-mediated rejection before clinical dysfunction remains attractive, more data are needed before concluding that treatment of this population will improve the long-term clinical course. What is the level of evidence provided by this article?
This is a narrative review article
Level of evidence grade 5
Ghalia sawaf
2 years ago
Evolution of immunosuppressive agents
Over time AR rates have steadily declined from nearly 100% in the first era of organ transplantation to approximately 10% more recently
With dramatic improvements in 1-year graft survival, especially after the introduction of cyclosporine in the mid-1980s and T cell–depleting induction in the mid-1990s
the classification of clinical AR
“steroid responsive” and “steroid nonresponsive,”
now either “T cell mediated” or “antibody mediated,”
Acute Rejection Risk
• level of anti-HLA sensitization (PRA),
• repeat transplant,
• black race,
• recipient age.
• pretransplant (DSA) / AMR /
• HLA A/B/DR mismatch / T cell–mediated rejection
• Patient with pretransplant DSA at titers strong enough to warrant desensitization before transplant will experience acute AMR, whereas lower-level antibodies do not appear to increase AR risk or graft survival
In the post-transplant period,
AR risk is largely determined by immunosuppression regimen
Currently in the United States, 90% receive tacrolimus and mycophenolate mofetil, with or without prednisone
Strategies to reduce (CNI) exposure using (mTOR’s) have generally been met with higher rates of AR
CNI free immunosuppression with the newer agent belatacept
Belaracept
has resulted in favorable, longer-term outcomes
but with higher rates of T cell–mediated rejection
significant reduction in DSA development in those receiving belatacept versus cyclosporine (1%–4% versus 12%,respectively)
Adamseta et al. study ; (AR rates of 51% with belatacept alone versus 16% with belatacept plus tacrolimus taper).
A high index of suspicion of AR , would be warranted in
• a young patient
• with lower tacrolimus trough levels
• during the first post-transplant year
• and/or suspected immunosuppression non-adherence.
Nonimmunologic causes may first be considered AR
• older patient
• who received rATG induction
• with consistently therapeutic tacrolimus level
Acute Rejection Diagnosis
1—- The gold standard for diagnosing is tissue biopsy.
Indications of graft biopsy
• acute, otherwise unexplained deterioration in graft function
• or the presence of a biomarker consistent with AR
Allograft histology is interpreted using the Banff classification of kidney allograft pathology
T cell–mediated rejection diagnostic criteria
has undergone little change in recent years,
include lymphocytic infiltrate of tubules (tubulitis)
and larger vessels (vasculitis),
with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field.
Banff classification of acute AMR
AMR required three features for diagnosis:
(1) active tissue injury,
(2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition, and
(3) circulating DSA.
EXceptions to these initial criteria, C4d -negative AMR .
2013 Banff criteria for AMR diagnosis removed the requirement for C4d detection and broadened this category to include
either
(1) positive C4d staining,
(2) at least moderate microvascular inflammation,
or (3) increased expression of endothelial gene transcripts
The most recent Banff consensus now removed the requirement for documented circulating DSA in the setting of positive C4d staining and microvascular inflammation
2—- urine and blood biomarkers,
such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have generally shown mixed sensitivity and specificity for identifying AR, differentiating T cell–mediated rejection from AMR
Decreased urinary miR-210 levels have been associated with T cell–mediated rejection
Recently, donor-derived cell free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of AMR.
This study associated cf-DNA levels with 242 biopsy specimens (204 clinically indicated) and showed a negative predictive value for antibody-mediated rejection of 96% when using a cut-off value of 1% in recipient blood; however, positive predictive value was only 44%
T Cell–Mediated Rejection treatment
pulse methylprednisolone at 250–500 mg daily for 3–5days,as recommended by international guidelines
Treatment is ultimately guided by biopsy findings, Banff class 1 lesions
responding to methylprednisolone alone.
(Banff II and III lesions)
generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection treatments
directed at removing antibody-producing B cells or plasma cells, removing antibodies (DSA),
and/or inhibiting the subsequent complement-regulated graft damage
A systematic review by Roberts et al. identified 12 comparative trials of AMR treatment from 1950 to 2011
The authors report low-quality evidence supporting antibody removal therapies (plasma exchange ), and very low-quality evidence for all other treatments.!!!
Nevertheless, plasma exchange and intravenous Ig (IVIG), with or without rituximab, was the most commonly used strategy and is generally considered standard of care for AMR.
Plasma exchange
daily or every other day plasma exchange consisting of 1.5 plasma volume
IVIG
100–200 mg/kg,
with or without Rituximab
a single dose at 3.75 mg/m2.
Patients receiving more intensive therapy experienced greater reduction in DSA with 92% graft survival at 3 years compared with 50% in those receiving IVIG alone.
alternative agents for AMR refractory to “standard” treatment regimens.
Bortezomib,
FDA approved for treatment of MM,
induce apoptosis in antibody-producing plasma cells;
minimal effect on DSA burden when used as a sole agent,
mixed results when used in combination with plasma exchange/IVIG.
eculizumab
With combination splenectomy
this aggressive regimen is with high rates of infection (UTI, bacteremia/sepsis, pneumonia) in those undergoing combination therapy
A pilot study of the anti-IL
tocilizumab has shown promising results for patients with chronic AMR
(C1-INH)
have recently been studied for the treatment of AMR.
poor outcomes after detection of C1q-binding DSA
Subclinical Rejection
protocol biopsy of stable grafts
or the use of screening biomarkers such as DSA
In 121 patients treated with tacrolimus, mycophenolate mofetil, and prednisone and randomized to protocol versus indication-only biopsies, the incidence of subclinical Tcell–mediated rejection was only 5%, with no difference in graft function at 6 months
Although the prospect of identifying subclinical AMR before clinical dysfunction remains attractive, more data are needed before concluding that treatment of this population will improve the long-term clinical course.
Level V
Hussein Bagha baghahussein@yahoo.com
2 years ago
Introduction
Graft rejection remains an important cause of graft dysfunction despite improvements in immunosuppressive therapy regimens. It is important to understand the mechanisms underlying graft rejection. Acute rejection significantly affects graft survival and should be high on the list of differential diagnosis for unexplained graft dysfunction in a transplant recipient.
Acute rejection can be broadly classified as either T cell mediated or antibody mediated. These forms result from separate mechanistic pathways and are associated with unique histologic findings and prognoses, and therefore require different approaches to management. Acute rejection risk
The immunologic risk of rejection at the time of transplant can be due to overall level of anti-HLA sensitization, repeat transplant, black race and recipient age. HLA A/B/DR mismatch has been shown to be the main predictor of T-cell mediated rejection and donor-specific antibodies (DSA) has been shown to be the main predictor of antibody-mediated rejection. In the post-transplant period, the risk of acute rejection also depends on the immunosuppression regimen and exposure. Acute rejection diagnosis
The gold standard for diagnosis acute rejection in kidney transplant recipients is tissue biopsy. The indications to biopsy are acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection. The assessment of the patient’s immunologic risk at the time of and after the transplant can help further determine the possibility of acute rejection. Allograft biopsy is generally considered a safe procedure and should be pursued without delay in patients with graft dysfunction not explained by other non-immunologic causes. Allograft histology is interpreted using the Banff classification of kidney allograft pathology.
The diagnostic criteria for T-cell mediated rejection include lymphocytic infiltrates of tubules and larger vessels. Antibody-mediated rejection requires three features for diagnosis: active tissue injury, immunohistologic evidence current or recent antibody interaction with vascular endothelium and circulatory DSA. Acute rejection treatment
The approach to treatment depends on the accurate diagnosis and classification of immunologic pathology. Graft prognosis depends on the severity and type of lesions.
For T-cell mediated rejection, initial treatment includes pulse methylprednisolone at 500mg daily for 3-5 days. For T-cell mediated rejection involving lymphocytic infiltrate vasculature, rATG is needed at 1.5 mg/kg for five to seven doses.
For antibody-mediated rejection, treatment is targeted at removing antibody-producing B cells or plasma cells, removing DSA or inhibiting the subsequent complement-regulated graft damage. Plasma exchange and intravenous Ig (at 100-200mg/kg), with or without rituximab is most commonly used.
Humanized mAb eculizumab is used in the treatment and prevention of antibody-mediated rejection as inhibits C5. But it has high rates of infection in patients undergoing combination therapy. Subclinical rejection
This approach involves the identification and treatment of alloimmune responses before the onset of clinical graft dysfunction by protocol biopsy of stable grafts or the use of screening biomarkers such as DSA, to identify patients at risk for subclinical T-cell mediated rejection.
More data is required before concluding that this approach will improve the long-term clinical course. Conclusion
It is crucial to identify early signs of acute rejection to initiate treatment. When feasible, kidney biopsy aids in targeted treatment for better rates of graft survival. In situations where kidney biopsy is not feasible and infections have been ruled out, empiric therapy with pulse methylprednisolone can be used while awaiting for DSAs. If the graft function does not resolve, then one can use ATG (if DSAs are negative) or plasma exchange (if DSAs are positive)
Level of evidence
This is a systemic review, therefore the level of evidence is V
Abdul Rahim Khan
2 years ago
Please summarise this article Acute rejection has negative effect on graft outcomes. Over the period of time the incidence is decreasing . This can be multifactorial and one of the factor is newer immune suppressive therapies and our understanding of immune response. Risk Factors for Acute Rejection Pre transplant DSA levels HLA Mismatch Repeated transplant Blood transfusions High PRA Diagnosis of Acute Rejection Gold standard is biopsy Indications of biopsy include – unexplained deterioration in graft function Presence of a biomarker consistent with acute rejection Interpretation is done using Banff Classification The diagnostic criteria for T cell–mediated rejection have been revised Acute T cell–mediated rejection (TCR) Ia .25% Interstitial inflammation with moderate tubulitis (t2) Ib .25% Interstitial inflammation with severe tubulitis (t3) IIa Mild-to-moderate intimal arteritis (v1) IIb Severe intimal arteritis (v2) III Transmural arteritis and/or fibrinoid necrosis For ABMR Acute antibody-mediated rejection (AMR): all three criteria below required Histologic evidence of tissue injury Evidence of current/recent antibody interaction with endothelium Serologic evidence of donor-specific antibodies (DSA) Treatment- TCMR- High doses of methylprednisolone rATG in Banff 2/3 ABMR- Options include- Plasmaphresis with IVIG with or without Rituximab other options include Boretizumib Eculizumib Tocilizumab C1 estrase inhibitors Conclusion Acute rejection episodes affect graft survival Prompt diagnosis and early treatment is mandatory. Biopsy should be performed in any patient with unexplained acute graft dysfunction Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition What is the level of evidence provided by this article? Level 5
Rihab Elidrisi
2 years ago
Acute rejection has long term adverse effect on the graft survival
· Should be on the top of list of differential diagnosis of acute graft dysfunction.
· cases with none adherence to therapy, early presentation post-transplant and not achieving target trough level of tacrolimus are at high risk of rejection.
· 1st step of management includes exclusion of none immunological causes as dehydration, prerenal injury, CNI toxicity and infections, then investigate rejection.
· Risk factors for rejection include:
o presence of HLA mismatch.
o pre-transplant DSA and its level.
o positive PRA.
o Previous transplantation and other sensitizing events as blood transfusion.
depend on Banff classification of the the kidney biopsy, after thorough assessment of recipient immunologic risk.
TCMR depends on the extent of involvement of interstitium and severity of tubular damage. Which is Stage 1a and 1b. Stage II describes the intimal arteritis involvement and Class III transmural inflammation.
ABMR:
Special revised criteria has been implemented with emphasis on evidences of endothelial inflammation secondary to interaction with systemic DSAs ,in the form of C4d staining which was substituted with evidence of endothelial inflammation or evidence of increased gene transcript of.
Treatment :
Depend on reversal of the rejection process , in TCMR with high doses of methylprednisolon.
For ABMR the approach is multiple with Plasma pheresis to remove the DSAs, Rituximab to abolish the B cell population responsive to the rejection stimulus. and IVIG to offset the immune system and replace the immunoglobulins. Furthermore , Bortezomib and Eculizumab might be implicated to salvage the allograft function.
Wael Jebur
2 years ago
Acute allograft rejection is the main complication encountered in the short term period post transplantation as well as the on the long run. It might harbor a detrimental consequences on the allograft survival.
Immunological risk factors includes:
!}PRA which reflect the entire HLA sensitization.
2} Repeat transplant.
3} black race
4} recipient age, young is more vulnerable then elderly people .
While pre transplant DSA level is the main anticipant for ABMR , HLA A, B DR mismatching are the main determinant of ACMR. Furthermore , the DSAs type is crucial in provoking the ABMR. An elevated DSAs level that is pertinent for desensitization protocol is potentially prone for ABMR post sensitization in 30-50% of the desensitized patients.
The immunosuppressive protocol is playing a pivotal role in preventing the rejection risk. The current protocol is based on rTAG for induction and Tacrolimus dependent maintenance protocol.
Protocols to reduce CNI toxicity involved using mTORs with lower dose of CNI was adopted , with higher incidence of acute rejection and side effects.
CNI free protocol featuring Belatacept as the main immunosuppressant is associated with improved long term outcome , however , with escalated risk of TCMR to affect 50% of the patients on Belatacept..
Interestingly, despite the fact that TCMR was commonly encountered in this protocol , ABMR incidence was significantly less reported and the DSAs level was crucially less than counterparts control cohort.
This soaring incidence of TCMR was curtailed by adding CNI to the regimen , resulting in reducing the incidence to 16% from 50% .
Tacrolimus trough level was allegedly linked to the risk of TCMR and development of de novo DSAs , Therefore Trough level below 8 was reported to cast higher risk than those above 8 ng/ml.
Acute rejection diagnosis:
Depend on Banff classification of the the kidney biopsy, after thorough assessment of recipient immunologic risk.
TCMR depends on the extent of involvement of interstitium and severity of tubular damage. Which is Stage 1a and 1b. Stage II describes the intimal arteritis involvement and Class III transmural inflammation.
ABMR:
Special revised criteria has been implemented with emphasis on evidences of endothelial inflammation secondary to interaction with systemic DSAs ,in the form of C4d staining which was substituted with evidence of endothelial inflammation or evidence of increased gene transcript of.
Treatment :
Depend on reversal of the rejection process , in TCMR with high doses of methylprednisolon.
For ABMR the approach is multiple with Plasma pheresis to remove the DSAs, Rituximab to abolish the B cell population responsive to the rejection stimulus. and IVIG to offset the immune system and replace the immunoglobulins. Furthermore , Bortezomib and Eculizumab might be implicated to salvage the allograft function.
· Acute rejection has long term adverse effect on the graft survival
· Should be on the top of list of differential diagnosis of acute graft dysfunction.
· cases with none adherence to therapy, early presentation post-transplant and not achieving target trough level of tacrolimus are at high risk of rejection.
· 1st step of management includes exclusion of none immunological causes as dehydration, prerenal injury, CNI toxicity and infections, then investigate rejection.
· Risk factors for rejection include:
o presence of HLA mismatch.
o pre-transplant DSA and its level.
o positive PRA.
o Previous transplantation and other sensitizing events as blood transfusion.
· Graft biopsy is the golden standard for diagnosis. Banff classification developed in 1990 and updated regularly.
· TCMR has recently included tubulitis and vasculitis.
· ABMR is diagnosed based on histological evidence of tissue damage in addition to evidence of C4D (complement activated and covalent bonding with peritubular capillaries) or circulating antibodies (DSA).
· Currently, at least moderate microvascular inflammation, or increased expression of endothelial gene transcripts can be used as an evidence of ABMR in c4d negative cases.
· New biomarkers as urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand can be utilized to avoid unnecessary biopsy and for early detection and diagnosis of rejection.
o Decreased urinary micro RNA levels have been associated with T cell–mediated rejection
o Donor-derived cell free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of antibody-mediated rejection
· Pulse steroids is the most common used drug and reverse graft dysfunction in most of cases.
· Additionally, rabbit ATG can be used for steroid refractory TCMR or Banff stage starting from II b, and IVIG and PEX can be used in ABMR.
· Bortezomib (plasma cells apoptosis) and Ecluzimab (terminal complement inhibition) can be considered in resistant ABMR.
· Nowadays, most of cases receive induction therapy then tacrolimus based triple maintenance immunosuppressive therapy with marked decline in the incidence of acute rejection.
I like your summary and analysis. I agree it is level 5 evidence. Ajay
Hadeel Badawi
2 years ago
Acute rejection, when it occurs, has the potential to significantly affect graft survival. Advances in immunosuppressive therapy have drastically improved acute rejection rates to approximately 10%, resulting in dramatic improvements in graft survival.
Acute rejection is now broadly characterized as:
-T cell-mediated rejection.
-Antibody-mediated rejection.
Factors that increase the immunologic risk at the time of transplant:
– Overall level of anti-HLA sensitization (panel reactive antibody).
– DSA level predicts ABMR, and HLA A/B/DR mismatch predicts TCR.
– Repeat transplant.
– Black
– Race.
– Recipient age
In the post-transplant period, AR risk is determined mainly by IS regimen and exposure.
AR should remain high on the differential diagnosis for unexplained graft dysfunction in a KTR; assessment of overall immunologic risk can help estimate AR probability.
Acute Rejection Diagnosis: Tissue biopsy is the gold standard and should be done in patients with graft dysfunction that is not explained by other nonimmunologic causes.
Allograft histology is interpreted using the Banff classification, and diagnostic criteria are revised.
The diagnostic criteria for TCMR; lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis).
The diagnostic criteria of ABMR include; active tissue injury, evidence for C4d deposition, and circulating DSA.
Multiple non-invasive biomarkers (Urine and blood)mixed sensitivity and specificity Donor-derived cell-free DNA (cf-DNA) PPV for ABMR of 69% with a NPV of 100%, but did not discriminate those with TCMR
Acute Rejection Treatment
Graft prognosis after treated AR also depends on type and severity. Thus, timely recognition and diagnosis of AR is crucial to promptly initiate appropriate treatment.
Biopsy findings ultimately guide treatment.
T Cell-Mediated Rejection
methylprednisolone at 250–500 mg daily for 3–5 days
T cell–depleting therapy, rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection:
PLEX and intravenous Ig (IVIG), with or without rituximab, were the most commonly used
PLEX consisting of 1.5 plasma volume removal daily or EOD
Followed by IVIG at 100–200 mg/kg,
with or without a single dose of rituximab at 375 mg/m2.
Other agents:
Bortezomib induces apoptosis in antibody-producing plasma cells
Eculizumab has been targeted in the prevention and treatment of ABMR.
Tocilizumab anti-IL 6 antibodies; for chronic antibody-mediated rejection.
C1-esterase inhibitors (C1-INH)
Subclinical Rejection:
The identification and treatment before the onset of clinical graft dysfunction may minimize the development of chronic
lesions that ultimately lead to graft loss.
This includes protocol biopsy or screening with DSA of stable grafts to identify patients at risk for subclinical immunologic lesions.
The incidence of subclinical TCMR is low and does not appear to be as severely affecting the long-term graft outcome.
In contrast, subclinical ABMR is attributed to poor long-term outcomes.
Few data exist to suggest treatment intervention, and further clinical data are needed to determine if treatment will alter
clinical outcomes.
I like your summary and analysis. I agree it is level 5 evidence. Ajay
Reem Younis
2 years ago
Please summarise this article
-Transplantation of donor organs to non-HLA identical recipients introduces a stimulus for alloimmune responses, clinically referred to as graft rejection. Acute Rejection Risk
-An individual’s immunologic risk at the time of transplant has conventionally been attributed to factors such as overall level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black
race, and recipient age.
-In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure. Acute Rejection Diagnosis
-The gold standard for diagnosing acute rejection in kidney transplant recipients is allograft biopsy. Acute Rejection Treatment
-The approach to treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology.
-Treatment strategies differ between T cell–mediated rejection and
antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
-Graft prognosis after treated acute rejection depends on type and severity ; however, any untreated clinical acute rejection episode will ultimately result in accelerated graft loss. T Cell–Mediated Rejection
– Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days, as recommended by international guideline.
– T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses. Antibody-Mediated Rejection
-Antibody mediated rejection treatments are directed at removing
antibody-producing B cells or plasma cells, removingantibodies (DSA), and/or inhibiting the subsequentcomplement-regulated graft damage .
-Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes. What is the level of evidence provided by this article?
Level 5
I like your summary and analysis. I agree it is level 5 evidence. Ajay
Yashu Saini
2 years ago
Introduction
Acute rejection significantly affects graft survival and it should be kept on high index of suspicion when graft dysfunction occurs.
Acute rejection is broadly characterized in two categories:
T-cell mediated rejection
Antibody mediated rejection
This review has summarized risk assessment, diagnosis and treatment of acute rejection.
Acute rejection risk
Factors contributing to immunologic risk of recipient:
Anti HLA sensitization
Repeat transplant
Black race
Recipient age
Pre transplant DSA predicts AMR
HLA A/B/DR mismatch predicts ACR.
In post transplant period, acute rejection risk is also primarily determined by the immunosuppression regimen. Induction immunosuppression in majority of recipients in USA is rATG and maintenance immunosuppression includes triple drug therapy (Tacrolimus, MMF, steroids)
Acute rejection risk
GOLD STANDARD for diagnosing ACUTE REJECTION is graft biopsy. it should be performed if :
Acute unexplained deterioration of graft function
Presence of biomarker consistent with acute rejection.
Grading of acute rejection is done using BANFF CLASIFICATION OF KIDNEY ALLOGRAFT PATHOLOGY which is continuously evolving and most updated version is of year 2017. Diagnostic criteria
T cell mediated rejection – Lymphocyte infilterate of tubules and larger vessals
Antibody mediated rejection – Active tissue injury / Peritubular capillary C4d complement deposition / Presence of circulating DSA
2017 Banff classification updates:
# Phenotypes of AMR without detectable C4d staining
#Lack of DSA in patients whose graft biopsy shows microvascular inflammation Newer Diagnostic techniques for acute rejection
Urine and blood biomarkers
Short non coding single stranded micro RNA
Donor derived cell free DNA cfDNA
But still biopsy remains the gold standard for diagnosis of acute rejection
Acute rejection treatment
TCR – methylprednisolone and rATG depending on staging of TCR
AMR – Antibody removal (plasma exchange), immunoadsorption, monoclonal antibodies, IVIG
Several drug combinations have been studied to treat rejection. The most commonly followed is Plasma exchange + IVIG + rituximab for AMR and rATG for any TCR with grade > II.
Newer antirejection medications:
Bortezomib
Eculizumab
C1 estrase inhibitors
Conclusion
With newer immunosuppression medications acute rejection episodes have decreased significantly
Ideally tissue biospy should be done in every patient with unexplained acute kidney dysfunction
Banff classification of acute rejection is continuously evolving
Combination of DSA and C4d are no longer required to make diagnosis of rejection
Timely identification of subclinical rejection helps to intervene before onset of clinical dysfunction.
I like your summary and analysis. It is level 5 evidence. Ajay
Hussam Juda
2 years ago
INTRODUCTION
· Acute rejection classified as “T cell mediated” (previously steroid responsive) “antibody mediated” (steroid nonresponsive)
· This review will summarize a modern approach to risk assessment, diagnosis, and treatment of acute rejection.
