Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single centre retrospective study. This is a retrospective study with level III evidence. Mechanism of chronic allograft injury 1. Immunological causes 2. Recurrence of primary glomerular diseases. 3. Infection. CMV, BKV. 4. CNI Toxicity. 5. Urinary tract obstruction. 6. Renal artery stenosis. Diagnostic strategies Careful history for the primary disease for end stage renal failure, any previous history of rejection. Induction protocol and immunosuppressants. Blood pressure and sugar control. Urinalysis help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively. A kidney ultrasound may exclude mechanical obstruction of urinary tract. Protocol kidney biopsy should be performed in the majority of patients with dysfunction and red flag features such as significant proteinuria or cellular casts are present. Protein and mRNA levels of CXCL9 is a great predictor of rejection (AUC 0.88) with an elevation in levels detected 30 days before a biopsy-proven rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection (AUC 0.85). High NKG2A+ cells after kidney transplantation correlated with the presence of DSA, cABMR and worse graft function.
Treatment strategies Desensitization with plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients . Potential alternatives to rituximab to reduce antibody production include bortezomib . Eculizumab is indicated in severe ABMR, IT inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy. Plasmapheresis, IV IG , IV Rituximab are among the suggested therapy for ABMR. The FDA currently has no approved therapy for chronic ABMR and mechanistic interventional clinical trials are needed to address the safety and efficacy of B cell and DSA depleting strategies for chronic rejection. It is important to treat the recurrence of primary diseases. In conclusion, chronic allograft injury can significantly affect long-term renal allograft survival. Therefore, preventive measures are significant to ensure good renal allograft outcome.
Esmat MD
2 years ago
It is a retrospective cohort study with level 2 of evidence Although chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies. Diagnosis of CAMR is based on presence of DSA, morphologic findings consist of microvascular inflammation/injury with or without capillary C4d deposition. Therapeutic approach in different studies consist of intravenous immunoglobulin (IVIG) plus rituximab, proteasome inhibitor-bortezomib, complement inhibitor-eculizumab, and IL-6 receptor blocker. All of these treatments don’t show effectiveness and are correlated with various adverse effects. Pathologic findings based on Banff 2017 criteria including Glomerulitis (g), peritubular capillaritis (ptc), transplant glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and mesangial matrix (mm) scores were assigned in each case. Criteria for CAMR consists of morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens) were meet. In this study, a total of 82 patients with biopsy proven chronic antibody-mediated rejection divided in 2 groups base on treatment strategies. Group 1 was treated with (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, anti-thymocyte globulin, bortezomib, or methylprednisolone pulse therapy, and group 2 received supportive therapy. Aggressive treatment for CAMR patients was associated with better graft survival and with treatment higher incidence of adverse events and a reduced adverse event free survival, whereas patient survival was not significantly different. The worst survival was shown in patients who were on supportive therapy. Proteinuria and supportive treatment were independent risk factors for graft loss. In other studies, transplant glomerulopathy was associated with poor response to therapy. On the other hand, high levels of microvascular injury, for example biopsies with g ≥ 2 and/or (g + ptc) ≥ 4 were correlated with better response to IVIG and rituximab.
Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events deserves personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.
MICHAEL Farag
2 years ago
The aggressive treatment for CAMR patients was associated with better graft survival. However, the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival. The factors independently associated with graft loss were proteinuria and supportive treatment. Currently, there are no approved treatments for CAMR. CMV infection was reported to be associated with Rituximab, ATG, and bortezomib treatment in renal transplant and myeloma patient. Despite the significantly higher rate of adverse events in the aggressive treatment group, there was no significant difference in patient survival (Fig. 2), implying that the patients still could have a reasonable chance of survival if these complications can be treated judiciously. There are limitations in our study. Firstly, there were no rules for treatment of CAMR in our cohort, and the need for treatment was determined by each clinical physician. Second, DSA was not performed for every recipients in our hospital, because Luminex® technology for HLA antibody detection in organ transplant is expensive in Taiwan.
retrospective study evidence III
Assafi Mohammed
2 years ago
Chronic ABMR is one of the contributory factor for graft loss. For diagnosis of chronic ABMR, DSA level is needed beside morphological evidence of injury with or without C4d deposition in the PTC.