Acute Rejection Risk
· pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch
· The use of rapamycin inhibitors (mTOR’s) to reduce CNI exposure have higher rates of acute rejection and side effects
· CNI free maintenance immunosuppression with belatacept has higher rates of T cell–mediated rejection
· Lower doses of Tacrolimus associated with higher risk of rejection
Acute Rejection Diagnosis
· The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy
· Banff classification of acute antibody mediated rejection required three features for diagnosis: (1) active tissue injury
(2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition
(3) circulating DSA
· the revised 2013 Banff criteria for antibody mediated rejection diagnosis removed the requirement for C4d detection, as it could be negative
· Recently, the requirement for documented circulating DSA in the setting of positive C4d staining and microvascular inflammation, had removed, as DSA can be negative
· Recently, donor-derived cellfree DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of antibody-mediated rejection, with high negative predictive value but positive predictive value was only 44%
Treatment of acute T Cell–Mediated Rejection
· Initial treatment pulse methylprednisolone at 250–500 mg daily for 3–5 days, guided by biopsy
· Banff class 1 lesions mostly respond to methylprednisolone alone
· Banff II and III lesions requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses
Treatment of acute Antibody-Mediated Rejection
· plasma exchange (daily or every other day) with 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2
Subclinical Rejection
· The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low, and longterm outcomes less severe than with subclinical antibody-mediated rejection
Conclusions
· Inspite of effective immunosuppressive protocols, acute rejection still occurs
· Tissue biopsy should be performed in any patient with unexplained acute graft dysfunction
· The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition
What is the level of evidence provided by this article?
Evidence 5
Summary
Introduction:
Before the use of immunosuppressive medications, graft rejection was significant. With the aid of scientific investigations and the development of new drugs that are immunosuppressive, the rejection or acute rejection of the graft has significantly reduced. There has been less acute rejection. With only about 10% of acute rejection as it relates to the immunosuppressive.
One of the main concerns is acute rejection which still is of major concern. It can be classified as either T CELL MEDIATED OR ANTIBODY MEDIATED.
This study is to identify the type of acute rejection and how it is managed.
To have acute graft rejection, there has been some form of risk factors and they are:
1) ANTI-HLA sensitization
2) Repeated graft transplantation
3) The black race and
4) The recipient’s age.
5) Post-transplant period the immunosuppression used
6) The lesser use of CNI IS RELATED WITH HIGHER REJECTION then using mTORi
7) With the introduction of newer medication, like belatacept has improved graft survival.
8) The use of other medications like tacrolimus has been a risk of acute graft rejection.
The diagnosis of acute rejection is totally dependent on kidney or graft biopsy. Using the Banff classification of kidney histology gives a concise idea of what type of rejection it is and as such the treatment of it. Apart from the kidney biopsy, other markers can be used but they are not as specific as the kidney or graft biopsy. For example, urine and blood markers like CXCL9, CXCL 10 perforin, etc., can be used but not as specific as the biopsy.
Once the biopsy has been performed it can classify acute rejection as:
1) T cell-mediated rejection
2) Antibody-mediated rejection.
T cell-mediated rejection two types of treatment can be used they are methylprednisone and the rATG.
In light of the antibody-mediated rejection, the medications that can be used are plasma exchange, IVIG, Bortezomib, eculizumab, tocilizumab, and C1 esterase inhibitors.
In conclusion, acute rejection is still a very important issue, especially if not detected on time. Once detected early with kidney biopsy and using Banff classification appropriate treatment can be given to allow the graft to function normally and to minimize rejection.
# The aim of the study:
To administer the caring for transplant recipients with an approach to immunologic risk evaluation and give a summary of new advances in the diagnosis and treatment of acute graft rejection.
# Introduction
*With time the immunosuppressant agents have become importantly inhibiting the transplant recipient’s immune response, as a result, the incidence of AR have steadily decreased from nearly 100% to10%.
*After the introduction of cyclosporine and T cell–depleting there is dramatic improvements in 1-year graft survival,
# Acute Rejection Risk:
* Wehmeier et al. recently conducted that pre-transplant (DSA) and HLA A/B/DR mismatch to be the main predictors of ABMR and TCMR respectively.
*The RA and repeat transplantation had no predictive effect.
* Around 30%–50% of pre-transplant DSA at titers strong enough to warrant desensitization before transplant will experience acute AMR whereas lower-level antibodies do not appear to increase AR risk or graft survival in the intermediate term.
*Post-transplant period, AR risk is determined by immunosuppression regimen -and exposure, recipients who received (rATG) induction, tacrolimus and mycophenolate mofetil, with or without prednisone, have lower rates of AR.
*Protocols used to decrease the (CNI) exposure by using (mTOR’s) associated with higher rates AR and S/E.
*CNI maintenance immunosuppression with the belatacept has lead to acceptable longer-term outcomes but with increase incidence of TCMR, but post hoc analysis has shown a n important reduction in DSA development in those receiving belatacept versus cyclosporine
* Adams et al. showed significant reduction in AR in patients have additional tacrolimus to the existing belatacept regimen followed by a steady taper over the first PKT year.
*Non-immunologic causes may first be considered in an older patient who received rATG induction with consistently therapeutic tacrolimus levels.
# Acute Rejection Diagnosis
*The gold standard for diagnosing AR in KT recipients is tissue biopsy.
*Indications
*AR include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with AR.
*Allograft biopsy is a safe procedure and should be pursued without delay in patients with graft dysfunction that is not explained by other non-immunologic
causes.
*Using the histologic criteria for diagnosing acute allograft rejection according to Banff 2017 guidelines for interpretation. *Acute T cell–mediated rejection (TCR) Ia .25% Interstitial inflammation with moderate tubulitis (t2) Ib .25% Interstitial inflammation with severe tubulitis (t3) IIa Mild-to-moderate intimal arteritis (v1) IIb Severe intimal arteritis (v2) III Transmural arteritis and/or fibrinoid necrosis
#Acute antibody-mediated rejection (AMR):
All three criteria below required Histologic evidence of tissue injury including one or more of the following:
*Microvascular inflammation (g.0 and/or ptc.0)
*Arteritis (v.0)
*Thrombotic microangiopathy
*Acute tubular injury Evidence of current/recent antibody interaction with endothelium including one or more of the following:
*Positive C4d staining of peritubular capillaries
*Moderate microvascular inflammation (g+ptc >/2)
*Increased expression of gene transcripts in biopsy tissue strongly associated with AMR Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA.
# Acute Rejection Treatment
*It is relies on accurate diagnosis and classification of the immunologic pathology.
* Treatment strategies differ between TCMR and ABMR, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
* The treatment options include: Methylprednisolone
* Indication: in TCR: Banff Ia, Ib
*Mechanism: it has multiple, anti-inflammatory glucocorticoids effects
*Adverse Effects: Hyperglycemia, hypertension, other metabolic effects
# T Cell–Mediated Rejection
*The initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days, as recommended by international guidelines *Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylprednisolone alone.
*The Banff II and III lesions requires T cell–depleting therapy, rATG dosed at 1.5 mg/kg for five to seven doses.
*An updated Cochrane Database review published in 2017 concluded antibody therapy was superior to steroid therapy in reversing TCMR with no effect on subsequent acute rejection incidence or patient survival.
#Antibody-Mediated Rejection
*ABMR treatments are directed at removing antibody-producing B cells or plasma cells, removing (DSA), and/or inhibiting the subsequent complement-regulated graft damage.
* (PE) and (IVIG), with or without rituximab, was the most commonly used
strategy and is generally considered standard of care for ABMR treatment.
* A typical regimen includes daily or every other day (AE) consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
* Patients receiving more intensive therapy experienced greater reduction in DSA with 92% graft survival at 3 years compared with 50% in those receiving IVIG alone.
*Study showed successful reduction in plasma cell infiltrate and stabilization of graft function after treatment with bortezomib in several patients with plasma cell-rich AR, a rare histologic finding historically associated with poor outcomes despite aggressive treatment.
*Eculizumab has been targeted in the prevention and treatment of antibody-mediated injury because of its mechanism of complement component C5 inhibition.
# Subclinical Rejection
*The use of protocol biopsy of or screening biomarkers such as DSA may detect the risk of subclinical immunologic rejection.
*The rate of subclinical T CMR in the modern era of immunosuppression is low and long term outcomes do not severely affected compared to subclinical ABMR.
# What is the level of evidence provided by this article?
*Level 5
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc >2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies:
Positive C4d staining or the presence of AMR-associated gene transcripts may substitute for DSA.
Recently, donor-derived cell-free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of antibody-mediated rejection. It is found to have a negative predictive value for rejection, thus normal results may offer a level of reassurance to providers and patients with abnormal clinical findings (DSA, graft dysfunction) in whom tissue biopsy is either not feasible or considered too high risk.
Acute Rejection Treatment
The approach to the treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology.
Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows the severity of lesions that are diagnosed.
Graft prognosis after treated acute rejection also depends on type and severity.
timely recognition and diagnosis of acute rejection is crucial to promptly initiate appropriate treatment.
T Cell–Mediated Rejection
Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days, as recommended by international guidelines.
Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylprednisolone alone.
T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection
treatments are directed at removing antibody-producing B cells or plasma cells, removing antibodies, and/or inhibiting the subsequent complement-regulated graft damage.
plasma exchange and intravenous Ig (IVIG), with or without rituximab, is the most commonly used strategy and is generally considered the standard of care for antibody-mediated rejection treatment.
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
Studies showed that a treatment regimen consisting only of IVIG is inadequate for most cases of acute antibody-mediated rejection.
In the RITUX-ERAH trial, There was no difference in the composite primary outcome of graft loss or improvement in graft function at day 12.
Bortezomib has received special focus because of its ability to induce apoptosis in antibody-producing plasma cells; however, it has a minimal effect on DSA burden when used as a sole agent.
eculizumab has been targeted in the prevention and treatment of antibody-mediated injury because of its mechanism of complement component C5 inhibition.
A pilot study of the anti-IL6 receptor antibody (tocilizumab) has shown promising results for patients with chronic antibody-mediated rejection.
C1-esterase inhibitors (C1-INH) have recently been studied in two small studies for the treatment of acute antibody-mediated rejection; there was no difference in the primary endpoint of graft loss or histology at 20 days; however, out of 14 patients with biopsies at 6 months, three of seven patients receiving placebo versus zero of seven patients receiving C1-INH showed transplant glomerulopathy.
Subclinical Rejection
The identification and treatment of alloimmune responses before the onset of clinical graft dysfunction y minimize the development of chronic lesions that ultimately lead to graft loss.
Protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions.
Subclinical antibody-mediated rejection, in contrast, represents an attractive therapeutic target given the attributed poor long-term outcomes, likely via progression to chronic antibody-mediated rejection over time.
Approximately 50% of patients with stable function and de novo DSA will show evidence of subclinical antibody-mediated rejection on biopsy.
Few data exist to suggest treatment intervention will alter the clinical course of subclinical ABMR.
Although the prospect of identifying subclinical antibody-mediated rejection before clinical dysfunction remains attractive, more data are needed before concluding that treatment of this population will improve the long-term clinical course.
I like your summary and analysis. I agree it is level 5 evidence.
Ajay
Mohammad Alshaikh
2 years ago
Please summarise this article Introduction: Acute rejection should be highly suspected when unexplained graft dysfunction ensue. The acute rejection has been decreasing significantly after introduction of cyclosporine in 1980’s, and after the T-cell depleting inductionin 1990’s. The acute rejection is more due to HLA mismatch that alleviate alloimmune response. Acute rejection risk: Pre-transplantation HLA A/B/DR mismatch, and donor specific antibodies are the best predictor of acute cellular and antibody mediated rejection, respectively. Panel reactive antibody (PRA), and repeat transplantations are no more a predictor for rejection. The risk of rejection decreased after the trend for induction therapy (rATG, basilixumab) and the use of tacrolimus. Acute rejection diagnosis: The gold standard for diagnosing acute rejection is tissue biopsy. T cell mediated rejection include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vascu[1]litis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field. Anti body mediated rejection required three features for diagnosis: (1) active tissue injury, (2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition, and (3) circulating DSA , (4) at least moderate microvascular inflammation, or (5) increased expression of endothelial gene transcripts. However C4d positive in only 40% of ABMR, DSA and endothelial transcript expression peers poor prognosis.
Acute rejection treatment: T-cell mediated: stages Ia,Ib treated with IV methylprednisolone 250-500 mg daily for 5 days, ATG at a dose of 1.5mg/kg daily, for 5-7 days reserved for severe graft dysfunction Stage II and III treated with IV methylprednisolone (3-5 days+ ATG 5-7 days)
Antibody mediated rejection: Treated with plasma exchange every other day with IVIG 100-200 mg/kg after each session +/-Rituximab. Bortezomib, Ecluzumab, Tosilizumab, all have been studied in small case series with proven benefit, but not superior to main protocol and can be considered add on. C1-esterase inhibitors (C1-INH) inhibits proximal enzymes in the classic complement pathway including C1q, and reports of poor outcomes after detection of C1q-binding DSA. Is a promising treatment choice under evaluation in large randomized trials.
Subclinical rejection: Protocol biopsy and DSA are used to identify patients at increased risk of subclinical rejection, the incidence of T-cell subclinical rejection is rare, and subclinical ABMR is 5%, severely affect long term graft outcomes.
Conclusion: Acute cellular or anti-body mediated rejection are the important treatable issues in differential diagnosis of any graft dysfunction after exclusion of anatomical, fluid collections, infections and drug toxicity issues, physicians should be familiar with the biomarkers used to diagnose and treat rejection. Cellular rejection treated with IV Methylprednisolone 250-500 mg x1 for 3-5 days, in severe cases ATG used for 5-7 days. ABMR treated with Plasma exchange +IVIG+/- Rituximab. Identifying subclinical antibody-mediated rejec[1]tion provides an opportunity to intervene before the onset of clinical dysfunction.
What is the level of evidence provided by this article? Level of evidence V
I like your summary and analysis. I agree it is level 5 evidence. Ajay
abosaeed mohamed
2 years ago
Acute rejection should be high on the list of differential diagnosis of unexplained graft dysfunction .
This review summarize an approach to risk assessment, diagnosis, and treatment of acute rejection. Wehmeier et al. recently examined traditional risk factors in 527 kidney recipients, showing pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation had no predictive effect. The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy , recommended in acute unexplained deterioration in graft function .
Histologic criteria for diagnosing acute allograft rejection according to Banff 2017 guidelines :
>>Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
>>Acute antibody-mediated rejection (AMR): all three criteria below required
– Histologic evidence of tissue injury including one or more of the following:
Microvascular inflammation (g.0 and/or ptc.0)
Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
– Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc $2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
– Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
>>algorithm for Treatment options : summarized in picture
I like your summary and analysis. I agree it is level 5 evidence. Ajay
Huda Mazloum
2 years ago
● A cute rejection rate is 10%
● factors risk for acute rejection
** panel reactive antibody
** repeat transplant
** black race
** recipient age
● 30%–50% of patients with pretransplant DSA with high level will experience AMR
● Strategies to reduce (CNI) exposure
** (mTOR’s) higher rates of acute rejection and side effects
** belatacept has resulted in favorable, longer-term outcomes but with higher rates of T cell–mediated rejection
● Non-immunologic causes may first be considered in an older patient who received rATG induction with consistently therapeutic tacrolimus levels.
● Biopsy is the gold standard for diagnosing acute rejection in kidney transplant recipients
● Allograft histology is interpreted using the Banff classification of kidney allograft pathology
● Antibody-mediated rejection required three features for diagnosis:
(1) active tissue injury
(2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition
(3) circulating DSA.
● urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand,Short non-coding single stranded microRNA have improved stability
in urine compared with mRNA
● decreased urinary miR-210 levels have been associated with T cell–mediated
rejection and subsequent 1-year GFR decline
● cf-DNA profiling has been applied to the noninvasive diagnosis of antibody mediated rejection
● Acute T Cell–Mediated Rejection treatment includes :
** pulse methylprednisolone at 250–500 mg daily for 3–5 days (Banff I ) lesions
** rATG dosed at 1.5 mg/kg for five to seven doses (Banff II and III ) lesions
● Antibody-Mediated Rejection treatment
** plasma exchange
** intravenous Ig (IVIG)
** with or without rituximab
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
● Level : 5
Hi Dr Huda, I like your summary and analysis. I agree it is level 5 evidence. Your headings and sub-headings should be in bold or underline. That will make it easy to read. Ajay
In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure.
Currently in the United States, 75% of kidney recipients receive rabbit antithymocyte globulin (rATG) induction and 90% receive maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, as these regimens have historically
been associated with lower rates of acute rejection
Acute Rejection Diagnosis
tissue biopsy is the gold standered
with Allograft histology is interpreted using the Banff classification of kidney allograft pathology
The diagnostic criteria for T cell–mediated rejection include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis)
with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field
Ia >25% Interstitial inflammation with moderate tubulitis (t2)
In >25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
Acute antibody-mediated rejection (AMR):
all three criteria below required Histologic evidence of tissue injury including one or more of the following:
*Microvascular inflammation (g.0 and/or ptc.0)
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
*Positive C4d staining of peritubular capillaries
*Moderate microvascular inflammation (g1ptc $2)
*Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA)
*Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Acute Rejection Treatment
T Cell–Mediated Rejection
1-pulse methylprednisolone at 250–500 mg daily for 3–5 day
2- rATG for Banff II and III
Antibody-Mediated Rejection
– plasma exchange,
-intravenous Ig (IVIG)
– with or without rituximab
Subclinical Rejection screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions.
The incidence of subclinical T cell–mediated rejection in the
modern era of immunosuppression is low and longterm outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection which represents an attractive therapeutic target given the attributed poor long-term.
Hi Dr Esraa, I like your summary and analysis. Ajay
KAMAL ELGORASHI
2 years ago
Summary of the article; Introduction; With advancing immunosuppressant during the last decades, acute rejection incidence decline from nearly 100% at first transplants to as least as 10%. This is reflected on the 1 year survival rate, specially after introduction of Cyclosporine in the mid-1980s, and T-cell depleting agent at mid-1990s. Acute rejection risk factors;
PRA, anti HLA sensitization.
Repeat transplant.
Black race.
Recipient age.
Wehmeier et al.; show DSA, and HLA MM, are the main indicator of AMR, and TCR respectively, with no predictive effects of PRA and repeated Tx.
Post Tx, acute rejection, largely determined by immunosuppressant regiment, and exposure.
Currently in the US, 75% recipients receive ATG induction, and >90% receive maintenance IS consist of TAC/MMF, with or without prednisolone, with resultant reduce incidence of AR. Regiment use mTOR instead of CNI, to reduce CNI exposure associated with higher rate of AR and side effects. CNI free maintenance IS with Belatacept, associated with favourable long term outcome, but with higher rate of ACR. Adams et al.; showed significant reduction in AR with Belataceopt/TAC regiment, with the steady taper over first post-transplant year, (AR was 51% with belatacept alone vs 16% with Belatacept plus TAC taper). In cohort of 538 consecutive Tx recipients, based on TAC triple therapy, at the University of Colorado, mean TAC level < 8 ng/ml, throughout the 1st year, associated with increased DSA development, and the level of 4-6 vs >8 associated with 2-3 fold higher risk of AR. Acute Rejection diagnosis;
Kidney biopsy is the gold standard for diagnosing AR.
Other Indication include; unexplained kidney function deterioration, or presence of biomarkers consistent with AR.
Histologic criteria for diagnosing Acute Allograft Rejection, according to the Banff 2017 guidelines; @ Acute T cell-mediated rejection, (TCR); Ia ===== >25% interstitial inflammation with moderate tubulitis (t2). Ib ===== >25% interstitial inflammation with severe tubulitis (t3). IIa ==== mild to moderate intimal arteritis (v1). IIb ==== sever intimal arteritis (v2). III ==== transmural arteritis and/or fibrinoid necrosis. @Acute antibody-mediated rejection; all three criteria below required Histologic evidence of tissue injury including one or more of the following; Microvascular inflammation (g>0 and/or ptc>0). Arteritis (v>0). TMA ATI Evidence of current / recent antibody interaction with endothelium including one or more of the following; positive C4d staining of peritubular capillaries Moderate microvascular inflammation (g+ptc>/2) Increased expression of gene transcripts in biopsy tissue strongly ass with AMR Serolgical evidence of donor-specific antibodies (DSA) Positive C4d staining or presence of AMR-ass gene transcripts may substitute for DSA. Acute rejection treatment;
Methylprednisolone, Indication (TCR; Banff Ia, Ib), Mechanisms (multiple, anti-inflammatory glucocortcoid), Side effect; (Hyperglycemia, HTN, Other metabolic effect)
Hi Dr Kamal, I like your summary and analysis. I agree it is level 5 evidence. Ajay
doaa elwasly
2 years ago
Introduction
Graft rejection rate dropped to 10% due to the evolution in immunosuppressive therapies.
Acute rejection is divided into T cell mediated and antibody mediated rejection ,each with a different mechanism . Acute Rejection Risk
Immunological risk for acute rejection at transplantation timeare multiple as HLA mismatch as the main risk , recipient’s age , PRA , anti HLA sensitization, number of transplants.
In the post transplant period ,the main factors include immunosuppressive regimen mostly in the form of induction with r ATG and maintenance with MMF ,Tac with or without steroidsand exposure.
Post hoc analysis revealed much reduction of DSA levels in those using belatacept than those used cyclosporine.
Another study published decreased rejection risk with the use of belatacept along with Tac rather than using belatacept on it’s own.
Meanwhile a cohort study stated that tacrolimus level <8ng/ml were accompanied with high DSA levels thereby graft rejection . Acute rejection diagnosis
This is done by renal biopsy that is necessary when there is deterioration of graft function or with a biomarker of rejection notified.
Banff criteria classifies the graft histopathology for antibody mediated rejection, initially including
· active tissue injury
· Peritubular capillary complement split-product C4d deposition
· circulating DSA.
But this old criteria lead to missing antibody mediated rejection cases , therefore latter revisions in 2013 the updated criteria introduced changes on the criteria to include C4d staining negative antibody-mediated rejection phenotype.
T cell–mediated rejection criteria were changed involving tubulitis and vasculitis.
Tissue biopsy remains the gold standard for diagnosis but it is liable to sampling error and variable interpretation.
Urine and blood biomarkers have variable sensitivity and specificity.
The low urinary levels of miR-210 have been associated with T cell–mediated rejection and 1-year GFR decline.
Donor-derived cell free DNA (cf-DNA) profiling has been associated with antibody-mediated rejection.
Those non invasive markers are non conclusive, rendering the biopsy still the golden standard . Acute rejection treatment
Treatment strategy depends upon the type and severity of the rejection which would affect the graft prognosis. T cell mediated rejection
Initial treatment is pulse methylprednisolone at 250–500 mg daily for 3–5 days, having good response for Banff class I.
Tcell depleting agents as r ATG for 5-7 doses can be needed for Banff class II and III lesions. Antibody mediated rejection
Therapy is directed at removingantibody-producing B cells or plasma cells, DSA and complement mediated graft damage .
The standard treatment involves plasma exchange and intravenous Ig (IVIG), with or without rituximab.
Studies tested other therapies for rejection refractory to the original regimen involving Bortezomib due to it’s inhibitory effect ob Ab producing plasma cells with minimal effect on DSA level when used on it’s own , the results were variable when used with plasma exchange and IVIG .
A recent study demonstrated graft function stabilisation in plasma cell-rich acute rejection with bortezomib usage.
Humanized mAb eculizumab as C5 inhibitor was used for prevention and treatment of antibody-mediated injury.
Orandi et al published acceptable outcomes for cases with severe antibody-mediated rejection after desensitization for positive crossmatch kidney transplant treated with splenectomy and eculizumab together but on the other side this regimen carries a high risk of infection.
Another pilot study revealed promising results with Tocilizumab for patients with chronic antibody mediated rejection.
C1-esterase inhibitors (C1-INH) use had poor outcomes. Subclinical rejection
Protocol biopsy of stable grafts or biomarkers as DSA can help discovering patients at risk for subclinical immunologic lesions.
Identifying such cases can improve the outcomes , but more data are needed before concluding this. Conclusion
Immunosuppressive protocols decreased the rejection episodes and improved graft survival.
Banff criteria doesnot require DSA and C4 deposition to diagnose antibody mediated rejection.
Hi Dr Doaa, I like your summary and analysis. I agree it is level 5 evidence.
Ajay
Last edited 2 years ago by Ajay Kumar Sharma
Mohamad Habli
2 years ago
Conventionally, the immunologic risk of an individual at the time of transplant has been attributed to characteristics such as the individual’s overall immunologic risk (PRA, DSA, HLA mismatch), repeat transplant, black race, and recipient age.
Recent research has demonstrated that pretransplant DSA and HLA A/B/DR mismatch are the most accurate predictors of antibody-mediated rejection and T cell-mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation have no predictive value.
The degree of immunologic danger posed by pretransplant DSA will depend on the nature of the identified antibodies. 30%–50% of patients with pretransplant DSA titers high enough to require desensitization before transplant will experience ABMR, although lower-level antibodies do not appear to affect the risk of acute rejection or graft survival in the intermediate term.
Acute rejection risk is mostly determined by immunosuppressive regimen(induction and maintenance) and exposure.
Acute Rejection Syndrome:
1- Kidney biopsy remains the gold standard for diagnosing acute rejection in transplant recipients, and noninvasive biomarkers have been unable to fully replace tissue diagnosis.
2-Normal results from assays with a strong negative predictive value, such as ddcf-DNA, may provide reassurance to physicians and patients with aberrant clinical signs (DSA, graft malfunction) in whom a tissue biopsy deemed too risky.
Diagnosing rejection mediated by T cells:
The following are diagnostic criteria for T cell-mediated rejection:
1-lymphocytic tubulitis (infiltration of tubules by lymphocytes).
2-larger vessels (vasculitis)
The severity of these lesions is proportional to the amount of lymphocytic infiltration per magnified field.
The diagnosis of antibody-mediated rejection is based on the Banff classification.
-Antibody-mediated rejection was identified for the first time in the Banff categorization between the early and mid-2000s and needed the presence of three characteristics:
1) Histological evidence of active tissue injury
2) Immunohistochemical evidence of complement split-product C4d deposits in peritubular capillaries.
3) Circulating DSA.
-The revised 2013 Banff criteria for the diagnosis of antibody-mediated rejection removed the requirement for C4d detection and expanded this category to include “evidence of current/recent antibody interaction with vascular endothelium,” which may include either; (1) positive C4d staining; or (2) negative C4d staining.
(2) at least mild microvascular irritation.
(3) enhanced endothelial gene transcript expression.
-The most recent Banff consensus acknowledges studies demonstrating a lack of circulating DSA in patients with biopsy specimens demonstrating significant microvascular inflammation and a low false positive rate of C4d staining, and has now removed the requirement for documented circulating DSA in the presence of positive C4d staining and microvascular inflammation.
Blood biomarkers for acute rejection diagnosis:
Numerous studies of urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have demonstrated variable sensitivity and specificity for identifying acute rejection, distinguishing T cell–mediated rejection from antibody-mediated rejection, and differentiating immunologic injury from other forms of graft damage.
Treatment
The method to treating a transplant recipient with acute rejection is dependent on the immunological risk, risk of infection, hemodynamic stability, kidney function.
The treatment strategy for T cell–mediated rejection and antibody–mediated rejection are distinct, and the aggressiveness of treatment is often proportional to the severity of the identified lesions.
Graft prognosis following treated acute rejection depends on nature and severity; nonetheless, any untreated clinical episode of acute rejection will result in accelerated graft loss.
T cell mediated Rejection :Conventionally, the initial treatment consists of a pulse of methylprednisolone at 250–500 mg per day for 3–5 days, as indicated by worldwide recommendations.
Methylprednisolone is the treatment of choice for the majority of Tcell mediated rejection starting with Banff class 1 lesions.
Banff II and III lesions typically necessitate T cell–depleting therapy, most frequently rATG in addition to steroids and optimization of maintenance treatment doses and trough levels.
Antibody-Mediated Rejection: Treatments for antibody-mediated rejection involve eliminating antibody-producing B cells or plasma cells, removing circulating antibodies, and/or preventing the following complement-induced graft damage.
Plasma exchange and intravenous immunoglobulin with or without rituximab, was the most frequently utilized therapy and is considered the standard of care for treating antibody-mediated rejection. A common therapy involves daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment, followed by IVIG, with or without rituximab.
Subclinical Rejection Despite the danger of adverse outcomes associated with subclinical antibody-mediated rejection, there are few evidence suggesting that therapy intervention will affect the clinical course.
Hi Dr Habli,
I like your summary and analysis.
I agree it is level 5 evidence.
Your headings and sub-headings should be in bold or underline. That will make it easy to read.
Ajay
Amit Sharma
2 years ago
Please summarise this article.
Introduction of immunosuppressants like calcineurin inhibitors and T cell depleting induction agents have improved 1 year graft survival with reduction in rates of acute rejection to 10%. Acute rejection affects graft survival.
The risk factors for acute rejection include presence of pre-transplant donor specific antibodies (DSA) and HLA mismatches (for antibody mediated rejection – ABMR, and T cell mediated rejection – TCMR respectively). Panel reactive antibody, low level DSA, and repeat transplant has no predictive value for acute rejection risk. DSA requiring desensitization have 30-50% risk of ABMR.
Acute rejection in post-transplant period depends on the immunosuppression used, more rejections being seen with mTOR inhibitors use. Belatacept use has decreased DSA development, but increased TCMR (51%, which decreased to 16% when used with tacrolimus tapered over 1 year). DSA development and acute rejection increases in patient with lower tacrolimus drug levels.
Diagnosis of acute rejection: An unexplained graft dysfunction (after excluding causes like infection, drug toxicity, pre-renal causes, obstruction etc.) should be evaluated. Presence of DSA should be assessed and a kidney biopsy (the gold standard for diagnosing acute rejection – as per the Banff classification – either acute TCMR or acute ABMR) should be performed, if not contraindicated.
Acute TCMR: Class Ia, Ib, IIa, IIb, and III – on basis of degree of interstitial inflammation and tubulits, and arteritis.
Acute ABMR: On basis of histologic evidence of tissue injury, interaction between antibody and endothelium, and serological evidence of DSA.
Treatment of Acute rejection:
1) Acute TCMR:
a. Banff Ia (or Ib with mild graft dysfunction): Injection methylprednisolone 500 mg IV once a day for 3-5 days
b. Banff II, or III (or Ib with severe graft dysfunction): Injection rabbit antithymocyte globulin (rATG) 1.5 mg/kg/day x 5-7 days or until recovery.
2) Acute ABMR: 1.5 volume Plasma exchange daily or alternate day for 5 sessions with injection IVIG 100-200 mg/kg following each plasma exchange, and injection Rituximab 375 mg/m2 following last exchange.
3) Mixed rejection: Treatment of ABMR plus TCMR treatment as per Banff class.
Bortezomib has been used in plasma cell-rich acute rejection, and C1 esterase inhibitors have been used in acute ABMR treatment. Eculizumab has been used in patients with chronic ABMR.
Subclinical rejection: It has been identified using protocol biopsies sand biomarkers like DSA. Subclinical TCMR, even without treatment, has similar long-term graft outcomes. Subclinical ABMR has been shown to have poorer graft outcomes, but even after treating, the overall outcomes do not differ, although on comparing with matched controls, treatment has been shown to decrease risk of graft loss.
2. What is the level of evidence provided by this article?
Hi Dr Amit
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Sherif Yusuf
2 years ago
Incidence of acute rejection
The incidence of AR decreased from 100% at the beginning of transplantation history and reached now to around 10%, with subsequent improvement of 1-year graft survival
This may be related to the invent in the management (such as use of CNI, desensitization, KPD), investigations (calculated PRA, HLA, cross matching, DSA assay) and understanding of the pathophysiology of AR
AR is classified into
TCMR
ABMR
Mixed rejection
Risk factors for AR
Presence of preformed DSA (especially if the titer is high), which is the main predictor of ABMR
HLA mismatches which is the main predictor of TCMR
Sensitization due to pregnancy, blood transfusion, previous transplantation with subsequent high cPRA, which was found by some to have no predictive value
Younger, African American recipient
Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
Non-compliance on immunosuppressive medication
Diagnosis
A- In case of allograft dysfunction we should do renal biopsy with C4d staining and DSA and according to the finding we diagnose AR and categorize rejection into:
Pure acute TCMR
Pure acute (active) ABMR
Mixed acute ABMR, TCMR
Acute TCMR
Ia : 25% Interstitial inflammation with moderate tubulitis (t2)
Ib : 25% Interstitial inflammation with severe tubulitis (t3)
3 components are required for the diagnosis of ABMR :
Histologic evidence of acute tissue injury including capillaritis (ptc> 0) and/or glomerulitis (g> 0), or ATN, or TMA
Evidence of antibody interaction with vascular endothelium including C4d staining in PTCs or moderate microvascular inflammation (g1+ ptc ≥2) or increased expression of gene transcripts in biopsy tissue
Serologic evidence of circulating DSAs
If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have ABMR, this means C4d staining can replace DSA, and C4d negative ABMR exists (ABMR without activation of complement cascade)
B- Donor-Derived Cell-Free DNA in blood > 1% has positive predictive value of ABMR of 44 % and have negative predictive value that reached 96%, so it is specific but not sensitive
Management of acute rejection
A rule is to treat all rejections appropriately (according to type and severity) in a timely manner
Acute TCMR
Intensification of maintenance immunosuppression
Pulse methylprednisolone 250-500 mg daily for 3-5 days followed by oral prednisolone tapering to maintenance dose used in patients with Banff grade Banff grade I, II or III rejection
rATG is given in patients with Banff grade IB rejection (if there is severe graft dysfunction and no improvement on pulse steroids) , Banff grade II or III rejection, the dose is 1.5 mg per kg /d for 5-7 days
Acute ABMR
A- First line therapy
Intensification of maintenance immunosuppression
Decreasing inflammation produced by rejection: high dose methylprednisolone 250-500 mg for 3-5 doses followed by rapid oral prednisone taper till reaching previous maintenance dose
Removing DSA using 5 sessions of plasmapharesis, 1.5 volume of exchange either daily or every other day
Decreasing production of antibodies using IVIG in a dose 100-200 mg/kg after each plasmapharesis session (use of IVIG alone without plasmapharesis is mostly inadequate)
Depleting B cells using one dose of rituximab 375mg/m2 only if there is biopsy evidence of active microvascular inflammation and given 1 week after completion of IVIG
Second line therapy if initial therapy failed
Bortezomib, eculizumab with or without splenectomy and C1-esterase inhibitors (C1-INH) may have benefit but associated with large number of side effects
Tocilizumab although may have a rule in treatment of chronic ABMR but it is not studied in acute ABMR
Mixed TCMR, ABMR
Treatment of ABMR with addition of ATG according to banff grade
Subclinical rejection
It is detected by protocol biopsy and monitoring of DSA
Subclinical ABMR is more significant than subclinical TCMR
Treatment of subclinical rejection including ABMR may not alter outcome
What is the level of evidence provided by this article?
Hi Dr Yusuf,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Nahla Allam
2 years ago
Introduction:
Advances in immunosuppressive therapy have drastically improved acute rejection rates in kidney transplant recipients over the past five decades
Acute Rejection Risk:
1-Over all level of anti-HLA sensitization (panel reactive antibody)
2-Repeat transplant,
3- Black race,
4- Recipient age.
In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure
Acute Rejection Diagnosis:
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy
Indications to graft biopsy:
1- over concern for acute rejection
2- unexplained deterioration in graft function
3- The presence of a biomarker consistent with acute rejection
Antibody-mediated rejection was first recognized within the Banff classification in the early and mid-2000s and required three features for diagnosis: (1) active tissue injury (2) ) immunohistologic evidence of peritubular capillary complement split-product C4d deposition, (3) circulating DSA.
The revised 2013 Banff criteria for antibodymediated rejection diagnosis: (1) positive C4d staining, (2) at least moderate microvascular inflammation, (3) increased expression of endothelial gene transcripts
Numerous studies of urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have generally shown mixed sensitivity and specificity for identifying acute rejection, differentiating T cell–mediated rejection from antibody-mediated rejection, and distinguishing immunologic injury from other forms of graft damage Acute Rejection Treatment:
Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, T Cell–Mediated Rejection:
methylprednisolone at 250–500 mg daily for 3–5 days.
rATG dosed at 1.5 mg/kg for five to seven doses. Antibody-Mediated Rejection:
Antibody mediated rejection treatments are directed at removing antibody-producing B cells or plasma cells, removing antibodies (DSA), and/or inhibiting the subsequent complement-regulated graft damage Plasma exchange Intravenous Ig (IVIG), Rituximab, Subclinical Rejection:
protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions
The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low
Level 5
Hi Dr Allam,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Mohammed Abdallah
2 years ago
Please summarise this article
Introduction
Acute rejection rate now is about 10% owing to evolution of immunosuppressive agents
Acute rejection should remain high on the differential diagnosis for unexplained graft dysfunction because it significantly affect graft survival
Acute rejection is now broadly classified as either T cell mediated or antibody mediated
Aim of the study: approach to risk factors, diagnosis, and treatment of acute rejection
Acute Rejection Risk
At the time of transplant: Anti-HLA sensitization (PRA), repeat transplant, black race, and recipient age
In the post-transplant period: immunosuppression regimen and exposure
Reduce CNI exposure and using mTORi leads to higher rates of acute rejection and side effects
CNI- free regimen with the newer agent belatacept has resulted in favorable, longer-term outcomes but with higher rates of T cell–mediated rejection (significant reduction in DSA in belatacept versus cyclosporine)
There are correlations with overall tacrolimus exposure and acute rejection risk
Acute Rejection Diagnosis
Tissue biopsy (the gold standard) is indicated when there is acute unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection
Allograft histology is interpreted using the Banff classification of kidney allograft pathology
Noninvasive biomarkers (failed to completely replace tissue diagnosis due in part to incon- sistent results between studies
Urine and blood biomarkers (CXCL9, CXCL10, granzyme B, perforin, and Fas ligand)
Short non- coding single-stranded microRNA and decreased urinary miR-210 levels have been associated with T cell–mediated rejection and subsequent 1-year GFR decline
Donor-derived cellfree DNA (cf-DNA) profiling (for diagnosis of antibody-mediated rejection)
Acute Rejection Treatment
T Cell–Mediated Rejection
Pulse methylprednisolone at 250–500 mg daily for 3–5 days (Banff Ia, Ib)
rATG dosed at 1.5 mg/kg for five to seven doses ((Banff II and III lesions)
Antibody-Mediated Rejection
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2
Other medications (refractory to “standard” treatment regimens):
1. Bortezomib (proteasome inhibitor): induce apoptosis in antibody-producing plasma cells with minimal effect on DSA burden when used alone
2. eculizumab (humanized mAb): for prevention and treatment of antibody-mediated injury because of its mechanism of complement component C5 inhibition
3. tocilizumab (anti-IL six receptor antibody): promising results for chronic antibody-mediated rejection
4. C1-esterase inhibitors (C1-INH): inhibits proximal enzymes in the classic complement pathway including C1q
Subclinical Rejection
Use protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions
Subclinical T cell–mediated rejection in the modern era of immunosuppression is low, in contrast to subclinical antibody-mediated rejection (poor long-term outcomes)
Using DSA as a biomarker, 50% of patients with stable function and de novo DSA will show evidence of subclinical antibody-mediated rejection on biopsy
Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection, few studies suggest treatment intervention will alter the clinical course
Conclusions
Acute rejection still affects graft survival despite effective immunosuppressive therapy
Tissue biopsy should be performed in any patient with unexplained acute graft dysfunction
The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition
Identification of subclinical antibody-mediated rejection provides a chance to intervene before the onset of clinical dysfunction
What is the level of evidence provided by this article?
Level 5
Hi Dr Mohammed,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Mohamed Mohamed
2 years ago
1. Please summarise this article Introduction
As a result of advances in IS therapy, AR rates have decreased from almost 100% in the 1stera of orga TX to about 10% more recently; however, when it occurs, can significantly affect graft survival &, therefore, should be highly whenever there is on unexplained graft dysfunction in a TXrecipient. Acute rejection risk
1.Pre-TX DSA & HLA A/B/DR mismatch are the main predictors of AMR & TCMR respectively.
2.PRA & re-TX had no predictive effect (Wehmeier et al.).
3.The degree of immunologic risk imposed by pre-TX DSA depends on characteristics of the antibodies detected:
-30%–50% of those with high pre-TX DSA titers warranting pre-TX desensitization will develop AMR; lower-levels do not increase AR risk or graft survival in the intermediate term.
4.Lower rates in recipients who receive rATG induction & maintenance IS with tacrolimus & MMF, with or without prednisone.
5. Regimens of mTOR’s with reduced CNI exposure is associated with higher rates of AR & S/Es.
6.CNI free maintenance IS with belatacept has resulted in favorable, longer-term outcomes but with higher rates of TCMR; post hoc analysis showed significant reduction in DSA development in those receiving belatacept versus cyclosporine.
7.Adams et al. recently reported significant reduction in AR in those treated with belatacept by adding tacrolimus to the existing belatacept regimen followed by a taper over the 1st post-TX year. AR Diagnosis
Tissue biopsy (the gold standard).
Graft biopsy is indicated if there is any acute unexplained graft dysfunction or in the presence of
a biomarker consistent with AR. Histologic criteria for diagnosing AR (Banff 2017 guidelines): A. Acute TCMR
Ia: >25% Interstitial inflammation + moderate tubulitis (t2)
Ib: >25% Interstitial inflammation with severe tubulitis (t3)
IIa: Mild-to-moderate intimal arteritis (v1)
IIb: Severe intimal arteritis (v2)
III: Transmural arteritis &/or fibrinoid necrosis B. Acute AMR: all 3 criteria below required
1) Histologic evidence of tissue injury including =/>1 of the following:
Microvascular inflammation (g>0 &/or ptc>0)
Arteritis (v> 0)
Thrombotic microangiopathy
Acute tubular injury
2) Evidence of current/recent antibody interaction with endothelium including =/>1 of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g+ptc =/>2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
3) Serologic evidence of DSA
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA Treatment options for acute allograft rejection 1.Methylprednisolone
Indication: TCR,Banff Ia, Ib
Mechanism: multiple, anti-inflammatory glucocorticoid
A/Es: hyperglycemia, hypertension, other metabolic effects 2.rATG
Indication:TCR: Banff Ib, IIa, IIb, III
Mechanism: T cell depletion
A/Es: Fever, chills, hypertension, hypotension, leukopenia, infusion reaction, serum sickness 3.PE:
Indication: AMR
Mechanism: Antibody removal
A/Es: Fever, chills, urticaria, TRALI, bleeding 4.IVIG
Indication: AMR
Mechanism: multiple “immunomodulatory” effects including antibody clearance, neutralization, and inhibited production, Fc receptor saturation, complement inhibition
A/Es: Infusion reaction (headache, fever, chills, urticaria, back pain, abdominal pain, nausea, vomiting). 5.Rituximab
Indication: AMR
Mechanism: Anti-CD20 B cell depletion
A/Es: Infusion reaction, HBV reactivation, PML 6.Bortezomib
Indication: AMR
Mechanism: Plasma cell apoptosis via proteasome inhibition
A/Es: peripheral neuropathy, fatigue, generalized weakness 7.Eculizumab
Indication: AMR
Mechanism: terminal complement C5 inhibition
A/Es: Meningococcal infection, influenza, peritonitis 8.C1-INH
Indication: AMR
Mechanism: Classic complement pathway inhibition
A/Es: Headache TCMR treatment Banff Ia:
-Solumedrol 500mgx3-5 days Banff Ib:
-Solumedrol 500mg X 3-5 days if mild graft dysfunction
-rATG 1.5mg/kg X 5-7 days or until recovery if severe graft dysfunction Banff IIa, IIb, or III:
-rATG 1.5mg/kg X 5-7 days or until recovery AMR treatment
-PE X 5
-IVIG 100-200 mg/kg following each PE
-Rituximab 375 mg/m2 following last treatment
-If evidence of TCMR on biopsy(mixed rejection): add TCMR treatment according to Banff category /////////////////////////////////// 2. What is the level of evidence provided by this article? Level V
Hi Dr Mohammed, I like your summary and analysis. I agree it is level 5 evidence. Ajay
Mohamed Essmat
2 years ago
Level 5 evidence Several risk factors for acute rejection include: -Previous transplant-Presence of DSA’s-recipient race and age Diagnosis of acute rejection: -Proper examination , hemodynamic check , exclusion of UTI and other infections , CNI toxicity, CMV PCR , US-duplex , renal biopsy and C4 d staining , DSA’s level . Treatment -AMR: Plasma exchange, IVIG, Mabthera, bortezumib and eclizumab . -T-Cell rejection: 250-500 mg solumedrol for 3-5 days ( Banff Ia,Ib)-rATG 1.5mg/kg/day for 5-7 days (Banff Ib, II & III ).
Hi Dr Essamat, I like your summary and analysis. I agree it is level 5 evidence. Ajay
ISAAC BUSAYO ABIOLA
2 years ago
SUMMARY
Introduction
The evolution in the development of various immunosuppressives drugs in the last five decade has not only reduces significantly the occurrence of acute kidney rejection but has also widened the understanding in the pathogenesis of different types of acute rejection. Similarly, it has also helped to appreciate the long-term impact of acute rejection on graft survival and different roles played by different induction and maintenance therapy.
Acute rejection risk
The conventional risk factors for acute rejection at the time of transplantation are
ant- HLA sensitization
repeat transplant
black race
recipient age
Wehmeier et al in his study of over 500 transplants patient found, DSA and HLA mismatches (A/B/DR) as risk factors for ABMR and cell mediated rejection respectively.
Acute rejection diagnosis
The goal standard still remains kidney biopsy despite been an invasive procedure and the indications are
acute deterioration in graft function
unexplained graft failure
presence of biomarker consistent with acute graft rejection
The goal standard for proper interpretation of histology report of the type of ongoing allograft rejection (ABMR or T-cell) is the Banff criteria which has gone through various modifications over the years. It helps in diagnosis and the appropriate use on rescue therapy to arrest on going rejection
The use of cell free donor derived DNA is helping as a non-invasive method of diagnosis
Treatment of acute rejection A) T – cell mediated rejection
pulse methylprednisolone 250-500mg daily for 3- 5 days
r-ATG dose at 1.5mg/kg daily for 5- 7 doses
B) Antibody mediated rejection
The aim is to remove or destroy circulating antibodies in the system of the recipient
plasma exchange
Ivig
with or without Rituximab
other agents that have been used or gaining recognition are Bortezomib, eculizumab, tocilizumab, and C1 -esterase inhibitor
Conclusion
Although the incidence of acute allograft rejection has reduced, there is still a need for high index of suspicion particularly subclinical rejection as to be able to deploy prompt use of rescue therapy to prevent rejection and improve long term survival of the graft and patient
Hi Dr Issac, I like your summary and analysis. I agree it is level 5 evidence. Ajay
Abhijit Patil
2 years ago
Acute Rejection Risk:
Approximately 30%–50% of patients with pretransplant DSA at titers strong enough to warrant desensitization before transplant experience acute antibody-mediated rejection
Suspicion:
A high index of suspicion would be warranted in a young patient with lower tacrolimus trough levels during the first post-transplant year and/or suspected immunosuppression non-adherence.