The article is about a retrospective study conducted over 7 years in Taichung Veterans General Hospital, assessing treatment outcome among patients with biopsy proven chronic ABMR. Patients were put on 2 categories, one who received aggressive therapy(DFPP plus one of ituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy) , the other group only received supportive therapy. Banff 2017 criteria for diagnosis of CAMR were met in all patients:
Evidence of tissue injury
Evidence of antibody interaction with vascular endothelium.
Evidence of DSA to HLA or other antigens.
Patients were followed up to an end point of the study (Graft loss, Death and end of the study time 2017). Predictors of graft loss in this study were; creatinine, proteinuria, PRA class II, cg ≥ 1, ci + ct ≥ 3, and supportive treatment. The study revealed that aggressive treatment was associated with better graft survival although serious adverse events were also related to aggressive therapy. Level of evidence: 3a
Alyaa Ali
2 years ago
CAMR is one of the major causes of graft loss.CAMR is diagnosed by the presence of DSAsand evidence of tissue injury plus +/-C4d staining.the treatment for CAMR has remained a major challenge.
This retrospective study is done to investigate the outcomes of CAMR by comparing graft survival between different treatment strategies.
From February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified. Three cases were excluded from the analysis owing to short follow up duration (less than 6).
The patients were divided in two groups according the treatment strategies:
Group 1 included 59 patients who received aggressive treatment, besides double filtration plasmapheresis (DFPP), 40 patients had received Rituximab, 10 patients had received IVIG, 10 patients had received bortezomib, whereas 4 patients had received antithymocyte globulin and 17 patients had received MP pulse therapy only.
Group 2 received no treatment or supportive treatment
After follow up for a median of 32.59 months after the diagnosis of CAMR. A total of 22 (26.82%) patients lost their allograft, including 11/59 patients (18.64%) in group 1 and 11/23 (47.83%) patients in group 2. Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively. Overall median graft survival was 5.6 years. Kaplan-Meier analysis of death-censored graft survival showed worse survival in group 2
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1, and 3/23 (13.04%) in group 2. All of the mortality cases in group 1 died of sepsis. Patient survival at the end of this study was not significantly different between these groups
Creatinine, proteinuria, PRA class II and supportive treatment were significant predictors of graft loss for CAMR .Supportive treatment and proteinuria were independently related to graft loss
There was a total of 54 adverse events in group 1, compared with 7 in group 2. Mean number of adverse events per patient was higher in group 1 (P < 0.001). Adverse
event free survival was significantly better in group 2 . The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia (PCP). Median adverse event free survival was 6.0 months in the aggressive treatment group.
Aggressive treatment resulted in better graft survival inpatients with proteinuria < 1.73 g/d , but not in patients with proteinuria ≥1.73 g/d
Conclusion : Aggressive treatment for CAMR patients was associated with better graft survival. However, the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival.The factors independently associated with graft loss were proteinuria and supportive treatment.
limitation of study :
Firstly, there were no rules for treatment of CAMR
Second, DSA was not performed for every recipients.
Summary
• Treatment of chronic active ABMR is still mater of debate. However, the current study concluded that it improves the long term graft and recipient survival.
• Diagnosis:
o Is based on combined presence of histo-pathological graft damage (immune mediated and chronic changes) plus detection of circulating DSA (evidence of antibody mediated graft damage) plus evidence of antibody interaction with tissue (+ve c4d).
o At least, one of DSA or c4d must be positive to diagnose chronic active ABMR.
o Pathology was revised by the same pathologist and staged according to the Banff 2017.
• Treatment of chronic active ABMR:
o No available RCT, all are retrospective studies.
o Available therapies include pulse steroids, plasmapheresis, IVIG, Rituximab, Bortezomib, ATG and Ecluizimab.
• Outcomes of treatment
o Assessment of graft outcome is evaluated by GFR and the degree of proteinuria as main indictors or predictors of graft function.
o Aggressive immunosuppressive therapy used increases risk of infections and malignancy.
o Infections as UTI, gastroenteritis, pneumonia and skin infections are increased so prophylaxis against PJP by trimethoprim-sulfamethoxazole is essential after treatment of each rejection episode.
o CMV infection is common especially with Rituximab, Bortezomib and ATG. Hence, Valganciclovir prophylaxis is mandatory for at least 6 months after antirejection therapy.
o The risk further increased in those who received prior aggressive immunosuppresses as in desensitization in ABO I transplantation and highly sensitized recipients.
o Appropriate treatment of these infections can lead to good graft and patient outcomes.