Alternatively, non immunologic causes may first be considered in an older patient who received rATG in duction with consistently therapeutic tacrolimus levels.
Acute Rejection Diagnosis
Indications to pursue graft biopsy over concern for acute rejection include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection Graft biopsy — Gold Standard
Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
Acute antibody-mediated rejection (AMR): all three criteria below required
Histologic evidence of tissue injury including one or more of the following:
Microvascular inflammation (g.0 and/or ptc.0)
Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc $2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Drug rATG
Indication TCR: Banff Ib, IIa, IIb, III
Mechanism T cell depletion
Drug Plasma exchange
Indication AMR
Mechanism Antibody removal
Drug IVIG
Indication AMR
Mechanism Multiple “immunomodulatory” effects including antibody clearance, neutralization, and inhibited production, Fc receptor saturation, complement inhibition
Drug Rituximab
Indication AMR
Mechanism Anti-CD20 B cell depletion
Drug Bortezomib
Indication AMR
Mechanism Plasma cell apoptosis via proteasome inhibition
Drug Eculizumab
Indication AMR
Mechanism Terminal complement C5 inhibition
Management of Acute T cell rejection:
Banff 1a: Steroids 500 mg for 3-5 days
Banff 1b: Steroids 500 mg for 3-5 days
rATG 1.5mg/kg for 5-7 doses or until recovery
Banff 2a, 2b, 3: rATG 1.5mg/kg for 5-7 doses or until recovery
Management of Acute B cell rejection
Plasmapheresis – 5 cycles
IVIG 100-200 mg/kg following each plasmapheresis
Rituximab 375 mg/m2 following last treatment
Noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies normal results from assays with high negative predictive value, such as donor-derived cf-DNA, may offer a level of reassurance to providers and patients with abnormal clinical findings (DSA, graft dysfunction) in whom tissue biopsy is either not feasible or considered too high risk.
Hi Dr PAtil, I like your summary and analysis. I agree it is level 5 evidence. Ajay
Nandita Sugumar
2 years ago
Summary
This study is relating to the assessment, recognition and management of acute rejection in kidney allografts following kidney transplant.
Pretransplant immunological risk of a patient is based on pre transplant DSA titers, ethnicity, age, previous transplant etc. In the post transplant period, acute rejection incidence is dependent on IS regimen and exposure. Lowest rates of acute rejection is seen with induction rATG and maintenance regimen of tacrolimus, MMF, prednisone. CNI free regimens can have higher rates of T cell mediated rejection. However, belatacept is associated with significant DSA reduction and better outcome.
The gold standard for diagnosing acute rejection is tissue biopsy. Indications for tissue biopsy in the post transplant period include :
acute or otherwise unexplained deterioration in graft function
biomarker consistent with acute rejection
Histology is classified according to Banff criteria. There are different changes that have been done to these criteria for T cell mediated rejection over the years, however, the major concepts are based on tubulitis, vasculitis and lymphocytic infiltration.
Micorvascular inflammation and C4d histology are crucial for assessment and recognition of AMR. Microarray analysis of endothelial transcripts help to a great extent in identifying C4d negative AMR.
Treatment options for acute rejection include different agents. TCR can be managed largely with steroids, i.e., methylprednisolone, and rATG. AMR can be managed with plasma exchange, IVIG, rituximab, bortezomib, eculizumab and C1-INH.
Ø An individual’s immunologic risk at the time of transplant has conventionally been attributed to factors such as:
1. overall level of anti-HLA sensitization (panel reactive antibody)
2. pretransplant DSA
3. repeat transplant
4. black race, and
5. recipient age
Ø In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure. Currently in the United States, 75% of kidney recipients receive rabbit antithymocyte globulin (rATG) induction and .90% receive maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, as these regimens have historically been associated with lower rates of acute rejection
Ø Calcineurin inhibitor free maintenance immunosuppression with the newer agent belatacept has resulted in favorable, longer-term outcomes but with higher rates of T cell–mediated rejection; however, post hoc analysis has shown a significant reduction in DSA development in those receiving belatacept versus cyclosporine (1%–4% versus 12%, respectively
Ø The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy. Indications to pursue graft biopsy over concern for acute rejection include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection.
Ø Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed:
Ø T Cell–Mediated Rejection
1. Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days
2. T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for 5 to 7 doses
Ø Antibody-Mediated Rejection: antibody removal therapies
1. Plasma exchange
2. IVIG
3. Rituximab
4. eculizumab
Ø Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
level 5
This article is about evaluation and treatment of acute rejection in kidney allograft.
Acute rejection is one of the major causes of graft dysfunction.
Careful assessment of the recipient regarding history and clinical examination is necessary. Investigations including US, drug level, infection screen is important to rule out other differential diagnoses. Renal biopsy remain the standard investigation modality for diagnosis depending on Banff classification of rejection.
Intravenous steroids and T cell depletion remain the standard therapy for
T cell–mediated rejection and are effective in reversing most cases. Plasma exchange and intravenous Ig, with or without rituximab, are most commonly used for the treatment of antibody-mediated rejection and several newer agents have recently been investigated for severe cases.
level 5
It is a review to diagnose kidney allograft rejection after excluding any other cause like sepsis or CNI toxicity
they are two types of rejection cellular and antibody mediated rejection
in most of cases they presented together
so ideally biopsy and PRA screening should be done but if it is not feasible we can start pulse steroid and took the PRA screening
treatment most probably depend on Histopathology it vary from ATG in vascular type of ACR to Plasmaexchange and rituxmab in ABMR
it is level 5 evidence
Acute rejection:
is either acute T cell mediated rejection or Ab mediated rejection and sometimes mixed rejection
Usually occurs in patients with high immunological risk like highly sensitized recepients ,high level of DSA ,,ABO incompatibility
1st possibility in case of delayed graft dysfunction
Diagnosed by Disney biopsy with spescific histological findings summariezed in BANFF classification
C4D staining is important in case of AMR
Prevention:
desensitization
Paired Donor exchange
Treatment:
AMR:IVIG ,plasmapheresis,Rituximab
T cell mediated rejection:ATG ,steroids
level 5 of evidence
The diagram for delayed graft function is good and informative
Please summarize this article
Acute rejection is classified into acute T-cell mediated and Antibody mediated rejection.
Factors that trigger the immune system to develop rejection include the following: HLA mismatches, previous sensitization, PRA, repeat transplant, presence of DSAs.
Recipients with pre-transplant DSA have 30-50% chance to experience antibody mediated rejection which is determined by immunosuppression regimen as well.
Belatacept and CNI free maintenance IS resulted in higher rates of T-cell mediated rejection and significant reduction of DSA compared to cyclosporine (1-4% vs 12%).
Acute rejection is diagnosed by a renal graft biopsy which is indicated when graft function deteriorates without obvious explanation.
Histopathological interpretation of graft biopsy using Banff classification which was developed since 1990 with continuous update.
T-cell mediated rejection histological findings include tubulitis, and large vessel vasculitis.
Antibody mediated rejection feature include active tissue injury, peri-tubular capilliritis with or without C4d deposition and circulating DSA. These Criteria was updated by Banff 2017.
Treatment of acute rejection:
1- Treatment of T-cell mediated rejection: pulse methyl-prednisolone for 3-5 days, then ATG is required for 5-7 doses if Banff II and III.
2- Treatment of antibody mediated rejection: includes plasma exchange followed by IVIG +/- Rituximab. Other lines of AMR treatment include Bortezomib, Eculizumab or C1-estrase inhibitors
Subclinical Rejection is diagnosed by protocol biopsy
What is the level of evidence provided by this article? Level V
When unexplained graft dysfunction occurs, non-immunological causes : infection, CNI toxicity, hemodynamic disorders and fluid collection need to be ruled out .The next step would be to check for presence of rejection through renal biopsy and DSA screening. We apply BANFF criteria to delineate the type of the rejection whether antibody mediated or cellular rejection. In case of antibody mediated rejection, then implementation of plasma exchange, IV IG and rituximab are the cornerstone treatment. If it is cellular rejection, then the use steroid and r ATG is required.
In biopsy is not feasible, we can give steroid empirically and do tests for DSA. If the serum creatinine is improving with negative DSA, the management will include optimization of immune-suppressants and close monitoring. If DSA were positive, the need for a biopsy is still there. If the AKI is not resolved with positive DSA, the treatment will be as a case of AMR. If the graft dysfunction is severe, ATG is used. If the DSA were negative then rATG alone will be enough. The need for renal biopsy remains valid except for cases with improved renal function & negative DSA.
Level 5 article.
II. Evaluation and Treatment of Acute Rejection in Kidney Allografts.
1) Please summarise this article.
Introduction:
With time the immunsupressive agents become effective in reducing the rejection accordingly the acute rejection rates reduced from nearly 100% in the first era of organ transplantation to approximately 10% . these rates mainly achieved by introduction of cyclosporine and T cell–depleting agents. Acute rejection broadly classified in to either T cell mediated” or antibody mediated
Acute Rejection Risk:
Immunological response generally depend on the level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black race, and recipient age.
Wehmeier et al. report that pretransplant donor-specific anti bodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection .
30%–50% of patients with high pre transplant DSA titers will experience acute antibody-mediated rejection . but lower-level not associated with rejection.
Acute rejection risk is associated with immunosuppression regimen and exposure.
75% of kidney recipients receive (rATG) induction and 90% receive maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone. With very good outcome .
Strategies to reduce calcineurin inhibitor (CNI) exposure include
1) By using mammalian target of rapamycin inhibitors (mTOR’s) associated with higher rates of acute rejection and side effects .
2) Calcineurin inhibitor free maintenance immunosuppression with belatacept associated with longer-term outcomes but higher rates of T cell–mediated rejection. With significant reduction in DSA development in those receiving belatacept versus cyclosporine.
3) Adams et al. report that adding tacrolimus to the existing belatacept regimen followed by a steady taper over the firs post-transplant year lead to significant acute rejection reduction. (acute rejection rates of 51% with belatacept alone versus 16% with belatacept plus tacrolimus taper).
Also there is a correlation between overall tacrolimus exposure and acute rejection risk.
Mean tacrolimus levels, 8 ng/ml through-out the first year increased the risk of DSA development and levels of 4–6 versus .8 ng/ml were associated with a 2.3-fold higher risk of acute rejection.
Of note non immunologic causes may be most likely in an older patient who received rATG induction with consistently therapeutic tacrolimus levels .
Acute Rejection Diagnosis
The gold standard for diagnosing acute rejection is tissue biopsy. Which is indicated in acute unexplained graft dysfunction or the presence of a biomarker consistent with acute rejection.
Allograft biopsy is a safe procedure and should be done in patients with graft dysfunction that is not explained by other no immunologic causes. Allograft histology is interpreted using the Banff classification of kidney allograft pathology.
NON INVASIVE BIOMARKERS
Umerous urine and blood biomarkers studies , such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have generally shown mixed sensitivity and specificity for
1) Identifying acute rejection.
2) differentiating T cell–mediated rejection.
3) antibody-mediated rejection.
4) distinguishing immunologic injury from other forms of graft damage.
single-stranded microRNA and donor-derived cellfree DNA (cf-DNA) are another biomarker .
in one study of cf-DNA levels showed that a negative predictive value for AMR of 96%.( cut-off value 1%) and the positive predictive value was only 44%.
Tissue biopsy remains the gold standard for diagnosing acute and noninvasive biomarkers have failed tocompletely replace tissue diagnosis. The high negative predictive value, of cf-DNA, may reassure nephrologist in patients with abnormal clinical findings (DSA, graft dysfunction) in whom tissuebiopsy is either not feasible or considered too high risk.
Acute Rejection Treatment:
Early recognition and diagnosis of acute rejection is important for early initiate appropriate of treatment.
T Cell–Mediated Rejection:
Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days.
Banff class 1 lesions responding to methylprednisolone alone. Banff II and III lesions generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
One study compared rATG with horse anti-thymocyte globulin, howing superior effectiveness of rATG over horse ATG.
Cochrane Database review concluded that antibody therapy was superior to steroid therapy in reversing T cell–mediated rejection.
Antibody-Mediated Rejection:
AMR treatments are directed at
· Removing antibody-producing B cells or plasma cells,
· Removing antibodies (DSA), and/or inhibiting the subsequent complement-regulated graft damage.
The a systematic review by Roberts et al. report low-quality evidence supporting antibody removal therapies (plasma exchange , immunoabsorption ), and very low-quality evidence for all other treatments.
plasma exchange and intravenous Ig (IVIG), with or without rituximab is most accepted regimen for treatment of AMR.
A typical regimen includes:
daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
Bortezomib:
It is used because of its ability to induce apoptosis in antibody-producing plasma cells. But there is minimal effect on DSA burden when used as a sole agent with mixed results when used in combination with plasma exchange/IVIG .
The humanized mAb eculizumab :
Orandi et al. severe antibody-mediated rejection by either splenectomy , eculizumab, or combination splenectomy and eculizumhab . there was high graft loss in the splenectomy and eculizumab groups, compared to combination splenectomy and eculizumab which show no graft loss and minimal transplant glomerulopathy on protocol biopsy
Anti-IL six receptor antibody tocilizumab:
This agent is not studied in the treatment of acute antibody-mediated rejection.
C1-esterase inhibitors (C1-INH): This agent lacks the efficacy for the treatment of AMR.
Subclinical Rejection:
involves protocol biopsy or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions. The incidence of subclinical T cell–mediated is low and long term outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection.
In one study , the incidence of subclinical T cell–mediated rejection was only 5%, with no difference in graft function despite treatment.
While Subclinical antibody-mediated rejection, is an attractive therapeutic target given the attributed poor long-term outcomes.
Using DSA as a biomarker, approximately 50% of patients with stable function and de novo DSA will show evidence of subclinical AMR on biopsy . Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection, few data exist to suggest treatment intervention will alterthe clinical course. Orandi et al. in their stusy report that overall rates of graft loss were similar between those treated and untreated.
2) What is the level of evidence provided by this article?
Level of evidence is 5 .
Acute Rejection Risk
An individual’s immunologic risk at the time of transplant has conventionally been attributed to factors such as overall level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black race, and recipient age. Wehmeier et al.recently examined traditional risk factors in 527 kidney recipients, showing pretransplant donor-specificantibodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation had no predictive effect. With this in mind, it is worth noting the degree of immunologic risk conferred by pretransplant DSA will depend on characteristics of the antibodies detected. Approximately 30%–50% of patients with pretransplant DSA at titers strong enough to warrant desensitization before transplant will experience acute antibody-mediated rejection (8), whereas lower-level antibodies do not appear to increase acute rejection risk or graft survival in the intermediate term
Acute Rejection Diagnosis
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy. Indications to pursue graft biopsy over concern for acute rejection include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection. As described in the preceding section, assessment of a patient’s immunologic risk at the time of and after transplant can help further define pretest probability of acute rejection when contemplating the utility of biopsy; however, allograft biopsy is generally considered a safe procedure and should be pursued without delay in patients with graft dysfunction that is not explained by other nonimmunologic causes. Allograft histology is interpreted using the Banff classification of kidney allograft pathology, which has undergone extensive updating and revision since its development in the 1990s The diagnostic criteria for T cell–mediated rejection have undergone little change in recent years, and include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field
Acute Rejection Treatment
The approach to treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology. Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed. Graft prognosis after treated acute rejection also depends on type and severity . however, any untreated clinical acute rejection episode will ultimately result in accelerated graft loss. Thus timely recognition and diagnosis of acute rejection is crucial to promptly initiate appropriate treatment.
T Cell–Mediated Rejection
The treatment of T cell–mediated rejection has changed little over time and few data exist comparing one strategy to another. Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5days,as recommended by international guidelines ). Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylprednisolone alone. T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses
Antibody-Mediated Rejection Similar to T cell–mediated rejection, few high-quality, randomized trials exist comparing treatment regimens for antibody-mediated rejection. In contrast to T cell–mediated rejection, however, several new therapeutic treatment options have been studied in recent years. Antibodymediated rejection treatments are directed at removing antibody-producing B cells or plasma cells, removing antibodies (DSA), and/or inhibiting the subsequent complement-regulated graft damage
Subclinical Rejection
The identification and treatment of alloimmune responses before the onset of clinical graft dysfunction may theoretically minimize the development of chronic lesions that ultimately lead to graft loss (47,48). This approach involves protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions. The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low and longterm outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection
Orandi et al.published a retrospective analysis of 77 patients with subclinical antibodymediated rejection diagnosed by protocol biopsy, 54% of which received treatment with various combinations of plasma exchange, IVIG, rituximab, and eculizumab. With a mean follow-up of 5.2 years, overall rates of graft loss were similar between those treated and untreated. However, when compared with matched controls, treated patients experienced a lower risk of graft loss versus untreated patients (hazard ratio, 1.73 [P50.21] versus 3.34 [P50.01], respectively). Thus, although the prospect of identifying subclinical antibody-mediated rejection before clinical dysfunction remains attractive
Conclusions
Despite historically low acute rejection rates thanks to increasingly effective immunosuppressive protocols, acute rejection episodes continue to affect graft survival and prompt recognition and treatment is crucial. When feasible tissue biopsy should be performed in any patient with unexplained acute graft dysfunction, and accurate assessment of immunologic risk can assist in determining the need for tissue diagnosis. The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA andC4ddeposition, with several new agents under investigation for treatment. Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
Level 5
Evaluation and treatment of Acute Rejection in kidney allograft.
Acute rejection previously classified as steroid responsive and steroid non responsive .now is characterized as either T cell mediated or antibody mediated acute rejection.
Each one has distinct separate mechanistic pathways, different histologic findings and prognosis with distinct approaches to treatment.
Acute rejection immunological risk assessment:
Pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch are the main predictors at AMR and T cell mediated rejection whereas PRA and repeat transplantation has no predictive effect. And the degree of immunological risk conferred by pretransplant DSA depends on antibodies characteristics.
High level antibodies warrant desensitization before transplantation will experience acute antibody mediated rejection, whereas low level antibodies do not appear to increase acute rejection risk or graft survival.
In post-transplant period , risk of acute rejection is determined by IS regimen and exposure.
Diagnosis of acute rejection:
Tissue biopsy is the gold standard for diagnosing acute rejection.
Banff classification of kidney allograft pathology used to interpreted allograft histology.
Histologic criteria for diagnosing acute allograft rejection according to Banff 2017 guidelines :
Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
Acute antibody-mediated rejection (AMR): all three criteria below required
Histologic evidence of tissue injury including one or more of the following:
Microvascular inflammation (g.0 and/or ptc.0) Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc $2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Noninvasive biomarkers have failed to replace tissue diagnosis, so it is remains the gold standard for diagnosing Acute rejection.
Acute Rejection Treatment:
Treatment options for acute allograft rejection
Acute Rejection Treatment
The approach to treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology. Treatment strategies differ between T cell–mediated rejection and antibody mediated rejection.
In case of unexplained graft dysfunction we must rule out non immunological causes of graft dysfunction like infection, drug toxicity, hemodynamics causes, anatomical/fluid collection or obstruction.
If all are normal, we proceed for tissue biopsy and assessment for de novo DSA.
If the biopsy not safe or feasible, we treat by solumedrol for 3-5 days . If AKI resolved , we assess DSA , if it’s negative, we continue by monitoring graft function with optimizing IS .
If the DSA’s positive, we monitor graft function and optimize IS, then obtain graft biopsy when feasible.
If the AKI not resolved after solumedrol , we assess DSA , if it’s positive, we do empiric PEX plus IVIG , and consider ATG if it’s severe and obtain biopsy if feasible.
If the DSA’s negative, we give ATG and obtain biopsy if feasible.
If we can obtain biopsy and diagnosed the dysfunction as immunological cause either T cell mediated or AMR.
T cell mediated rejection treated by steroid and ATG
AMR treated by PEX and zIVIG followed by RTx after the last session.
If mixed rejection add T cell mediated rejection treatment according to banff category.
Level of evidence 5
Introduction :
Despite the development in the immunosuppression medication rejection still in the top of differential diagnosis of any renal impairment post renal transplantation .
because of its effect in long term graft survival early diagnosis and optimal management is mandatory in this cases .
Tissue biopsy remains the gold standard for evaluating immunologic graft damage, and the histologic definition of acute rejection .
Two types of rejection T cell mediated and AMR are founded each one needs specific management .
Risk factor for rejection :
Diagnosis :
tissue biopsy remains the gold standard for diagnosing acute rejection in transplant recipients and noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies .
lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field
All three criteria below required :
Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Management :
management attached in picture
Despite advances in immunosuppression in recent decades, acute rejection is still an event of great importance, as it has the potential to significantly affect graft survival. And understanding the pre and post-transplant risk factors for acute rejection can help estimate the probability of immunologic graft damage, and accurate identification of the type and severity of acute rejection will guide appropriate investigate and treatment.
Today acute rejection is classificated in: T cell mediated or antibody mediated. Normally, acute rejection has been attributed to pre-transplant factors such as overall level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black race, and recipient age, but recent studies has showing that panel reactive antibody and repeat transplantation had no predictive effect. And pretransplant donor-specific antibodies (DSA) for antibody-mediated rejection and HLA A/B/DR mismatch to T cell–mediated rejection, are main predictors .
Post-transplant factors largely determined by immunosuppression regimen and exposure and encompasses immunosuppressants used from induction to maintenance. Regimens with induction through rabbit antithymocyte globulin (rATG) and maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, seem to be associated with lower rates of acute rejection. The control of Tacrolimus concentration is the biggest challenge of these regimens, due to its adverse effects. Regimens that attempt to spare the calcineurin inhibitor appear to have higher rates of acute rejection and side effects.
ACUTE REJECTION DIAGNOSIS
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy, so, in cases of unexplained deterioration in graft function, the performance of biopsy should be evaluated. Banff classification contains the criteria for the diagnosis of T cell–mediated and antibody rejection, which involve the presence of: lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the degree of lymphocytic infiltrate, active tissue injury, immunohistologic evidence of peritubular capillary complement split-product C4d deposition, and circulating DSA.
ACUTE REJECTION TREATMENT
Differentiating diagnoses is essential for defining treatment. Among the most used possibilities we have:
A)T-cell mediated rejection: has changed little treatment over the years. There are few data evaluating the two types of treatment.
– Methylprednisolone: Banff class 1 lesions
– rATG: Banff II and III lesions
B)Antibody-mediated rejection: there is also little comparative evidence between treatments, however new proposals have emerged recently.
– Plasma Exchange: remove antibodies DSA
-IVIG: is the most commonly used treatment, with or without Rituximab.
– Rituximab: known to have good effects associated with IVIG, but ongoing studies on rituximab as rescue therapy for treatment insufficient efficacy
– Bortezomib: initially approved proteasome inhibitor for treatment of multiple myeloma, has better effect when used in association with Plasma Exchange or IVIG
– Eculizumab: possibility of replacing the effect of splenectomy
– C1-INH: inhibits proximal enzymes in the classic complement pathway
The possibility of subclinical rejection still exists, but its incidence has been decreasing since the new therapies.
Your evidence is 05 – narrative review
Evaluation and Treatment of Acute Rejection in Kidney Allografts
Transplantation of donor organs to non-HLA identical recipients introduces stimulants for an alloimmune response. Any graft dysfunction in the transplant recipient still may need to rule out acute rejection. Acute rejection is either T-cell-mediated or antibody-mediated rejection. This review summarize the recent approach to M3K assessment, diagnosis, and treatment of acute rejection.
Acute rejection risk:
Risk factors at the time of transplant:
Ø PRA
Ø Recipient transplant
Ø Black race
Ø Recipient age
Ø In the post-transplant period, acute rejection risk is based on the immunosuppression regimen and exposure
In the united states, 75% of kidney recipients receive rATG induction and >90% receive tacrolimus and mycophenolate mofetil, with or without prednisolone, this regimen is associated with loa were rate of acute rejection.
mTOR is associated with high rate of acute rejection and maintenance
CNI-free maintenance immunosuppression with the result gent belatacept has result in a few recommendations come.
recommendation for appropriate dose and exposure of tacrolimus to prevent acute rejection have not been established.
In cohort 53 transplant recipient on TAC based therapythe level <8ng/ml throughout first year increased the risk of DSA development and 4-6ng/ml
Serum <8ng/ml 2-3 folder higher risk of acute rejection.
Acute rejection diagnosis:
Gold slandered to diagnose acute rejection is kidney biopsy.
Indication for kidney biopsy:
1. Acute or unexplained deterioration of graft function
2. Presence of biomarker consistent with acute rejection
Allograft histology is interoperated using the Banff classification of kidney allograft pathology.
Diagnostic criteria for T-cell mediated rejection depend on the degree of lymphocyte infiltrate per high-powered field which can involve tubules and large vessels.
Antibody-mediated rejection required 3 features:
1. Acute tissue injury
2. Evidence of current/recurrent antibody interaction with endothelium
3. Serological evidence of DSA or positive c4d or AMR-associated transcripts.
As tissue biopsy is a potential risk for the patient with possible sample error.
Other biomarkers recently emerged to aid in the diagnosis of acute rejection:
1. miR-210 level associated with T cell-mediated rejection
2. cf-DNA donor-derived cell-free DNA in blood for diagnosis of active kidney transplant recipients
tissue biopsy remains the gold standard for diagnosis of acute rejection and biomarker failed completely replace tissue diagnosis.
Acute rejection treatment:
Treatment approach of the transplant recipient with acute rejection relies on accurate diagnosis. Classification of immunological pathology. and type of acute rejection.
T cell-mediated rejection:
Initial treatment phase methylprednisolone at 250—500mg daily for 3-5 days.
T cell-mediated rejection. Banff II and III less as to treat by rATG 1.5mg/kg for 5-7 days.
Antibody-mediated rejection:
Plasma exchange and intravenous Ig with or without a single dose of rituximab limited data in this field
Although there are different approaches. In this type of therapy that no difference in the primary outcome.
Bortezomib and eculizumab CI-Inff medication this role in treatment of AMR still needed more studies.
Subclinical rejection:
Use potential biopsy of stable graft or serum for DSA are used to identify alloimmune response before the onset of clinical graft dysfunction to minimize chronic losses and subsequent graft loss.
Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection for data exist to suggest treatment intervention will affect the clinical cause.
Conclusion:
Treatment of acute rejection episode and effective immunosuppression therapy is mandatory as to preserve graft survival
Tissue biopsy still remaining the gold standard to evaluate acute graft dysfunction.
The Banff criteria for diagnosing antibody-mediated rejection not require the confirmation of DSA and c4d deposition
Several new agents under investigation for treatment.
Further clinical data are needed to determine if the treatment for AMR
Transplantation of donor organs to non-HLA identical recipients introduces stimulants for an alloimmune response. Any graft dysfunction in the transplant recipient still may need to rule out acute rejection. Acute rejection is either T-cell-mediated or antibody-mediated rejection. This review summarize the recent approach to M3K assessment, diagnosis, and treatment of acute rejection.
Acute rejection risk:
Risk factors at the time of transplant:
Ø PRA
Ø Recipient transplant
Ø Black race
Ø Recipient age
Ø In the post-transplant period, acute rejection risk is based on the immunosuppression regimen and exposure
In the united states, 75% of kidney recipients receive rATG induction and >90% receive tacrolimus and mycophenolate mofetil, with or without prednisolone, this regimen is associated with loa were rate of acute rejection.
mTOR is associated with high rate of acute rejection and maintenance
CNI-free maintenance immunosuppression with the result gent belatacept has result in a few recommendations come.
recommendation for appropriate dose and exposure of tacrolimus to prevent acute rejection have not been established.
In cohort 53 transplant recipient on TAC based therapythe level <8ng/ml throughout first year increased the risk of DSA development and 4-6ng/ml
Serum <8ng/ml 2-3 folder higher risk of acute rejection.
Acute rejection diagnosis:
Gold slandered to diagnose acute rejection is kidney biopsy.
Indication for kidney biopsy:
1. Acute or unexplained deterioration of graft function
2. Presence of biomarker consistent with acute rejection
Allograft histology is interoperated using the Banff classification of kidney allograft pathology.
Diagnostic criteria for T-cell mediated rejection depend on the degree of lymphocyte infiltrate per high-powered field which can involve tubules and large vessels.
Antibody-mediated rejection required 3 features:
1. Acute tissue injury
2. Evidence of current/recurrent antibody interaction with endothelium
3. Serological evidence of DSA or positive c4d or AMR-associated transcripts.
As tissue biopsy is a potential risk for the patient with possible sample error.
Other biomarkers recently emerged to aid in the diagnosis of acute rejection:
1. miR-210 level associated with T cell-mediated rejection
2. cf-DNA donor-derived cell-free DNA in blood for diagnosis of active kidney transplant recipients
tissue biopsy remains the gold standard for diagnosis of acute rejection and biomarker failed completely replace tissue diagnosis.
Acute rejection treatment:
Treatment approach of the transplant recipient with acute rejection relies on accurate diagnosis. Classification of immunological pathology. and type of acute rejection.
T cell-mediated rejection:
Initial treatment phase methylprednisolone at 250—500mg daily for 3-5 days.
T cell-mediated rejection. Banff II and III less as to treat by rATG 1.5mg/kg for 5-7 days.
Antibody-mediated rejection:
Plasma exchange and intravenous Ig with or without a single dose of rituximab limited data in this field
Although there are different approaches. In this type of therapy that no difference in the primary outcome.
Bortezomib and eculizumab CI-Inff medication this role in treatment of AMR still needed more studies.
Subclinical rejection:
Use potential biopsy of stable graft or serum for DSA are used to identify alloimmune response before the onset of clinical graft dysfunction to minimize chronic losses and subsequent graft loss.
Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection for data exist to suggest treatment intervention will affect the clinical cause.
Conclusion:
Treatment of acute rejection episode and effective immunosuppression therapy is mandatory as to preserve graft survival
Tissue biopsy still remaining the gold standard to evaluate acute graft dysfunction.
The Banff criteria for diagnosing antibody-mediated rejection not require the confirmation of DSA and c4d deposition
Several new agents under investigation for treatment.
Further clinical data are needed to determine if the treatment for AMR
subclinical will alter outcome, so more studies needed
evidence 5
The rejection could be T cell mediated, Antibody mediated.
The diagnosis is confirmed by gold standard method like graft biopsy. The biopsy is assessed and treatment started according to BENIFF. However, it should confirmed that the level is not high enough causing MAHA/ vasoconstriction/ CNI toxicity, non immunological causes like infection.
After confirming treatment is given accordingly.
Level of evidence V
Please summarise this article
In cases of unexplained graft dysfunction, non-immunological cause such as infection, CNI toxicity, hemodynamic causes and fluid collection need to be excluded. If these are not present, then the next step would be to assess for presence of rejection through renal biopsy and DSA screening. We could apply BANFF criteria to define the type of the rejection whether antibody mediated or cellular rejection. If it is antibody mediated rejection, then provision of plasma exchange, IV IG and rituximab are the mainstay treatment. If the rejection is cellular then the use steroid and rATG is mandatory.
In cases where the biopsy is not feasible, we need to give steroid empirically and do tests for DSA. If the serum creatinine is better in the presence of negative DSA, the management will include optimization of immune-suppressants and follow up. If DSA were positive, then the need for a biopsy is still there once it is feasible. In cases where the AKI is not resolved with positive DSA, then the treatment will be as cases of AMR. If the dysfunction of the graft is severe, ATG is used. If the DSA were negative then rATG alone will be used. The need for renal biopsy is still there except for cases with improved renal function with negative DSA.
What is the level of evidence provided by this article?
Level 5
What is the level of evidence provided by this article?
Level V (review article)
Acute Rejection Risk
An individual’s immunologic risk at the time of transplant has conventionally been attributed to
– overall level of anti-HLA sensitization (panel reactive antibody).
– repeat transplant
– Black race, and
– recipient age.
NB: recently examined traditional risk factors in 527 kidney recipients, showing pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation had no predictive effect.
In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure
Acute Rejection Diagnosis
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy. Allograft histology is interpreted using the Banff classification of kidney allograft pathology.
Many biomarkers have undergone investigations to be used as indicator for acute rejection but still graft biopsy is the gold diagnostic tool
Acute Rejection Treatment
Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
A) T Cell–Mediated Rejection
– Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days for most of Banff class I
– T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
B) Antibody-Mediated Rejection
– A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2
This combination regimen between IVIG& PE is relatively superior to using IVIG /PE alone
– alternative agents for antibody-mediated rejection refractory to “standard” treatment regimens e.g. Bortezomib, The humanized mAb eculizumab, the anti-IL six receptor
antibody tocilizumab, C1-esterase inhibitors (C1-INH)
Types of acute graft rejection :
T cell mediated rejection
Antibody mediated rejection
Each one is associated with unique histologic findings and prognoses, and require distinct approaches to treatment.
Risk factors :
anti-HLA sensitization (PRA), repeat transplant, black race, and recipient age.
Pretransplant DSA and HLA mismatch
Diagnosis of AR:
tissue biopsy is the gold standard for diagnosing and is indicated when there is an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with AR.
Banff classification of kidney allograft pathology help to determind the level of rejection and type of management
TCMR include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis)
AMR (1)Active tissue injury.(2) Immunohistologic evidence of peritubular capillary complement split-product C4d deposition. (3) Circulating DSA.
Treatment :
Treatment strategies differ between TCMR and AMR.
Any untreated clinical AR episode will ultimately result in accelerated graft loss.
TCMR treatment: pulse methylpred at 250–500 mg daily for 3–5 days.
In addittion toT cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
AMR treatment:
Plasma exchange and IVIG, with or without rituximab, was the most commonly used strategy.
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 375 mg/m2.
A recent case series describes successful reduction in plasma cell infiltrate and stabilization of graft function after treatment with bortezomib in patients with plasma cell-rich AR.,
level of evidence: V
Despite historically low acute rejection rates thanks to increasingly effective immunosuppressive protocols, acute rejection episodes continue to affect graft survival and prompt recognition and treatment is crucial. When feasible tissue biopsy should be performed in any patient with unexplained acute graft dysfunction, and accurate assessment of immunologic risk can assist in determining the need for tissue diagnosis. The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition, with several new agents under investigation for treatment. Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
level V
Evaluation and Treatment of Acute Rejection in Kidney Allografts:
___________________________
▪︎The aim of this review is to provide the general nephrologist caring for transplant recipients with an approach to immunologic risk assessment & a summary of recent advances in the diagnosis and treatment of acute graft rejection.
♧Introduction
Initially acute rejection (AR) episodes was known as “steroid responsive” and “steroid nonresponsive,” but now it is broadly characterized as either “T cell mediated (TCMR)” or “antibody mediated (AMR),” respectively.
▪︎These two forms of AR result from separate mechanistic PWs, are associated with unique histologic findings and prognoses, and require distinct approaches to treatment.
♧ Acute Rejection Risk
Immunologic risks at the time of transplant: overall level of anti-HLA sensitization (PRA), repeat transplant, black race, and recipient age.
▪︎Pretransplant DSA and HLA A/B/DR mismatch are the main predictors of AMR
and TCMR, respectively,
▪︎The degree of immunologic risk conferred by pretransplant DSA depends on characteristics of the antibodies detected.
▪︎Lower-level antibodies do not appear to increase AR risk or graft survival in the intermediate term.
▪︎ In the post-transplant period, AR risk is largely determined by immunosuppression regimen and exposure.
♧Diagnosis of AR:
▪︎Assessment of a patient’s immunologic risk at the time of & after transplant.
▪︎A tissue biopsy is the gold standard for diagnosing and is indicated when there is an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with AR.
▪︎Allograft histology is interpreted using the Banff classification of kidney allograft pathology.
▪︎The diagnostic criteria for TCMR include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis), with the severity of these lesions depending on the
degree of lymphocytic infiltrate per high-powered field.
▪︎ Banff classification of acute AMR continues to evolve first was recognized in the early and mid-2000s and required three features for diagnosis:
(1)Active tissue injury.
(2) Immunohistologic evidence of peritubular capillary complement split-product C4d deposition.
(3) Circulating DSA.
▪︎The revised 2013 Banff criteria for AMR diagnosis removed the requirement for C4d detection and broadened this category to include “evidence of current/recent antibody interaction with vascular endothelium,” which may include either (1) positive C4d staining, (2) at least moderate microvascular
inflammation, or (3) increased expression of endothelial gene transcripts.
▪︎The most recent Banff consensus notes studies showing a lack of DSA in patients with biopsy specimens demonstrating significant microvascular inflammation as well as a low false +ve rate of C4d staining, & has now removed the requirement for documented circulating DSA in the setting of positive C4d staining and microvascular inflammation.
▪︎Numerous studies of urine & blood biomarkers, such as CXCL9, CXCL10,
granzyme B, perforin, & Fas ligand, have generally shown mixed sensitivity and specificity for identifying AR, differentiating TCMR from AMR, and distinguishing immunologic injury from other forms of graft damage.
▪︎Short noncoding single-stranded microRNA have improved stability in urine compared with mRNA & decreased urinary miR-210 levels have been associated with TCMR and subsequent 1-year GFR decline.
Recently, donor-derived cell free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of AMR, with results from the multicenter “Circulating Despite the tissue biopsy downfalls, it remains the gold standard for diagnosing AR in transplant recipients and noninvasive biomarkers have failed to
completely replace tissue diagnosis due in part to inconsistent performance between studies.
♧Acute Rejection Treatment
▪︎The approach to treatment of the AR relies on accurate diagnosis and
classification of the immunologic pathology.
▪︎Treatment strategies differ between TCMR and AMR.
▪︎Any untreated clinical AR episode will ultimately result in accelerated graft loss.
♧ TCMR treatment:
▪︎ The treatment of T cell–mediated rejection has changed little over time.
▪︎ Initial treatment conventionally includes pulse methylpred at 250–500 mg daily for 3–5 days.
▪︎Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylpred alone.
▪︎TCMR involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
♧ AMR treatment:
▪︎ Is directed at removing antibody-producing B cells or plasma cells, removing DSA (by plasma exchange, immunoabsorption) , and/or inhibiting the subsequent complement-regulated graft damage.
▪︎Plasma exchange and IVIG, with or without rituximab, was the most commonly used strategy.
▪︎A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2. Or to recieve;
▪︎Monotherapy with IVIG at 2 gm/kg every 3 weeks four doses or a more intensive regime consisting of plasma exchange, IVIG, and 2 doses of rituximab.
▪︎A recent case series describes successful reduction in plasma cell
infiltrate and stabilization of graft function after treatment with bortezomib in patients with plasma cell-rich AR.,
▪︎ The humanized eculizumab has been targeted in the prevention and treatment of AMR.
▪︎Severe AMR are treated with either splenectomy, eculizumab or combination splenectomy& eculizumab.
▪︎A pilot study of the anti-IL six receptor antibody tocilizumab has shown promising results for
patients with chronic AMR.
▪︎C1-esterase inhibitors (C1-INH) have recently been studied for the treatment of acute AMR in patients with AMR deemed non-responsive to conventional treatment.
♧Level of evidence: V
AR has the potential to significantly affect graft survival. Advances IS therapy have improved incidence of AR to approximately 10% and improvements in graft survival.
AR is classified as:
Risk Factors for AR:
Diagnosis:
Tissue biopsy is the gold standard and should be done even in graft dysfunction that is not explained by other nonimmunologic causes.
The diagnostic criteria for TCMR; tubulities and vasculitis
The diagnostic criteria of ABMR include active tissue injury, evidence for C4d deposition, and circulating DSA.
Donor-derived cell-free DNA (cf-DNA) positive predictive value for ABMR of 69% with negative predictive value of 100%, but could not discriminate TCMR
Treatment:
TCMR
methylprednisolone at 250–500 mg daily for 3–5 days
rATG dosed at 1.5 mg/kg for 5-7 doses.
ABMR
PLEX and IVIG, with or without rituximab
PLEX consisting of 1.5 plasma volume removal
IVIG at 100–200 mg/kg
+/- a single dose of rituximab at 375 mg/m2.
Newer drugs:
Bortezomib
Eculizumab
Tocilizumab used for chronic antibody-mediated rejection.
C1-INH
Level of evidence: 5 narrative review.
Summary of the article
“Evaluation and Treatment of Acute Rejection in Kidney Allografts”
This is a review article, aims to provide an approach to immunologic risk assessment and a summary of recent advances in the diagnosis and treatment of acute graft rejection.
Acute Rejection Risk
1) Immunologic risk at the time of transplant has conventionally been attributed to:
a) overall level of anti-HLA sensitization (panel reactive antibody).
b) repeat transplant.
c) black race.
d) recipient age.
2) Wehmeier et al. recently examined traditional risk factorsin KTRs:
a) pretransplant DSA and HLA A/B/DR mismatch to be the main predictors of antibody-mediated rejection and T cell–mediated rejection, respectively.
b) PRA and repeat transplantation had no predictive effect.
3) In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure.
a) Induction with rATG and maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, have historically been associated with lower rates of acute rejection.
b) Strategies to reduce CNI exposure; using mTOR’s have generally been met with higher rates of acute rejection and side effects.
c) CNI- free maintenance immunosuppression with the newer agent belatacept has resulted in favorable, longer-term outcomes but with higher rates of TCMR.
d) Belatacept (versus cyclosporine) has shown a significant reduction in DSA development.
e) Adams et al.; center’s experience showing significant reduction in acute rejection in patients treated with belatacept by adding tacrolimus to the existing belataept regimen followed by a steady taper over the first post-transplant year (acute rejection rates of 51% with belatacept alone versus 16% with belatacept plus tacrolimus taper).
Acute Rejection Diagnosis
1. Tissue biopsy is the gold standard for diagnosing acute rejection in kidney transplant recipient. Allograft histology is interpreted using the Banff classification of kidney allograft pathology. Indications for graft biopsy:
a) unexplained deterioration in graft function.
b) the presence of a biomarker consistent with acute rejection.
2. AMR; features for diagnosis:
a) Active tissue injury.
b) Immunohistologic evidence of peritubular capillary complement split-product C4d deposition.
c) Circulating DSA.
3. TCMR; diagnostic criteria include:
a) Lymphocytic infiltrate of tubules (tubulitis) and larger vessels(vasculitis).
b) With the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field.
4. Histologic criteria for diagnosing acute allograft rejection(according to Banff 2017 guidelines)
A. Acute T cell–mediated rejection (TCR)
Ia: >25% Interstitial inflammation with moderate tubulitis (t2).
Ib: >25% Interstitial inflammation with severe tubulitis (t3).
IIa: Mild-to-moderate intimal arteritis (v1).
Iib: Severe intimal arteritis (v2).
III: Transmural arteritis and/or fibrinoid necrosis.
B. Acute antibody-mediated rejection (AMR): all three criteria below required
1) Histologic evidence of tissue injury including one or more of the following:
a) Microvascular inflammation (g.0 and/or ptc.0) Arteritis (v>0).
b) Thrombotic microangiopathy.
c) Acute tubular injury
2) Evidence of current/recent antibody interaction with endothelium including one or more of the following:
a) Positive C4d staining of peritubular capillaries.
b) Moderate microvascular inflammation (g+ptc³2).
c) Increased expression of gene transcripts in biopsy tissue strongly associated with AMR.
5. Noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies.
3) Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Acute Rejection Treatment
1. Management relies on:
· Timely recognition and accurate diagnosis.
· Classification of the immunologic pathology.
2. Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
3. T Cell–Mediated Rejection:
a) Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days.
b) T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
4. Antibody-Mediated Rejection:
a) Antibody- mediated rejection treatments are directed at:
· removing antibody-producing B cells or plasma cells.
· removing antibodies (DSA).
· inhibiting the subsequent complement-regulated graft damage.
b) Standard of care for AMR(“standard” treatment regimens): plasma exchange and intravenous Ig (IVIG), with or without rituximab, was the most commonly used strategy.
· A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
· Lefaucheur et al. randomized 24 patients with antibody-mediated rejection to receive either monotherapy with IVIG at 2 gm/kg every 3 weeks(four doses) or a more intensive regimen consisting of plasma exchange, IVIG, and two doses of rituximab.Patients receiving more intensive therapy experienced greater reduction in DSA with 92% graft survival at 3 years compared with 50% in those receiving IVIG alone.
· Sautenet et al. (34) attempted to clarify the utility of rituximab in combination with standard plasma exchange/IVIG therapy with the multicenter, blinded, randomized, placebo-controlled “Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Trans- plantation” (RITUX-ERAH) trial. There was no difference in the composite primary outcome of graft loss or improvement in graft function at day 12; however, a large crossover between groups limits accurate interpretation of these data.
5. Alternative agents for AMR refractory to “standard” treatment regimens:
· Bortezomib, an approved proteasome inhibitor for treatment of multiple myeloma; there is minimal effect on DSA burden when used as a sole agent , with mixed results when used in combination with plasma exchange/IVIG.
· Eculizumab, the humanized mAb (C5 inhibitor) has been targeted in the prevention and treatment of antibody-mediated injury.
· Tocilizumab, anti-IL-6 receptor antibody has shown promising results for patients with chronic antibody-mediated rejection. (43), a disease for which there is currently no proven treatment; however, this agent has not been studied in the treatment of acute AMR.
· C1-esterase inhibitors (C1-INH) have recently been studied in two small studies for the treatment of acute AMR. C1-INH inhibits proximal enzymes in the classic complement pathway including C1q, and reports of poor outcomes after detection of C1q-binding DSA provide further rational for its use in AMR.
6. Subclinical Rejection:
a) to identify and treat alloimmune responses before the onset of clinical graft dysfunction, this approach involves:
· Protocol biopsy of stable grafts.
· Screening biomarkers such as DSA.
b) The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low, and long- term outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection.
· In 121 patients treated with tacrolimus, mycophenolate mofetil, and prednisone and randomized to protocol versus indication-only biopsies, the incidence of subclinical T cell–mediated rejection was only 5%, with no difference in graft function at 6 months despite those with subclinical rejection receiving treatment.
c) Subclinical antibody-mediated rejection, in contrast, represents an attractive therapeutic target given the attributed poor long-term outcomes, likely via progression to chronic antibody-mediated rejection over time.
· Using DSA as a biomarker, studies have shown approximately 50% of patients with stable function and de novo DSA will show evidence of subclinical antibody-mediated rejection on biopsy.
· Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection, few data exist to suggest treatment intervention will alter the clinical course.