Level of evidence: retrospective cohort (level III).
Ahmed Omran
2 years ago
Chronic active antibody mediated rejection ;CAMR, frequently leads to graft failure.
A retrospective study; evidence III, It included:
* Group I :included 59patients ,with different treatment modalities including, bortezomib, Rituximab, IVIG, pulse steroid and ATG.
–*Group II included 23 cases, with supportive treatment.
Graft and patients survival at the end of 2017 was the endpoint.
Diagnosis of CAMR according to Banff 2017 criteria. All 3 criteria were there :
1-Evidence of chronic tissue injury
2- evidence of antibody interaction with vascular endothelium
3-DSA.
Patients survival was followed for a median of 32.59 (IQR 24.01–49.89) months following diagnosis of CAMR.
Results revealed total of 22 patients had allograft loss, including 18.64% in group I and 47.83% patients in group II.10.97% patients died after diagnosis of CAMR, including 10.16% patients in group I; due to sepsis, and13.04%in group II.
– Survival without adverse events was significantly better in group II.
– Infectious diseases were more common group with aggressive treatment included CMV disease, leucopenia, uti, pneumonia, infectious diarrhea, and Pneumocystis pneumonia.
Conclusion: CAMR treated aggressively before advanced tissue injury is associated with better graft outcome ,but with higher incidence of adverse events. Appropriate PCP and CMV prophylaxis must be implemented following aggressive treatment for rejection
Type of study :Retrospective study grade III
This study done at Taichung Veterans General Hospital.
Data collected from 2009 to 2017 from 82 patients with biopsy showing CAMR
and divided into 2 groups:
Group 1:
this group contains 59 patients receiving aggressive treatment as DFPP beside one of the following: ATG , IVIG, rituximab, bortezomab and MP pulse
Group 2:
containing 23 patients on supportive therapy
All biopsies were examined by LM , IF , EM and classified according to Banff critria
To diagnose CAMR, the following must be present :
-evidence of chronic tissue injury
-evidence of recent or current interaction between antibodies and vascular endothelium .
-presence of DSA
End points of the study:
Death or Graft loss or end of 2017
Results and Discussion:
Group 1 with aggressive treatment showed better graft survival but infection as CMV , UTI , PCP Pneumonia
Sahar elkharraz
2 years ago
Evidence 3
Sahar elkharraz
2 years ago
Treatment-of-chronic-active-antibody-mediated-rejection-in-renal-transplant-recipients-–-a-single-center-retrospective-study
It’s retrospective study done in single centre between 2009 to 2017 focus on outcome of CABR with different immunosuppressive protocols.
CABR defined as presence of circulating DSA and morphological changes of chronic micro vascular damage with or without C4d staining.
All transplant patients to avoid graft loss should receive induction therapy of intravenous ATG or Basiliximab and maintenance therapy of tacrolimus/ mycophenolate / prednisone.
In this study patients with chronic changes receiving pulse therapy of steroid and double filtration plasma exchange with intravenous rituximab and Iv ATG.
The patients divided into 2 groups: first group receive aggressive treatment and second group receive supportive treatment by control blood pressure and sugar/ control lipid and avoid nephrotoxic agents.
The end points of this study are returning to dialysis, retransplant, death or end of 2017.
To diagnosing CABR the biopsy done and classified according to banff 2017 and C4d staining done.
Criteria of diagnosis are presence of circulating DSA and morphological chronic changes of micro vascular inflammation and tubular atrophy and antibodies reactions between endothelial vessels and C4d staining.
The group who received aggressive treatment ( Intravenous rituximab and intravenous immunoglobulin), have good outcome of graft but high risk of infection like CMV and urinary tract infection and infected diarrhoea, leukopenia and pneumocystic carinii pneumonia.
Conclusion:
Chronic antibodies mediated rejection with aggressive immunosuppressive therapy responded with good graft outcome but still risk of opportunity infection.
ahmed saleeh
2 years ago
the importance of aggressive treatment in CAMR at an earlier stage and with a higher
degree of microvascular injury.
The most common adverse events in our patients were CMV disease, urinary
tract infection, bacterial / PCP pneumonia, and infectious
diarrhea.