· Orandi et al. published a retrospective analysis of 77 patients with subclinical antibody- mediated rejection diagnosed by protocol biopsy, 54% of which received treatment with various combinations of plasma exchange, IVIG, rituximab, and eculizumab. With a mean follow-up of 5.2 years, overall rates of graft loss were similar between those treated and untreated. However, when compared with matched controls, treated patients experienced a lower risk of graft loss versus untreated patients. Thus, although the prospect of identifying subclinical antibody-mediated rejection before clinical dysfunction remains attractive, more data are needed before concluding that treatment of this population will improve the long-term clinical course.
What is the level of evidence provided by this article?
This is a narrative review article
Level of evidence grade 5
Evolution of immunosuppressive agents
Over time AR rates have steadily declined from nearly 100% in the first era of organ transplantation to approximately 10% more recently
With dramatic improvements in 1-year graft survival, especially after the introduction of cyclosporine in the mid-1980s and T cell–depleting induction in the mid-1990s
the classification of clinical AR
“steroid responsive” and “steroid nonresponsive,”
now either “T cell mediated” or “antibody mediated,”
Acute Rejection Risk
• level of anti-HLA sensitization (PRA),
• repeat transplant,
• black race,
• recipient age.
• pretransplant (DSA) / AMR /
• HLA A/B/DR mismatch / T cell–mediated rejection
• Patient with pretransplant DSA at titers strong enough to warrant desensitization before transplant will experience acute AMR, whereas lower-level antibodies do not appear to increase AR risk or graft survival
In the post-transplant period,
Belaracept
A high index of suspicion of AR , would be warranted in
• a young patient
• with lower tacrolimus trough levels
• during the first post-transplant year
• and/or suspected immunosuppression non-adherence.
Nonimmunologic causes may first be considered AR
• older patient
• who received rATG induction
• with consistently therapeutic tacrolimus level
Acute Rejection Diagnosis
1—- The gold standard for diagnosing is tissue biopsy.
Indications of graft biopsy
Allograft histology is interpreted using the Banff classification of kidney allograft pathology
T cell–mediated rejection diagnostic criteria
Banff classification of acute AMR
AMR required three features for diagnosis:
(1) active tissue injury,
(2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition, and
(3) circulating DSA.
EXceptions to these initial criteria, C4d -negative AMR .
2013 Banff criteria for AMR diagnosis removed the requirement for C4d detection and broadened this category to include
either
(1) positive C4d staining,
(2) at least moderate microvascular inflammation,
or (3) increased expression of endothelial gene transcripts
The most recent Banff consensus now removed the requirement for documented circulating DSA in the setting of positive C4d staining and microvascular inflammation
2—- urine and blood biomarkers,
such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have generally shown mixed sensitivity and specificity for identifying AR, differentiating T cell–mediated rejection from AMR
Decreased urinary miR-210 levels have been associated with T cell–mediated rejection
Recently, donor-derived cell free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of AMR.
This study associated cf-DNA levels with 242 biopsy specimens (204 clinically indicated) and showed a negative predictive value for antibody-mediated rejection of 96% when using a cut-off value of 1% in recipient blood; however, positive predictive value was only 44%
T Cell–Mediated Rejection treatment
pulse methylprednisolone at 250–500 mg daily for 3–5days,as recommended by international guidelines
Treatment is ultimately guided by biopsy findings,
Banff class 1 lesions
responding to methylprednisolone alone.
(Banff II and III lesions)
generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection treatments
A systematic review by Roberts et al. identified 12 comparative trials of AMR treatment from 1950 to 2011
The authors report low-quality evidence supporting antibody removal therapies (plasma exchange ), and very low-quality evidence for all other treatments.!!!
Nevertheless, plasma exchange and intravenous Ig (IVIG), with or without rituximab, was the most commonly used strategy and is generally considered standard of care for AMR.
daily or every other day plasma exchange consisting of 1.5 plasma volume
100–200 mg/kg,
a single dose at 3.75 mg/m2.
Patients receiving more intensive therapy experienced greater reduction in DSA with 92% graft survival at 3 years compared with 50% in those receiving IVIG alone.
alternative agents for AMR refractory to “standard” treatment regimens.
Bortezomib,
eculizumab
A pilot study of the anti-IL
tocilizumab has shown promising results for patients with chronic AMR
(C1-INH)
have recently been studied for the treatment of AMR.
poor outcomes after detection of C1q-binding DSA
Subclinical Rejection
Level V
Introduction
Graft rejection remains an important cause of graft dysfunction despite improvements in immunosuppressive therapy regimens. It is important to understand the mechanisms underlying graft rejection. Acute rejection significantly affects graft survival and should be high on the list of differential diagnosis for unexplained graft dysfunction in a transplant recipient.
Acute rejection can be broadly classified as either T cell mediated or antibody mediated. These forms result from separate mechanistic pathways and are associated with unique histologic findings and prognoses, and therefore require different approaches to management.
Acute rejection risk
The immunologic risk of rejection at the time of transplant can be due to overall level of anti-HLA sensitization, repeat transplant, black race and recipient age. HLA A/B/DR mismatch has been shown to be the main predictor of T-cell mediated rejection and donor-specific antibodies (DSA) has been shown to be the main predictor of antibody-mediated rejection. In the post-transplant period, the risk of acute rejection also depends on the immunosuppression regimen and exposure.
Acute rejection diagnosis
The gold standard for diagnosis acute rejection in kidney transplant recipients is tissue biopsy. The indications to biopsy are acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection. The assessment of the patient’s immunologic risk at the time of and after the transplant can help further determine the possibility of acute rejection. Allograft biopsy is generally considered a safe procedure and should be pursued without delay in patients with graft dysfunction not explained by other non-immunologic causes. Allograft histology is interpreted using the Banff classification of kidney allograft pathology.
The diagnostic criteria for T-cell mediated rejection include lymphocytic infiltrates of tubules and larger vessels. Antibody-mediated rejection requires three features for diagnosis: active tissue injury, immunohistologic evidence current or recent antibody interaction with vascular endothelium and circulatory DSA.
Acute rejection treatment
The approach to treatment depends on the accurate diagnosis and classification of immunologic pathology. Graft prognosis depends on the severity and type of lesions.
For T-cell mediated rejection, initial treatment includes pulse methylprednisolone at 500mg daily for 3-5 days. For T-cell mediated rejection involving lymphocytic infiltrate vasculature, rATG is needed at 1.5 mg/kg for five to seven doses.
For antibody-mediated rejection, treatment is targeted at removing antibody-producing B cells or plasma cells, removing DSA or inhibiting the subsequent complement-regulated graft damage. Plasma exchange and intravenous Ig (at 100-200mg/kg), with or without rituximab is most commonly used.
Humanized mAb eculizumab is used in the treatment and prevention of antibody-mediated rejection as inhibits C5. But it has high rates of infection in patients undergoing combination therapy.
Subclinical rejection
This approach involves the identification and treatment of alloimmune responses before the onset of clinical graft dysfunction by protocol biopsy of stable grafts or the use of screening biomarkers such as DSA, to identify patients at risk for subclinical T-cell mediated rejection.
More data is required before concluding that this approach will improve the long-term clinical course.
Conclusion
It is crucial to identify early signs of acute rejection to initiate treatment. When feasible, kidney biopsy aids in targeted treatment for better rates of graft survival. In situations where kidney biopsy is not feasible and infections have been ruled out, empiric therapy with pulse methylprednisolone can be used while awaiting for DSAs. If the graft function does not resolve, then one can use ATG (if DSAs are negative) or plasma exchange (if DSAs are positive)
Level of evidence
This is a systemic review, therefore the level of evidence is V
Please summarise this article
Acute rejection has negative effect on graft outcomes. Over the period of time the incidence is decreasing . This can be multifactorial and one of the factor is newer immune suppressive therapies and our understanding of immune response.
Risk Factors for Acute Rejection
Pre transplant DSA levels
HLA Mismatch
Repeated transplant
Blood transfusions
High PRA
Diagnosis of Acute Rejection
Gold standard is biopsy
Indications of biopsy include –
unexplained deterioration in graft function
Presence of a biomarker consistent with acute rejection
Interpretation is done using Banff Classification
The diagnostic criteria for T cell–mediated rejection have been revised
Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
For ABMR
Acute antibody-mediated rejection (AMR): all three criteria below required
Histologic evidence of tissue injury
Evidence of current/recent antibody interaction with endothelium
Serologic evidence of donor-specific antibodies (DSA)
Treatment-
TCMR- High doses of methylprednisolone
rATG in Banff 2/3
ABMR-
Options include-
Plasmaphresis with IVIG with or without Rituximab
other options include
Boretizumib
Eculizumib
Tocilizumab
C1 estrase inhibitors
Conclusion
Acute rejection episodes affect graft survival
Prompt diagnosis and early treatment is mandatory.
Biopsy should be performed in any patient with unexplained acute graft dysfunction
Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition
What is the level of evidence provided by this article?
Level 5
Acute rejection has long term adverse effect on the graft survival
· Should be on the top of list of differential diagnosis of acute graft dysfunction.
· cases with none adherence to therapy, early presentation post-transplant and not achieving target trough level of tacrolimus are at high risk of rejection.
· 1st step of management includes exclusion of none immunological causes as dehydration, prerenal injury, CNI toxicity and infections, then investigate rejection.
· Risk factors for rejection include:
o presence of HLA mismatch.
o pre-transplant DSA and its level.
o positive PRA.
o Previous transplantation and other sensitizing events as blood transfusion.
depend on Banff classification of the the kidney biopsy, after thorough assessment of recipient immunologic risk.
TCMR depends on the extent of involvement of interstitium and severity of tubular damage. Which is Stage 1a and 1b. Stage II describes the intimal arteritis involvement and Class III transmural inflammation.
ABMR:
Special revised criteria has been implemented with emphasis on evidences of endothelial inflammation secondary to interaction with systemic DSAs ,in the form of C4d staining which was substituted with evidence of endothelial inflammation or evidence of increased gene transcript of.
Treatment :
Depend on reversal of the rejection process , in TCMR with high doses of methylprednisolon.
For ABMR the approach is multiple with Plasma pheresis to remove the DSAs, Rituximab to abolish the B cell population responsive to the rejection stimulus. and IVIG to offset the immune system and replace the immunoglobulins. Furthermore , Bortezomib and Eculizumab might be implicated to salvage the allograft function.
Acute allograft rejection is the main complication encountered in the short term period post transplantation as well as the on the long run. It might harbor a detrimental consequences on the allograft survival.
Immunological risk factors includes:
!}PRA which reflect the entire HLA sensitization.
2} Repeat transplant.
3} black race
4} recipient age, young is more vulnerable then elderly people .
While pre transplant DSA level is the main anticipant for ABMR , HLA A, B DR mismatching are the main determinant of ACMR. Furthermore , the DSAs type is crucial in provoking the ABMR. An elevated DSAs level that is pertinent for desensitization protocol is potentially prone for ABMR post sensitization in 30-50% of the desensitized patients.
The immunosuppressive protocol is playing a pivotal role in preventing the rejection risk. The current protocol is based on rTAG for induction and Tacrolimus dependent maintenance protocol.
Protocols to reduce CNI toxicity involved using mTORs with lower dose of CNI was adopted , with higher incidence of acute rejection and side effects.
CNI free protocol featuring Belatacept as the main immunosuppressant is associated with improved long term outcome , however , with escalated risk of TCMR to affect 50% of the patients on Belatacept..
Interestingly, despite the fact that TCMR was commonly encountered in this protocol , ABMR incidence was significantly less reported and the DSAs level was crucially less than counterparts control cohort.
This soaring incidence of TCMR was curtailed by adding CNI to the regimen , resulting in reducing the incidence to 16% from 50% .
Tacrolimus trough level was allegedly linked to the risk of TCMR and development of de novo DSAs , Therefore Trough level below 8 was reported to cast higher risk than those above 8 ng/ml.
Acute rejection diagnosis:
Depend on Banff classification of the the kidney biopsy, after thorough assessment of recipient immunologic risk.
TCMR depends on the extent of involvement of interstitium and severity of tubular damage. Which is Stage 1a and 1b. Stage II describes the intimal arteritis involvement and Class III transmural inflammation.
ABMR:
Special revised criteria has been implemented with emphasis on evidences of endothelial inflammation secondary to interaction with systemic DSAs ,in the form of C4d staining which was substituted with evidence of endothelial inflammation or evidence of increased gene transcript of.
Treatment :
Depend on reversal of the rejection process , in TCMR with high doses of methylprednisolon.
For ABMR the approach is multiple with Plasma pheresis to remove the DSAs, Rituximab to abolish the B cell population responsive to the rejection stimulus. and IVIG to offset the immune system and replace the immunoglobulins. Furthermore , Bortezomib and Eculizumab might be implicated to salvage the allograft function.
Its a narrative paper with level 5 of incidence
Evidence *
Club 2 ; Acute rejection
Summary:
· Acute rejection has long term adverse effect on the graft survival
· Should be on the top of list of differential diagnosis of acute graft dysfunction.
· cases with none adherence to therapy, early presentation post-transplant and not achieving target trough level of tacrolimus are at high risk of rejection.
· 1st step of management includes exclusion of none immunological causes as dehydration, prerenal injury, CNI toxicity and infections, then investigate rejection.
· Risk factors for rejection include:
o presence of HLA mismatch.
o pre-transplant DSA and its level.
o positive PRA.
o Previous transplantation and other sensitizing events as blood transfusion.
· Graft biopsy is the golden standard for diagnosis. Banff classification developed in 1990 and updated regularly.
· TCMR has recently included tubulitis and vasculitis.
· ABMR is diagnosed based on histological evidence of tissue damage in addition to evidence of C4D (complement activated and covalent bonding with peritubular capillaries) or circulating antibodies (DSA).
· Currently, at least moderate microvascular inflammation, or increased expression of endothelial gene transcripts can be used as an evidence of ABMR in c4d negative cases.
· New biomarkers as urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand can be utilized to avoid unnecessary biopsy and for early detection and diagnosis of rejection.
o Decreased urinary micro RNA levels have been associated with T cell–mediated rejection
o Donor-derived cell free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of antibody-mediated rejection
· Pulse steroids is the most common used drug and reverse graft dysfunction in most of cases.
· Additionally, rabbit ATG can be used for steroid refractory TCMR or Banff stage starting from II b, and IVIG and PEX can be used in ABMR.
· Bortezomib (plasma cells apoptosis) and Ecluzimab (terminal complement inhibition) can be considered in resistant ABMR.
· Nowadays, most of cases receive induction therapy then tacrolimus based triple maintenance immunosuppressive therapy with marked decline in the incidence of acute rejection.
· Level of evidence: narrative review (level V)
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Acute rejection, when it occurs, has the potential to significantly affect graft survival. Advances in immunosuppressive therapy have drastically improved acute rejection rates to approximately 10%, resulting in dramatic improvements in graft survival.
Acute rejection is now broadly characterized as:
-T cell-mediated rejection.
-Antibody-mediated rejection.
Factors that increase the immunologic risk at the time of transplant:
– Overall level of anti-HLA sensitization (panel reactive antibody).
– DSA level predicts ABMR, and HLA A/B/DR mismatch predicts TCR.
– Repeat transplant.
– Black
– Race.
– Recipient age
In the post-transplant period, AR risk is determined mainly by IS regimen and exposure.
AR should remain high on the differential diagnosis for unexplained graft dysfunction in a KTR; assessment of overall immunologic risk can help estimate AR probability.
Acute Rejection Diagnosis:
Tissue biopsy is the gold standard and should be done in patients with graft dysfunction that is not explained by other nonimmunologic causes.
Allograft histology is interpreted using the Banff classification, and diagnostic criteria are revised.
The diagnostic criteria for TCMR; lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis).
The diagnostic criteria of ABMR include; active tissue injury, evidence for C4d deposition, and circulating DSA.
Multiple non-invasive biomarkers (Urine and blood) mixed sensitivity and specificity
Donor-derived cell-free DNA (cf-DNA) PPV for ABMR of 69% with a NPV of 100%, but did not discriminate those with TCMR
Acute Rejection Treatment
Graft prognosis after treated AR also depends on type and severity. Thus, timely recognition and diagnosis of AR is crucial to promptly initiate appropriate treatment.
Biopsy findings ultimately guide treatment.
T Cell-Mediated Rejection
methylprednisolone at 250–500 mg daily for 3–5 days
T cell–depleting therapy, rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection:
PLEX and intravenous Ig (IVIG), with or without rituximab, were the most commonly used
PLEX consisting of 1.5 plasma volume removal daily or EOD
Followed by IVIG at 100–200 mg/kg,
with or without a single dose of rituximab at 375 mg/m2.
Other agents:
Bortezomib induces apoptosis in antibody-producing plasma cells
Eculizumab has been targeted in the prevention and treatment of ABMR.
Tocilizumab anti-IL 6 antibodies; for chronic antibody-mediated rejection.
C1-esterase inhibitors (C1-INH)
Subclinical Rejection:
The identification and treatment before the onset of clinical graft dysfunction may minimize the development of chronic
lesions that ultimately lead to graft loss.
This includes protocol biopsy or screening with DSA of stable grafts to identify patients at risk for subclinical immunologic lesions.
The incidence of subclinical TCMR is low and does not appear to be as severely affecting the long-term graft outcome.
In contrast, subclinical ABMR is attributed to poor long-term outcomes.
Few data exist to suggest treatment intervention, and further clinical data are needed to determine if treatment will alter
clinical outcomes.
Level of evidence: 5 narrative review.
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Please summarise this article
-Transplantation of donor organs to non-HLA identical recipients introduces a stimulus for alloimmune responses, clinically referred to as graft rejection.
Acute Rejection Risk
-An individual’s immunologic risk at the time of transplant has conventionally been attributed to factors such as overall level of anti-HLA sensitization (panel reactive antibody), repeat transplant, black
race, and recipient age.
-In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure.
Acute Rejection Diagnosis
-The gold standard for diagnosing acute rejection in kidney transplant recipients is allograft biopsy.
Acute Rejection Treatment
-The approach to treatment of the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology.
-Treatment strategies differ between T cell–mediated rejection and
antibody-mediated rejection, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
-Graft prognosis after treated acute rejection depends on type and severity ; however, any untreated clinical acute rejection episode will ultimately result in accelerated graft loss.
T Cell–Mediated Rejection
– Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days, as recommended by international guideline.
– T cell–mediated rejection involving lymphocytic infiltrate of the vasculature (Banff II and III lesions) generally requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection
-Antibody mediated rejection treatments are directed at removing
antibody-producing B cells or plasma cells, removingantibodies (DSA), and/or inhibiting the subsequentcomplement-regulated graft damage .
-Identifying subclinical antibody-mediated rejection provides an opportunity to intervene before the onset of clinical dysfunction; however, further clinical data are needed to determine if treatment will alter clinical outcomes.
What is the level of evidence provided by this article?
Level 5
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Introduction
Acute rejection significantly affects graft survival and it should be kept on high index of suspicion when graft dysfunction occurs.
Acute rejection is broadly characterized in two categories:
This review has summarized risk assessment, diagnosis and treatment of acute rejection.
Acute rejection risk
Factors contributing to immunologic risk of recipient:
Pre transplant DSA predicts AMR
HLA A/B/DR mismatch predicts ACR.
In post transplant period, acute rejection risk is also primarily determined by the immunosuppression regimen. Induction immunosuppression in majority of recipients in USA is rATG and maintenance immunosuppression includes triple drug therapy (Tacrolimus, MMF, steroids)
Acute rejection risk
GOLD STANDARD for diagnosing ACUTE REJECTION is graft biopsy. it should be performed if :
Grading of acute rejection is done using BANFF CLASIFICATION OF KIDNEY ALLOGRAFT PATHOLOGY which is continuously evolving and most updated version is of year 2017.
Diagnostic criteria
2017 Banff classification updates:
# Phenotypes of AMR without detectable C4d staining
#Lack of DSA in patients whose graft biopsy shows microvascular inflammation
Newer Diagnostic techniques for acute rejection
But still biopsy remains the gold standard for diagnosis of acute rejection
Acute rejection treatment
Several drug combinations have been studied to treat rejection. The most commonly followed is Plasma exchange + IVIG + rituximab for AMR and rATG for any TCR with grade > II.
Newer antirejection medications:
Conclusion
I like your summary and analysis.
It is level 5 evidence.
Ajay
INTRODUCTION
· Acute rejection classified as “T cell mediated” (previously steroid responsive) “antibody mediated” (steroid nonresponsive)
· This review will summarize a modern approach to risk assessment, diagnosis, and treatment of acute rejection.
Acute Rejection Risk
· pretransplant donor-specific antibodies (DSA) and HLA A/B/DR mismatch
· The use of rapamycin inhibitors (mTOR’s) to reduce CNI exposure have higher rates of acute rejection and side effects
· CNI free maintenance immunosuppression with belatacept has higher rates of T cell–mediated rejection
· Lower doses of Tacrolimus associated with higher risk of rejection
Acute Rejection Diagnosis
· The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy
· Banff classification of acute antibody mediated rejection required three features for diagnosis: (1) active tissue injury
(2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition
(3) circulating DSA
· the revised 2013 Banff criteria for antibody mediated rejection diagnosis removed the requirement for C4d detection, as it could be negative
· Recently, the requirement for documented circulating DSA in the setting of positive C4d staining and microvascular inflammation, had removed, as DSA can be negative
· Recently, donor-derived cellfree DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of antibody-mediated rejection, with high negative predictive value but positive predictive value was only 44%
Treatment of acute T Cell–Mediated Rejection
· Initial treatment pulse methylprednisolone at 250–500 mg daily for 3–5 days, guided by biopsy
· Banff class 1 lesions mostly respond to methylprednisolone alone
· Banff II and III lesions requires T cell–depleting therapy, most commonly rATG dosed at 1.5 mg/kg for five to seven doses
Treatment of acute Antibody-Mediated Rejection
· plasma exchange (daily or every other day) with 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2
Subclinical Rejection
· The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low, and longterm outcomes less severe than with subclinical antibody-mediated rejection
Conclusions
· Inspite of effective immunosuppressive protocols, acute rejection still occurs
· Tissue biopsy should be performed in any patient with unexplained acute graft dysfunction
· The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition
What is the level of evidence provided by this article?
Evidence 5
Well done conclusions are clear Thankyou
Summary
Introduction:
Before the use of immunosuppressive medications, graft rejection was significant. With the aid of scientific investigations and the development of new drugs that are immunosuppressive, the rejection or acute rejection of the graft has significantly reduced. There has been less acute rejection. With only about 10% of acute rejection as it relates to the immunosuppressive.
One of the main concerns is acute rejection which still is of major concern. It can be classified as either T CELL MEDIATED OR ANTIBODY MEDIATED.
This study is to identify the type of acute rejection and how it is managed.
To have acute graft rejection, there has been some form of risk factors and they are:
1) ANTI-HLA sensitization
2) Repeated graft transplantation
3) The black race and
4) The recipient’s age.
5) Post-transplant period the immunosuppression used
6) The lesser use of CNI IS RELATED WITH HIGHER REJECTION then using mTORi
7) With the introduction of newer medication, like belatacept has improved graft survival.
8) The use of other medications like tacrolimus has been a risk of acute graft rejection.
The diagnosis of acute rejection is totally dependent on kidney or graft biopsy. Using the Banff classification of kidney histology gives a concise idea of what type of rejection it is and as such the treatment of it. Apart from the kidney biopsy, other markers can be used but they are not as specific as the kidney or graft biopsy. For example, urine and blood markers like CXCL9, CXCL 10 perforin, etc., can be used but not as specific as the biopsy.