PCP is a major cause of morbidity and mortality in patients receiving immunosuppressant
therapies. Previous CMV
infection, acute graft rejection and intensity of immunosuppressive therapy had been
reported as risk factors
for PCP in kidney transplant recipients
Despite the significantly higher rate of adverse events in the aggressive treatment group,
there was no significant
difference in patient survival , implying that the patients still could have a
reasonable chance of survival if these complications can be treated judiciously.
aggressive treatment for CAMR before advanced tissue injury is still
associated with better graft outcome in our series. However,
higher incidence of adverse events cannot be overlooked.
To mitigate potential life-threatening infections, longer
duration of PCP and CMV
prophylaxis should be considered after aggressive treatment for rejection.
nawaf yehia
2 years ago
Chronic active antibody-mediated rejection ( CAMR ) is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies.this retrospective study was designed to compare graft survival and patient survival according to the treatment strategy for CAMR
Methods: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection.
The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte
globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment.
Results: From February 2009 to December 2017, a total of 82 patients with biopsy-proven CAMR were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2
Although group 1 showed better graft survival but on conditiuon that proteinuria is less htan 1.73 g/d , which concludes that proteinuria is an independant predictor for graft loss
. Adverse event-free survival was lower in group 1 where infections & sepsis wrer more common in the form of ( CMV , UTI , leucopenia , pneumonia , PCP , infectious diarrhea ) whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis.
Conclusions: Appropriate prophylactic antibiotics ( TMP , Valganciclovir ) are recommended for longer period (5-6 months ) inpatients undergoing aggressive treatment.
reflectoin on my practice : its results encourages the institution of aggrressive treatment strategy should CAMR be diagnosed by a protocol or ofor cause biopsy with attention toward the high incidence of serious infections and considering the adherence to the prophylactic antimicrobials routinely prescribed .
Level of evidence : level III
Wee Leng Gan
2 years ago
This is a retrospective single center study at Taichung Veterans General Hospital from February 2009 to December 2017. This is a level 3 evidence study. The main objective of this study is to assess the outcome of biopsy proven Chronic active antibody mediated rejection (CAMR) among kidney transplant recipients of the center. A total of 82 patients recruited of which 59 patients ( Group 1) received aggressive immunosuppressive therapy and 23 patients ( Group 2 ) were on supportive therapy following CAMR diagnosis. The follow up period was 32.59 months (IQR 24.01–49.89). Graft survival more favorable for group 1 which is statistically significant. The median graft survival was 6.45 years for group 1 and 3.68 years in group 2. On the other hands, adverse event-free survival was lower in group 1 but patient survival was not significantly different between these two groups. Multivariate analysis shown that proteinuria and conservative management were independent risk factors associated with graft loss. The limitation of this study include no standardize consensus on the treatment protocol for CAMR. Besides, DSA not performed for all kidney transplant recipients and PRA only done one a year. In conclusion, we need to personalize the management of CAMR
Naglaa Abdalla
2 years ago
This is a retrospective study from Taichung Veterans General Hospital.
Computerized data for 7 years(2009-2017) were collected from 82 patients with biopsy diagnosis of chronic active antibody mediated rejection(CAMR), using Kaplan-Meir analysis of death-censored graft survival between 2 groups.
Chronic active antibody mediated rejection(CAMR) is one of the major causes graft loss, despite this no presence of agreemental universal treatment
Group 1:
59 patients received aggressive treatment of DFPP and one of the followings: rituximab, IVIG, ATG, bortezomib or MP pulse therapy.
Group 2:
23 patients received supportive treatment.
All renal biopsies were examined by light microscopy, IF and EM and graded according to Banff criteria. for Glomerulitis(g), peritubular cappillaritis(ptc), transplant glomerulopathy(cg), interstitial fibrosis(ci), tubular atrophy(ct) and mesangial matrix(mm).
The diagnosis was done due to presence of all of the following:
1- Morphological changes of chronic tissue injury.
2- Evidence of current/recent antibody interaction with vascular endothelium.
3- Presence of DSA.
End points:
The patient were followed until graft loss or death or end of 2017.
Results and Discussion:
No statistical difference between the 2 groups regarding age, donor type, treatment duration, follow up, DM or hepatitis B or C, PRA, class1&2 titer percentages of patients who received induction treatment, immunosuppressive regimen, serum creatinine, proteinuria and Banff criteria scores.
Aggressive treatment group showed better graft survival in patients with proteinuria or equal 1.37 g/d.
Higher incidence of adverse effect and infection in the 1st group mainly: CMV disease, bacterial pneumonia, UTI, infectious diarrhea and leukopenia.
In the 1st group 3 of them died due to sepsis.