Once the biopsy has been performed it can classify acute rejection as:
1) T cell-mediated rejection
2) Antibody-mediated rejection.
T cell-mediated rejection two types of treatment can be used they are methylprednisone and the rATG.
In light of the antibody-mediated rejection, the medications that can be used are plasma exchange, IVIG, Bortezomib, eculizumab, tocilizumab, and C1 esterase inhibitors.
In conclusion, acute rejection is still a very important issue, especially if not detected on time. Once detected early with kidney biopsy and using Banff classification appropriate treatment can be given to allow the graft to function normally and to minimize rejection.
The level of the article is level 5
Thank you
#Please summarise this article
# The aim of the study:
To administer the caring for transplant recipients with an approach to immunologic risk evaluation and give a summary of new advances in the diagnosis and treatment of acute graft rejection.
# Introduction
*With time the immunosuppressant agents have become importantly inhibiting the transplant recipient’s immune response, as a result, the incidence of AR have steadily decreased from nearly 100% to10%.
*After the introduction of cyclosporine and T cell–depleting there is dramatic improvements in 1-year graft survival,
# Acute Rejection Risk:
* Wehmeier et al. recently conducted that pre-transplant (DSA) and HLA A/B/DR mismatch to be the main predictors of ABMR and TCMR respectively.
*The RA and repeat transplantation had no predictive effect.
* Around 30%–50% of pre-transplant DSA at titers strong enough to warrant desensitization before transplant will experience acute AMR whereas lower-level antibodies do not appear to increase AR risk or graft survival in the intermediate term.
*Post-transplant period, AR risk is determined by immunosuppression regimen -and exposure, recipients who received (rATG) induction, tacrolimus and mycophenolate mofetil, with or without prednisone, have lower rates of AR.
*Protocols used to decrease the (CNI) exposure by using (mTOR’s) associated with higher rates AR and S/E.
*CNI maintenance immunosuppression with the belatacept has lead to acceptable longer-term outcomes but with increase incidence of TCMR, but post hoc analysis has shown a n important reduction in DSA development in those receiving belatacept versus cyclosporine
* Adams et al. showed significant reduction in AR in patients have additional tacrolimus to the existing belatacept regimen followed by a steady taper over the first PKT year.
*Non-immunologic causes may first be considered in an older patient who received rATG induction with consistently therapeutic tacrolimus levels.
# Acute Rejection Diagnosis
*The gold standard for diagnosing AR in KT recipients is tissue biopsy.
*Indications
*AR include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with AR.
*Allograft biopsy is a safe procedure and should be pursued without delay in patients with graft dysfunction that is not explained by other non-immunologic
causes.
*Using the histologic criteria for diagnosing acute allograft rejection according to Banff 2017 guidelines for interpretation.
*Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
#Acute antibody-mediated rejection (AMR):
All three criteria below required
Histologic evidence of tissue injury including one or more of the following:
*Microvascular inflammation (g.0 and/or ptc.0)
*Arteritis (v.0)
*Thrombotic microangiopathy
*Acute tubular injury
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
*Positive C4d staining of peritubular capillaries
*Moderate microvascular inflammation (g+ptc >/2)
*Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA.
# Acute Rejection Treatment
*It is relies on accurate diagnosis and classification of the immunologic pathology.
* Treatment strategies differ between TCMR and ABMR, and aggressiveness of treatment generally follows severity of lesions that are diagnosed.
* The treatment options include:
Methylprednisolone
* Indication: in TCR: Banff Ia, Ib
*Mechanism: it has multiple, anti-inflammatory glucocorticoids effects
*Adverse Effects: Hyperglycemia, hypertension, other metabolic effects
rATG
* Indication: TCR: Banff Ib, IIa, IIb, III
*Mechanism: T cell depletion
*Adverse Effects: Fever, chills, hypertension, hypotension, leukopenia, infusion reaction, serum sickness
Plasma exchange
* Indication: AMR
*Mechanism: Antibody removal
*Adverse Effects: Fevera, chillsa, urticariaa, TRALIa, bleeding
IVIG
* Indication: AMR
*Mechanism: Multiple “immunomodulatory” effects including antibody
clearance, neutralization, and inhibited production, Fc receptor saturation,
complement inhibition
*Adverse Effects: Infusion reaction including headache,
fever, chills, urticaria, back pain, abdominal pain, nausea, vomiting
Rituximab
* Indication:
*Mechanism: AMR Anti-CD20 B cell depletion
*Adverse Effects: Infusion reaction, HBV reactivation, PML
Bortezomib
* Indication: AMR
*Mechanism: Plasma cell apoptosis via proteasome inhibition
*Adverse Effects: Peripheral neuropathy, fatigue, generalized weakness
Eculizumab
* Indication: AMR
*Mechanism: Terminal complement C5 inhibition
*Adverse Effects: Meningococcal infection, influenza, peritonitis
C1-INH
* Indication: AMR
*Mechanism: Classic complement pathway inhibition
*Adverse Effects: Headache
# T Cell–Mediated Rejection
*The initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily for 3–5 days, as recommended by international guidelines *Treatment is ultimately guided by biopsy findings, with the majority of Banff class 1 lesions responding to methylprednisolone alone.
*The Banff II and III lesions requires T cell–depleting therapy, rATG dosed at 1.5 mg/kg for five to seven doses.
*An updated Cochrane Database review published in 2017 concluded antibody therapy was superior to steroid therapy in reversing TCMR with no effect on subsequent acute rejection incidence or patient survival.
#Antibody-Mediated Rejection
*ABMR treatments are directed at removing antibody-producing B cells or plasma cells, removing (DSA), and/or inhibiting the subsequent complement-regulated graft damage.
* (PE) and (IVIG), with or without rituximab, was the most commonly used
strategy and is generally considered standard of care for ABMR treatment.
* A typical regimen includes daily or every other day (AE) consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
* Patients receiving more intensive therapy experienced greater reduction in DSA with 92% graft survival at 3 years compared with 50% in those receiving IVIG alone.
*Study showed successful reduction in plasma cell infiltrate and stabilization of graft function after treatment with bortezomib in several patients with plasma cell-rich AR, a rare histologic finding historically associated with poor outcomes despite aggressive treatment.
*Eculizumab has been targeted in the prevention and treatment of antibody-mediated injury because of its mechanism of complement component C5 inhibition.
# Subclinical Rejection
*The use of protocol biopsy of or screening biomarkers such as DSA may detect the risk of subclinical immunologic rejection.
*The rate of subclinical T CMR in the modern era of immunosuppression is low and long term outcomes do not severely affected compared to subclinical ABMR.
# What is the level of evidence provided by this article?
*Level 5
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Summary:
Acute Rejection Risk:
Traditional risk factors for rejection:
Acute Rejection Diagnosis:
Acute T cell-mediated rejection (TCR):
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
Acute antibody-mediated rejection (AMR):
All three criteria below required:
Microvascular inflammation (g.0 and/or ptc.0)
Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc >2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Positive C4d staining or the presence of AMR-associated gene transcripts may substitute for DSA.
Recently, donor-derived cell-free DNA (cf-DNA) profiling has been applied to the noninvasive diagnosis of antibody-mediated rejection. It is found to have a negative predictive value for rejection, thus normal results may offer a level of reassurance to providers and patients with abnormal clinical findings (DSA, graft dysfunction) in whom tissue biopsy is either not feasible or considered too high risk.
Acute Rejection Treatment
T Cell–Mediated Rejection
Antibody-Mediated Rejection
Subclinical Rejection
Level of Evidence:
Level 5 ( review article ).
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
thank you
Transplantation of donor organ to HLA noncomptable recipient initiate an immunological
response leads to rejection, which reduced I incidence now from 100 percent to only
10%.
Acute Rejection Risk:
Pretransplant:
DSA) and HLA A/B/DR mismatch.
Posttransplant:
Immunosuppression .
CNI free regimen associate with risk of rejection, adequate dose and trough level reduce
risk of rejection. Calcineurin inhibitor free maintenance immunosuppression with the
newer agent belatacept has resulted in favorable, longer-term outcomes but with higher
rates of rejection also.
A high index of suspicion, young patient with lower tacrolimus trough levels during the
first post-transplant year and/or suspect noncompliant.
Diagnosis of AR:
BIOPSY IS STANDARD TOOL:
INDICATION;
Acute, otherwise unexplained deterioration in graft function or the presence of a
biomarker consistent with acute rejection.
Allograft histology is interpreted using the Banff classification.
Urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas
ligand, have generally shown mixed sensitivity and specificity for identifying acute
rejection, differentiating T cell–mediated rejection from antibody-mediated rejection, and
distinguishing immunologic injury from other forms of graft damage.
Decreased urinary miR-210 levels have been associated with T cell–mediated rejection
and subsequent 1-year GFR decline.
Donor-Derived Cell-Free DNA in Blood, high negative predictive value.
Treatment of acute rejection, depend on either TCM or ABMR.
SUMMARY OF TREAMENT:
Methylprednisolone TCR: Banff IA, IB
rATG TCR: Banff Ib, IIa, IIb, III.
Plasma exchange : AMR Antibody
IVIG: AMR.
Rituximab: AMR
Bortezomib: AMR,
Eculizumab: AMR
C1-INH: AMR
T Cell–Mediated Rejection:
Initial treatment conventionally includes pulse methylprednisolone at 250–500 mg daily
for 3–5 days, as recommended by international guidelines.
Majority of Banff class one lesions responding to methylprednisolone.
Banff II and III lesions: generally requires T cell–depleting therapy, most commonly
rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody mediated rejection:
Plasma exchange and intravenous Ig (IVIG), with or without rituximab, was the most
commonly used strategy and is generally considered standard of care for antibody-
mediated rejection treatment
A typical regimen includes daily or every other day plasma exchange consisting of 1.5
plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or
without a single dose of rituximab at 3.75 mg/m.
More data needed for subclinical rejection.
2-What is the level of evidence provided by this article?
Level of evidence V.
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Please summarise this article
Introduction:
Acute rejection should be highly suspected when unexplained graft dysfunction ensue.
The acute rejection has been decreasing significantly after introduction of cyclosporine in 1980’s, and after the T-cell depleting inductionin 1990’s.
The acute rejection is more due to HLA mismatch that alleviate alloimmune response.
Acute rejection risk:
Pre-transplantation HLA A/B/DR mismatch, and donor specific antibodies are the best predictor of acute cellular and antibody mediated rejection, respectively.
Panel reactive antibody (PRA), and repeat transplantations are no more a predictor for rejection.
The risk of rejection decreased after the trend for induction therapy (rATG, basilixumab) and the use of tacrolimus.
Acute rejection diagnosis:
The gold standard for diagnosing acute rejection is tissue biopsy.
T cell mediated rejection include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vascu[1]litis), with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field.
Anti body mediated rejection required three features for diagnosis: (1) active tissue injury, (2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition, and (3) circulating DSA , (4) at least moderate microvascular inflammation, or (5) increased expression of endothelial gene transcripts. However C4d positive in only 40% of ABMR, DSA and endothelial transcript expression peers poor prognosis.
Acute rejection treatment:
T-cell mediated: stages Ia,Ib treated with IV methylprednisolone 250-500 mg daily for 5 days, ATG at a dose of 1.5mg/kg daily, for 5-7 days reserved for severe graft dysfunction
Stage II and III treated with IV methylprednisolone (3-5 days+ ATG 5-7 days)
Antibody mediated rejection: Treated with plasma exchange every other day with IVIG 100-200 mg/kg after each session +/-Rituximab.
Bortezomib, Ecluzumab, Tosilizumab, all have been studied in small case series with proven benefit, but not superior to main protocol and can be considered add on.
C1-esterase inhibitors (C1-INH) inhibits proximal enzymes in the classic complement pathway including C1q, and reports of poor outcomes after detection of C1q-binding DSA. Is a promising treatment choice under evaluation in large randomized trials.
Subclinical rejection:
Protocol biopsy and DSA are used to identify patients at increased risk of subclinical rejection, the incidence of T-cell subclinical rejection is rare, and subclinical ABMR is 5%, severely affect long term graft outcomes.
Conclusion:
Acute cellular or anti-body mediated rejection are the important treatable issues in differential diagnosis of any graft dysfunction after exclusion of anatomical, fluid collections, infections and drug toxicity issues, physicians should be familiar with the biomarkers used to diagnose and treat rejection.
Cellular rejection treated with IV Methylprednisolone 250-500 mg x1 for 3-5 days, in severe cases ATG used for 5-7 days.
ABMR treated with Plasma exchange +IVIG+/- Rituximab.
Identifying subclinical antibody-mediated rejec[1]tion provides an opportunity to intervene before the onset of clinical dysfunction.
What is the level of evidence provided by this article?
Level of evidence V
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
>>Acute T cell–mediated rejection (TCR)
Ia .25% Interstitial inflammation with moderate tubulitis (t2)
Ib .25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
>>Acute antibody-mediated rejection (AMR): all three criteria below required
– Histologic evidence of tissue injury including one or more of the following:
Microvascular inflammation (g.0 and/or ptc.0)
Arteritis (v.0)
Thrombotic microangiopathy
Acute tubular injury
– Evidence of current/recent antibody interaction with endothelium including one or more of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g1ptc $2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
– Serologic evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
>>algorithm for Treatment options : summarized in picture
>>algorithm for Treatment options : summarized in picture
Hi Dr Mohamed,
I agree it is level 5 evidence.
You have uploaded a picture of algorithm. What is the source of that table?
Ajay
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
● A cute rejection rate is 10%
● factors risk for acute rejection
** panel reactive antibody
** repeat transplant
** black race
** recipient age
● 30%–50% of patients with pretransplant DSA with high level will experience AMR
● Strategies to reduce (CNI) exposure
** (mTOR’s) higher rates of acute rejection and side effects
** belatacept has resulted in favorable, longer-term outcomes but with higher rates of T cell–mediated rejection
● Non-immunologic causes may first be considered in an older patient who received rATG induction with consistently therapeutic tacrolimus levels.
● Biopsy is the gold standard for diagnosing acute rejection in kidney transplant recipients
● Allograft histology is interpreted using the Banff classification of kidney allograft pathology
● Antibody-mediated rejection required three features for diagnosis:
(1) active tissue injury
(2) immunohistologic evidence of peritubular capillary complement split-product C4d deposition
(3) circulating DSA.
● urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand,Short non-coding single stranded microRNA have improved stability
in urine compared with mRNA
● decreased urinary miR-210 levels have been associated with T cell–mediated
rejection and subsequent 1-year GFR decline
● cf-DNA profiling has been applied to the noninvasive diagnosis of antibody mediated rejection
● Acute T Cell–Mediated Rejection treatment includes :
** pulse methylprednisolone at 250–500 mg daily for 3–5 days (Banff I ) lesions
** rATG dosed at 1.5 mg/kg for five to seven doses (Banff II and III ) lesions
● Antibody-Mediated Rejection treatment
** plasma exchange
** intravenous Ig (IVIG)
** with or without rituximab
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2.
● Level : 5
Hi Dr Huda,
I like your summary and analysis.
I agree it is level 5 evidence.
Your headings and sub-headings should be in bold or underline. That will make it easy to read.
Ajay
Acute Rejection Risk;
*level of anti-HLA sensitization
(panel reactive antibody)
*repeated transplant
*blackrace
*recipient age.
In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure.
Currently in the United States, 75% of kidney recipients receive rabbit antithymocyte globulin (rATG) induction and 90% receive maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil, with or without prednisone, as these regimens have historically
been associated with lower rates of acute rejection
Acute Rejection Diagnosis
tissue biopsy is the gold standered
with Allograft histology is interpreted using the Banff classification of kidney allograft pathology
The diagnostic criteria for T cell–mediated rejection include lymphocytic infiltrate of tubules (tubulitis) and larger vessels (vasculitis)
with the severity of these lesions depending on the degree of lymphocytic infiltrate per high-powered field
Ia >25% Interstitial inflammation with moderate tubulitis (t2)
In >25% Interstitial inflammation with severe tubulitis (t3)
IIa Mild-to-moderate intimal arteritis (v1)
IIb Severe intimal arteritis (v2)
III Transmural arteritis and/or fibrinoid necrosis
Acute antibody-mediated rejection (AMR):
all three criteria below required
Histologic evidence of tissue injury including one or more of the following:
*Microvascular inflammation (g.0 and/or ptc.0)
* Arteritis (v.0)
*Thrombotic microangiopathy
*Acute tubular injury
Evidence of current/recent antibody interaction with endothelium including one or more of the following:
*Positive C4d staining of peritubular capillaries
*Moderate microvascular inflammation (g1ptc $2)
*Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
Serologic evidence of donor-specific antibodies (DSA)
*Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Acute Rejection Treatment
T Cell–Mediated Rejection
1-pulse methylprednisolone at 250–500 mg daily for 3–5 day
2- rATG for Banff II and III
Antibody-Mediated Rejection
– plasma exchange,
-intravenous Ig (IVIG)
– with or without rituximab
Subclinical Rejection
screening biomarkers such as DSA to identify
patients at risk for subclinical immunologic lesions.
The incidence of subclinical T cell–mediated rejection in the
modern era of immunosuppression is low and longterm outcomes do not appear to be as severely affected compared with subclinical antibody-mediated rejection which represents an attractive therapeutic target given the attributed poor long-term.
Hi Dr Esraa,
I like your summary and analysis.
Ajay
Summary of the article;
Introduction;
With advancing immunosuppressant during the last decades, acute rejection incidence decline from nearly 100% at first transplants to as least as 10%.
This is reflected on the 1 year survival rate, specially after introduction of Cyclosporine in the mid-1980s, and T-cell depleting agent at mid-1990s.
Acute rejection risk factors;
Currently in the US, 75% recipients receive ATG induction, and >90% receive maintenance IS consist of TAC/MMF, with or without prednisolone, with resultant reduce incidence of AR.
Regiment use mTOR instead of CNI, to reduce CNI exposure associated with higher rate of AR and side effects.
CNI free maintenance IS with Belatacept, associated with favourable long term outcome, but with higher rate of ACR.
Adams et al.; showed significant reduction in AR with Belataceopt/TAC regiment, with the steady taper over first post-transplant year, (AR was 51% with belatacept alone vs 16% with Belatacept plus TAC taper).
In cohort of 538 consecutive Tx recipients, based on TAC triple therapy, at the University of Colorado, mean TAC level < 8 ng/ml, throughout the 1st year, associated with increased DSA development, and the level of 4-6 vs >8 associated with 2-3 fold higher risk of AR.
Acute Rejection diagnosis;
Histologic criteria for diagnosing Acute Allograft Rejection, according to the Banff 2017 guidelines;
@ Acute T cell-mediated rejection, (TCR);
Ia ===== >25% interstitial inflammation with moderate tubulitis (t2).
Ib ===== >25% interstitial inflammation with severe tubulitis (t3).
IIa ==== mild to moderate intimal arteritis (v1).
IIb ==== sever intimal arteritis (v2).
III ==== transmural arteritis and/or fibrinoid necrosis.
@Acute antibody-mediated rejection; all three criteria below required
Histologic evidence of tissue injury including one or more of the following;
Microvascular inflammation (g>0 and/or ptc>0).
Arteritis (v>0).
TMA
ATI
Evidence of current / recent antibody interaction with endothelium including one or more of the following;
positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g+ptc>/2)
Increased expression of gene transcripts in biopsy tissue strongly ass with AMR
Serolgical evidence of donor-specific antibodies (DSA)
Positive C4d staining or presence of AMR-ass gene transcripts may substitute for DSA.
Acute rejection treatment;
Conclusion;
Level of evidence ((V)). article review
Hi Dr Kamal,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Introduction
Graft rejection rate dropped to 10% due to the evolution in immunosuppressive therapies.
Acute rejection is divided into T cell mediated and antibody mediated rejection ,each with a different mechanism .
Acute Rejection Risk
Immunological risk for acute rejection at transplantation timeare multiple as HLA mismatch as the main risk , recipient’s age , PRA , anti HLA sensitization, number of transplants.
In the post transplant period ,the main factors include immunosuppressive regimen mostly in the form of induction with r ATG and maintenance with MMF ,Tac with or without steroidsand exposure.
Post hoc analysis revealed much reduction of DSA levels in those using belatacept than those used cyclosporine.
Another study published decreased rejection risk with the use of belatacept along with Tac rather than using belatacept on it’s own.
Meanwhile a cohort study stated that tacrolimus level <8ng/ml were accompanied with high DSA levels thereby graft rejection .
Acute rejection diagnosis
This is done by renal biopsy that is necessary when there is deterioration of graft function or with a biomarker of rejection notified.
Banff criteria classifies the graft histopathology for antibody mediated rejection, initially including
· active tissue injury
· Peritubular capillary complement split-product C4d deposition
· circulating DSA.
But this old criteria lead to missing antibody mediated rejection cases , therefore latter revisions in 2013 the updated criteria introduced changes on the criteria to include C4d staining negative antibody-mediated rejection phenotype.
T cell–mediated rejection criteria were changed involving tubulitis and vasculitis.
Tissue biopsy remains the gold standard for diagnosis but it is liable to sampling error and variable interpretation.
Urine and blood biomarkers have variable sensitivity and specificity.
The low urinary levels of miR-210 have been associated with T cell–mediated rejection and 1-year GFR decline.
Donor-derived cell free DNA (cf-DNA) profiling has been associated with antibody-mediated rejection.
Those non invasive markers are non conclusive, rendering the biopsy still the golden standard .
Acute rejection treatment
Treatment strategy depends upon the type and severity of the rejection which would affect the graft prognosis.
T cell mediated rejection
Initial treatment is pulse methylprednisolone at 250–500 mg daily for 3–5 days, having good response for Banff class I.
Tcell depleting agents as r ATG for 5-7 doses can be needed for Banff class II and III lesions.
Antibody mediated rejection
Therapy is directed at removing antibody-producing B cells or plasma cells, DSA and complement mediated graft damage .
The standard treatment involves plasma exchange and intravenous Ig (IVIG), with or without rituximab.
Studies tested other therapies for rejection refractory to the original regimen involving Bortezomib due to it’s inhibitory effect ob Ab producing plasma cells with minimal effect on DSA level when used on it’s own , the results were variable when used with plasma exchange and IVIG .
A recent study demonstrated graft function stabilisation in plasma cell-rich acute rejection with bortezomib usage.
Humanized mAb eculizumab as C5 inhibitor was used for prevention and treatment of antibody-mediated injury.
Orandi et al published acceptable outcomes for cases with severe antibody-mediated rejection after desensitization for positive crossmatch kidney transplant treated with splenectomy and eculizumab together but on the other side this regimen carries a high risk of infection.
Another pilot study revealed promising results with Tocilizumab for patients with chronic antibody mediated rejection.
C1-esterase inhibitors (C1-INH) use had poor outcomes.
Subclinical rejection
Protocol biopsy of stable grafts or biomarkers as DSA can help discovering patients at risk for subclinical immunologic lesions.
Identifying such cases can improve the outcomes , but more data are needed before concluding this.
Conclusion
Immunosuppressive protocols decreased the rejection episodes and improved graft survival.
Banff criteria doesnot require DSA and C4 deposition to diagnose antibody mediated rejection.
-level of evidence is 5
Hi Dr Doaa,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Conventionally, the immunologic risk of an individual at the time of transplant has been attributed to characteristics such as the individual’s overall immunologic risk (PRA, DSA, HLA mismatch), repeat transplant, black race, and recipient age.
Recent research has demonstrated that pretransplant DSA and HLA A/B/DR mismatch are the most accurate predictors of antibody-mediated rejection and T cell-mediated rejection, respectively, whereas panel reactive antibody and repeat transplantation have no predictive value.
The degree of immunologic danger posed by pretransplant DSA will depend on the nature of the identified antibodies. 30%–50% of patients with pretransplant DSA titers high enough to require desensitization before transplant will experience ABMR, although lower-level antibodies do not appear to affect the risk of acute rejection or graft survival in the intermediate term.
Acute rejection risk is mostly determined by immunosuppressive regimen(induction and maintenance) and exposure.
Acute Rejection Syndrome:
1- Kidney biopsy remains the gold standard for diagnosing acute rejection in transplant recipients, and noninvasive biomarkers have been unable to fully replace tissue diagnosis.
2-Normal results from assays with a strong negative predictive value, such as ddcf-DNA, may provide reassurance to physicians and patients with aberrant clinical signs (DSA, graft malfunction) in whom a tissue biopsy deemed too risky.
Diagnosing rejection mediated by T cells:
The following are diagnostic criteria for T cell-mediated rejection:
1-lymphocytic tubulitis (infiltration of tubules by lymphocytes).
2-larger vessels (vasculitis)
The severity of these lesions is proportional to the amount of lymphocytic infiltration per magnified field.
The diagnosis of antibody-mediated rejection is based on the Banff classification.
-Antibody-mediated rejection was identified for the first time in the Banff categorization between the early and mid-2000s and needed the presence of three characteristics:
1) Histological evidence of active tissue injury
2) Immunohistochemical evidence of complement split-product C4d deposits in peritubular capillaries.
3) Circulating DSA.
-The revised 2013 Banff criteria for the diagnosis of antibody-mediated rejection removed the requirement for C4d detection and expanded this category to include “evidence of current/recent antibody interaction with vascular endothelium,” which may include either; (1) positive C4d staining; or (2) negative C4d staining.
(2) at least mild microvascular irritation.
(3) enhanced endothelial gene transcript expression.
-The most recent Banff consensus acknowledges studies demonstrating a lack of circulating DSA in patients with biopsy specimens demonstrating significant microvascular inflammation and a low false positive rate of C4d staining, and has now removed the requirement for documented circulating DSA in the presence of positive C4d staining and microvascular inflammation.
Blood biomarkers for acute rejection diagnosis:
Numerous studies of urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have demonstrated variable sensitivity and specificity for identifying acute rejection, distinguishing T cell–mediated rejection from antibody-mediated rejection, and differentiating immunologic injury from other forms of graft damage.
Treatment
The method to treating a transplant recipient with acute rejection is dependent on the immunological risk, risk of infection, hemodynamic stability, kidney function.
The treatment strategy for T cell–mediated rejection and antibody–mediated rejection are distinct, and the aggressiveness of treatment is often proportional to the severity of the identified lesions.
Graft prognosis following treated acute rejection depends on nature and severity; nonetheless, any untreated clinical episode of acute rejection will result in accelerated graft loss.
T cell mediated Rejection :Conventionally, the initial treatment consists of a pulse of methylprednisolone at 250–500 mg per day for 3–5 days, as indicated by worldwide recommendations.
Methylprednisolone is the treatment of choice for the majority of Tcell mediated rejection starting with Banff class 1 lesions.
Banff II and III lesions typically necessitate T cell–depleting therapy, most frequently rATG in addition to steroids and optimization of maintenance treatment doses and trough levels.
Antibody-Mediated Rejection: Treatments for antibody-mediated rejection involve eliminating antibody-producing B cells or plasma cells, removing circulating antibodies, and/or preventing the following complement-induced graft damage.
Plasma exchange and intravenous immunoglobulin with or without rituximab, was the most frequently utilized therapy and is considered the standard of care for treating antibody-mediated rejection. A common therapy involves daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment, followed by IVIG, with or without rituximab.
Subclinical Rejection Despite the danger of adverse outcomes associated with subclinical antibody-mediated rejection, there are few evidence suggesting that therapy intervention will affect the clinical course.
Level of evidence: level 5 / Review article
Hi Dr Habli,
I like your summary and analysis.
I agree it is level 5 evidence.
Your headings and sub-headings should be in bold or underline. That will make it easy to read.
Ajay
Introduction of immunosuppressants like calcineurin inhibitors and T cell depleting induction agents have improved 1 year graft survival with reduction in rates of acute rejection to 10%. Acute rejection affects graft survival.
The risk factors for acute rejection include presence of pre-transplant donor specific antibodies (DSA) and HLA mismatches (for antibody mediated rejection – ABMR, and T cell mediated rejection – TCMR respectively). Panel reactive antibody, low level DSA, and repeat transplant has no predictive value for acute rejection risk. DSA requiring desensitization have 30-50% risk of ABMR.
Acute rejection in post-transplant period depends on the immunosuppression used, more rejections being seen with mTOR inhibitors use. Belatacept use has decreased DSA development, but increased TCMR (51%, which decreased to 16% when used with tacrolimus tapered over 1 year). DSA development and acute rejection increases in patient with lower tacrolimus drug levels.
Diagnosis of acute rejection: An unexplained graft dysfunction (after excluding causes like infection, drug toxicity, pre-renal causes, obstruction etc.) should be evaluated. Presence of DSA should be assessed and a kidney biopsy (the gold standard for diagnosing acute rejection – as per the Banff classification – either acute TCMR or acute ABMR) should be performed, if not contraindicated.
Acute TCMR: Class Ia, Ib, IIa, IIb, and III – on basis of degree of interstitial inflammation and tubulits, and arteritis.
Acute ABMR: On basis of histologic evidence of tissue injury, interaction between antibody and endothelium, and serological evidence of DSA.
Treatment of Acute rejection:
1) Acute TCMR:
a. Banff Ia (or Ib with mild graft dysfunction): Injection methylprednisolone 500 mg IV once a day for 3-5 days
b. Banff II, or III (or Ib with severe graft dysfunction): Injection rabbit antithymocyte globulin (rATG) 1.5 mg/kg/day x 5-7 days or until recovery.
2) Acute ABMR: 1.5 volume Plasma exchange daily or alternate day for 5 sessions with injection IVIG 100-200 mg/kg following each plasma exchange, and injection Rituximab 375 mg/m2 following last exchange.
3) Mixed rejection: Treatment of ABMR plus TCMR treatment as per Banff class.
Bortezomib has been used in plasma cell-rich acute rejection, and C1 esterase inhibitors have been used in acute ABMR treatment. Eculizumab has been used in patients with chronic ABMR.
Subclinical rejection: It has been identified using protocol biopsies sand biomarkers like DSA. Subclinical TCMR, even without treatment, has similar long-term graft outcomes. Subclinical ABMR has been shown to have poorer graft outcomes, but even after treating, the overall outcomes do not differ, although on comparing with matched controls, treatment has been shown to decrease risk of graft loss.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review
Hi Dr Amit
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Incidence of acute rejection
AR is classified into
Risk factors for AR
Diagnosis
A- In case of allograft dysfunction we should do renal biopsy with C4d staining and DSA and according to the finding we diagnose AR and categorize rejection into:
Acute TCMR
Acute ABMR
3 components are required for the diagnosis of ABMR :
If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have ABMR, this means C4d staining can replace DSA, and C4d negative ABMR exists (ABMR without activation of complement cascade)
B- Donor-Derived Cell-Free DNA in blood > 1% has positive predictive value of ABMR of 44 % and have negative predictive value that reached 96%, so it is specific but not sensitive
Management of acute rejection
A rule is to treat all rejections appropriately (according to type and severity) in a timely manner
Acute TCMR
Acute ABMR
A- First line therapy
Second line therapy if initial therapy failed
Mixed TCMR, ABMR
Subclinical rejection
What is the level of evidence provided by this article?
Hi Dr Yusuf,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Introduction:
Advances in immunosuppressive therapy have drastically improved acute rejection rates in kidney transplant recipients over the past five decades
Acute Rejection Risk:
1-Over all level of anti-HLA sensitization (panel reactive antibody)
2-Repeat transplant,
3- Black race,
4- Recipient age.
In the post-transplant period, acute rejection risk is largely determined by immunosuppression regimen and exposure
Acute Rejection Diagnosis:
The gold standard for diagnosing acute rejection in kidney transplant recipients is tissue biopsy
Indications to graft biopsy:
1- over concern for acute rejection
2- unexplained deterioration in graft function
3- The presence of a biomarker consistent with acute rejection
Antibody-mediated rejection was first recognized within the Banff classification in the early and mid-2000s and required three features for diagnosis:
(1) active tissue injury
(2) ) immunohistologic evidence of peritubular capillary complement split-product C4d deposition,
(3) circulating DSA.
The revised 2013 Banff criteria for antibodymediated rejection diagnosis:
(1) positive C4d staining,
(2) at least moderate microvascular inflammation,
(3) increased expression of endothelial gene transcripts
Numerous studies of urine and blood biomarkers, such as CXCL9, CXCL10, granzyme B, perforin, and Fas ligand, have generally shown mixed sensitivity and specificity for identifying acute rejection, differentiating T cell–mediated rejection from antibody-mediated rejection, and distinguishing immunologic injury from other forms of graft damage
Acute Rejection Treatment:
Treatment strategies differ between T cell–mediated rejection and antibody-mediated rejection,
T Cell–Mediated Rejection:
methylprednisolone at 250–500 mg daily for 3–5 days.
rATG dosed at 1.5 mg/kg for five to seven doses.
Antibody-Mediated Rejection:
Antibody mediated rejection treatments are directed at removing antibody-producing B cells or plasma cells, removing antibodies (DSA), and/or inhibiting the subsequent complement-regulated graft damage
Plasma exchange
Intravenous Ig (IVIG),
Rituximab,
Subclinical Rejection:
protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions
The incidence of subclinical T cell–mediated rejection in the modern era of immunosuppression is low
Level 5
Hi Dr Allam,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Please summarise this article
Introduction
Acute rejection rate now is about 10% owing to evolution of immunosuppressive agents
Acute rejection should remain high on the differential diagnosis for unexplained graft dysfunction because it significantly affect graft survival
Acute rejection is now broadly classified as either T cell mediated or antibody mediated
Aim of the study: approach to risk factors, diagnosis, and treatment of acute rejection
Acute Rejection Risk
At the time of transplant: Anti-HLA sensitization (PRA), repeat transplant, black race, and recipient age
In the post-transplant period: immunosuppression regimen and exposure
Reduce CNI exposure and using mTORi leads to higher rates of acute rejection and side effects
CNI- free regimen with the newer agent belatacept has resulted in favorable, longer-term outcomes but with higher rates of T cell–mediated rejection (significant reduction in DSA in belatacept versus cyclosporine)
There are correlations with overall tacrolimus exposure and acute rejection risk
Acute Rejection Diagnosis
Tissue biopsy (the gold standard) is indicated when there is acute unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection
Allograft histology is interpreted using the Banff classification of kidney allograft pathology
Noninvasive biomarkers (failed to completely replace tissue diagnosis due in part to incon- sistent results between studies
Urine and blood biomarkers (CXCL9, CXCL10, granzyme B, perforin, and Fas ligand)
Short non- coding single-stranded microRNA and decreased urinary miR-210 levels have been associated with T cell–mediated rejection and subsequent 1-year GFR decline
Donor-derived cellfree DNA (cf-DNA) profiling (for diagnosis of antibody-mediated rejection)
Acute Rejection Treatment
T Cell–Mediated Rejection
Pulse methylprednisolone at 250–500 mg daily for 3–5 days (Banff Ia, Ib)
rATG dosed at 1.5 mg/kg for five to seven doses ((Banff II and III lesions)
Antibody-Mediated Rejection
A typical regimen includes daily or every other day plasma exchange consisting of 1.5 plasma volume removal with each treatment followed by IVIG at 100–200 mg/kg, with or without a single dose of rituximab at 3.75 mg/m2
Other medications (refractory to “standard” treatment regimens):
1. Bortezomib (proteasome inhibitor): induce apoptosis in antibody-producing plasma cells with minimal effect on DSA burden when used alone
2. eculizumab (humanized mAb): for prevention and treatment of antibody-mediated injury because of its mechanism of complement component C5 inhibition
3. tocilizumab (anti-IL six receptor antibody): promising results for chronic antibody-mediated rejection
4. C1-esterase inhibitors (C1-INH): inhibits proximal enzymes in the classic complement pathway including C1q
Subclinical Rejection
Use protocol biopsy of stable grafts or the use of screening biomarkers such as DSA to identify patients at risk for subclinical immunologic lesions
Subclinical T cell–mediated rejection in the modern era of immunosuppression is low, in contrast to subclinical antibody-mediated rejection (poor long-term outcomes)
Using DSA as a biomarker, 50% of patients with stable function and de novo DSA will show evidence of subclinical antibody-mediated rejection on biopsy
Despite the risk of poor outcomes associated with subclinical antibody-mediated rejection, few studies suggest treatment intervention will alter the clinical course
Conclusions
Acute rejection still affects graft survival despite effective immunosuppressive therapy
Tissue biopsy should be performed in any patient with unexplained acute graft dysfunction
The Banff criteria for diagnosing antibody-mediated rejection continue to evolve and no longer require the combination of DSA and C4d deposition
Identification of subclinical antibody-mediated rejection provides a chance to intervene before the onset of clinical dysfunction
What is the level of evidence provided by this article?
Level 5
Hi Dr Mohammed,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
1. Please summarise this article
Introduction
As a result of advances in IS therapy, AR rates have decreased from almost 100% in the 1stera of orga TX to about 10% more recently; however, when it occurs, can significantly affect graft survival &, therefore, should be highly whenever there is on unexplained graft dysfunction in a TXrecipient.
Acute rejection risk
1.Pre-TX DSA & HLA A/B/DR mismatch are the main predictors of AMR & TCMR respectively.
2.PRA & re-TX had no predictive effect (Wehmeier et al.).
3.The degree of immunologic risk imposed by pre-TX DSA depends on characteristics of the antibodies detected:
-30%–50% of those with high pre-TX DSA titers warranting pre-TX desensitization will develop AMR; lower-levels do not increase AR risk or graft survival in the intermediate term.
4.Lower rates in recipients who receive rATG induction & maintenance IS with tacrolimus & MMF, with or without prednisone.
5. Regimens of mTOR’s with reduced CNI exposure is associated with higher rates of AR & S/Es.
6.CNI free maintenance IS with belatacept has resulted in favorable, longer-term outcomes but with higher rates of TCMR; post hoc analysis showed significant reduction in DSA development in those receiving belatacept versus cyclosporine.
7.Adams et al. recently reported significant reduction in AR in those treated with belatacept by adding tacrolimus to the existing belatacept regimen followed by a taper over the 1st post-TX year.
AR Diagnosis
Tissue biopsy (the gold standard).
Graft biopsy is indicated if there is any acute unexplained graft dysfunction or in the presence of
a biomarker consistent with AR.
Histologic criteria for diagnosing AR (Banff 2017 guidelines):
A. Acute TCMR
Ia: >25% Interstitial inflammation + moderate tubulitis (t2)
Ib: >25% Interstitial inflammation with severe tubulitis (t3)
IIa: Mild-to-moderate intimal arteritis (v1)
IIb: Severe intimal arteritis (v2)
III: Transmural arteritis &/or fibrinoid necrosis
B. Acute AMR: all 3 criteria below required
1) Histologic evidence of tissue injury including =/>1 of the following:
Microvascular inflammation (g>0 &/or ptc>0)
Arteritis (v> 0)
Thrombotic microangiopathy
Acute tubular injury
2) Evidence of current/recent antibody interaction with endothelium including =/>1 of the following:
Positive C4d staining of peritubular capillaries
Moderate microvascular inflammation (g+ptc =/>2)
Increased expression of gene transcripts in biopsy tissue strongly associated with AMR
3) Serologic evidence of DSA
Positive C4d staining or presence of AMR-associated gene transcripts may substitute for DSA
Treatment options for acute allograft rejection
1.Methylprednisolone
Indication: TCR,Banff Ia, Ib
Mechanism: multiple, anti-inflammatory glucocorticoid
A/Es: hyperglycemia, hypertension, other metabolic effects
2.rATG
Indication:TCR: Banff Ib, IIa, IIb, III
Mechanism: T cell depletion
A/Es: Fever, chills, hypertension, hypotension, leukopenia, infusion reaction, serum sickness
3.PE:
Indication: AMR
Mechanism: Antibody removal
A/Es: Fever, chills, urticaria, TRALI, bleeding
4.IVIG
Indication: AMR
Mechanism: multiple “immunomodulatory” effects including antibody clearance, neutralization, and inhibited production, Fc receptor saturation, complement inhibition
A/Es: Infusion reaction (headache, fever, chills, urticaria, back pain, abdominal pain, nausea, vomiting).
5.Rituximab
Indication: AMR
Mechanism: Anti-CD20 B cell depletion
A/Es: Infusion reaction, HBV reactivation, PML
6.Bortezomib
Indication: AMR
Mechanism: Plasma cell apoptosis via proteasome inhibition
A/Es: peripheral neuropathy, fatigue, generalized weakness
7.Eculizumab
Indication: AMR
Mechanism: terminal complement C5 inhibition
A/Es: Meningococcal infection, influenza, peritonitis
8.C1-INH
Indication: AMR
Mechanism: Classic complement pathway inhibition
A/Es: Headache
TCMR treatment
Banff Ia:
-Solumedrol 500mgx3-5 days
Banff Ib:
-Solumedrol 500mg X 3-5 days if mild graft dysfunction
-rATG 1.5mg/kg X 5-7 days or until recovery if severe graft dysfunction
Banff IIa, IIb, or III:
-rATG 1.5mg/kg X 5-7 days or until recovery
AMR treatment
-PE X 5
-IVIG 100-200 mg/kg following each PE
-Rituximab 375 mg/m2 following last treatment
-If evidence of TCMR on biopsy(mixed rejection): add TCMR treatment according to Banff category
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2. What is the level of evidence provided by this article?
Level V
Hi Dr Mohammed,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Level 5 evidence
Several risk factors for acute rejection include:
-Previous transplant-Presence of DSA’s-recipient race and age
Diagnosis of acute rejection:
-Proper examination , hemodynamic check , exclusion of UTI and other infections , CNI toxicity, CMV PCR , US-duplex , renal biopsy and C4 d staining , DSA’s level .
Treatment
-AMR: Plasma exchange, IVIG, Mabthera, bortezumib and eclizumab .
-T-Cell rejection: 250-500 mg solumedrol for 3-5 days ( Banff Ia,Ib)-rATG 1.5mg/kg/day for 5-7 days (Banff Ib, II & III ).
Hi Dr Essamat,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
SUMMARY
Introduction
The evolution in the development of various immunosuppressives drugs in the last five decade has not only reduces significantly the occurrence of acute kidney rejection but has also widened the understanding in the pathogenesis of different types of acute rejection. Similarly, it has also helped to appreciate the long-term impact of acute rejection on graft survival and different roles played by different induction and maintenance therapy.
Acute rejection risk
The conventional risk factors for acute rejection at the time of transplantation are
Wehmeier et al in his study of over 500 transplants patient found, DSA and HLA mismatches (A/B/DR) as risk factors for ABMR and cell mediated rejection respectively.
Acute rejection diagnosis
The goal standard still remains kidney biopsy despite been an invasive procedure and the indications are
The goal standard for proper interpretation of histology report of the type of ongoing allograft rejection (ABMR or T-cell) is the Banff criteria which has gone through various modifications over the years. It helps in diagnosis and the appropriate use on rescue therapy to arrest on going rejection
The use of cell free donor derived DNA is helping as a non-invasive method of diagnosis
Treatment of acute rejection
A) T – cell mediated rejection
B) Antibody mediated rejection
The aim is to remove or destroy circulating antibodies in the system of the recipient
Conclusion
Although the incidence of acute allograft rejection has reduced, there is still a need for high index of suspicion particularly subclinical rejection as to be able to deploy prompt use of rescue therapy to prevent rejection and improve long term survival of the graft and patient
The level of evidence is 5
Hi Dr Issac,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Acute Rejection Risk:
Approximately 30%–50% of patients with pretransplant DSA at titers strong enough to warrant desensitization before transplant experience acute antibody-mediated rejection
Suspicion:
A high index of suspicion would be warranted in a young patient with lower tacrolimus trough levels during the first post-transplant year and/or suspected immunosuppression non-adherence.
Alternatively, non immunologic causes may first be considered in an older patient who received rATG in duction with consistently therapeutic tacrolimus levels.
Acute Rejection Diagnosis
Indications to pursue graft biopsy over concern for acute rejection include either an acute, otherwise unexplained deterioration in graft function or the presence of a biomarker consistent with acute rejection
Graft biopsy — Gold Standard
Acute T cell–mediated rejection (TCR)
Acute antibody-mediated rejection (AMR): all three criteria below required
Treatment :
Drug Methylprednisolone
Indication TCR: Banff Ia, Ib
Mechanism Multiple, anti-inflammatory glucocorticoid
Drug rATG
Indication TCR: Banff Ib, IIa, IIb, III
Mechanism T cell depletion
Drug Plasma exchange
Indication AMR
Mechanism Antibody removal
Drug IVIG
Indication AMR
Mechanism Multiple “immunomodulatory” effects including antibody clearance, neutralization, and inhibited production, Fc receptor saturation, complement inhibition
Drug Rituximab
Indication AMR
Mechanism Anti-CD20 B cell depletion
Drug Bortezomib
Indication AMR
Mechanism Plasma cell apoptosis via proteasome inhibition
Drug Eculizumab
Indication AMR
Mechanism Terminal complement C5 inhibition
Management of Acute T cell rejection:
rATG 1.5mg/kg for 5-7 doses or until recovery
Management of Acute B cell rejection
Noninvasive biomarkers have failed to completely replace tissue diagnosis due in part to inconsistent performance between studies normal results from assays with high negative predictive value, such as donor-derived cf-DNA, may offer a level of reassurance to providers and patients with abnormal clinical findings (DSA, graft dysfunction) in whom tissue biopsy is either not feasible or considered too high risk.
Level of evidence:
Level V (Review)
Hi Dr PAtil,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay
Summary
This study is relating to the assessment, recognition and management of acute rejection in kidney allografts following kidney transplant.
Pretransplant immunological risk of a patient is based on pre transplant DSA titers, ethnicity, age, previous transplant etc. In the post transplant period, acute rejection incidence is dependent on IS regimen and exposure. Lowest rates of acute rejection is seen with induction rATG and maintenance regimen of tacrolimus, MMF, prednisone. CNI free regimens can have higher rates of T cell mediated rejection. However, belatacept is associated with significant DSA reduction and better outcome.
The gold standard for diagnosing acute rejection is tissue biopsy. Indications for tissue biopsy in the post transplant period include :
Histology is classified according to Banff criteria. There are different changes that have been done to these criteria for T cell mediated rejection over the years, however, the major concepts are based on tubulitis, vasculitis and lymphocytic infiltration.
Micorvascular inflammation and C4d histology are crucial for assessment and recognition of AMR. Microarray analysis of endothelial transcripts help to a great extent in identifying C4d negative AMR.
Treatment options for acute rejection include different agents. TCR can be managed largely with steroids, i.e., methylprednisolone, and rATG. AMR can be managed with plasma exchange, IVIG, rituximab, bortezomib, eculizumab and C1-INH.
Level of evidence
Level of evidence is 5.
HI Dr NAndita,
I like your summary and analysis.
I agree it is level 5 evidence.
Ajay