In the 2nd group one died of sepsis and the second died of hemorrhagic shock due to hemothorax.
Conclusion:
Aggressive treatment of CAMR before advanced tissue injury has a better graft survival but increased risk of life threatening infections.
Appropriate prophylaxis duration for PCP and CMV is needed.
This study is level 3 evidence.
Shereen Yousef
2 years ago
-This is a retrospective study addressing different protocols of mangment of Chronic active antibody mediated rejection.
Level of evidence III
-Chronic active antibody mediated rejection (CAMR) is one of the major causes of graft failure.
– it is Diagnosed by presence of DSAs and specific morphologic lesions( microvascular inflammation/injury,with or without capillary C4d deposition).
– treatment for CAMR remains a major challenge.
-this is a study of 82 patients with biopsy-proven chronic antibody mediated rejection
in 7 years duration.
The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis with one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment.
-Results
*Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
*Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2.
* Adverse event-free survival was lower in group 1.
*Proteinuria was independent risk factors for graft loss in multivariate analysis.
*The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia (PCP)
*All of the mortality cases in group 1 died of sepsis. On the other hand, two of those in group 2 died of sepsis.
*Patient survival at the end of this study was not significantly different between these groups
*Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d.
*patients with proteinuria < 1.73 g/d , there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff scores.
-Conclusion of the study
aggressive treatment for CAMR patients was associated with better graft survival.
the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival.
The factors independently associated with graft loss were proteinuria and supportive treatment.
Currently, there are no approved treatments for CAMR.
it was reported that IVIG and rituximab significantly reduced or stabilized the progressive loss of transplant function
But it still controversial.
randomized double-blind clinical trial for evaluation the efficacy and safety of IVIG with rituximab also revealed no difference .
there was evidence that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury, for example biopsies with g ≥ 2 and/or (g + ptc) ≥ 4.
On the contrary, patients with low microvascular injury scores appeared less likely to benefit from antihumoral therapy.
*limitations of thestudy
-no rules for treatment of CAMR .
-the need for treatment was determined by each clinical physician.
-DSA was not performed for every recipients.
Ibrahim Omar
2 years ago
Summarise this study and reflect on your practice :
chronic active antibody mediated rejection (AMR) is a major cause of graft loss in renal transplant recipients. however, there is no consensus on the optimal treatment.
this article was for a retrospective study for evaluation of the variable treatments of chronic AMR. this study included 82 patients that were managed in Taichung Veterans General Hospital, in the period of 2009 to 2017and was diagnosed with biospy-proven chronic AMR.
those patients were divided into 2 groups according to their management of their chronic AMR as following :
1- the 1st group received aggressive treatment including double filtration plasmapharesis and one of the following : Rituximab, IVIG, ATG, Bortezomab, pulse steroids.
2- the 2nd group received only supportive treatment.
the results of that study was the following :
1- graft survival was better in patients of the 1st group. however, there was a higher incidence of adverse events related to intensive immunosuppression.
2- patient survival wasn’t significantly different in both groups of patients.
to decrease the incidence of the serious infections associated with intensive immunosuppression, prolonged prophylactic ttt was recommended for both PJP and CMV.
for my parctice, I will adhere to the local protocol in my transplant center and also highly recommend the intensive therapy
What is the level of evidence?
III
Filipe prohaska Batista
2 years ago
This paper is a single-center retrospective study (level 3 evidence) evaluating proposed treatments for chronic active antibody-mediated rejection. Data were collected over a period of seven years.
Several strategies have been used, but there is still no evidence of which would be the most effective method. The strategies were: 1. no treatment; 2. pulse therapy with methylprednisolone for three days; 3. double filtration plasmapheresis; 4. rituximab; 5. intravenous immunoglobulin (IVIG); and rATG. Graft loss criteria include return to dialysis, retransplantation, or patient death.
CAMR criteria are morphological evidence of chronic tissue damage, evidence of active interaction between antibody and endothelium, evidence of DSA. C4d deposit is also considered.
1. Survival Analysis
There was no difference in survival between patients, but the graft was lost in 18.64% in Group 1 versus 47.83% in Group 2 (p = 0.015).
2. Predictors of graft loss
Creatinine, proteinuria, PRA Class II, and supportive care were markers of graft loss. Supportive treatment HR 2.86 and proteinuria HR 1.39 were independent predictors of graft loss.
3. Adverse Events
The aggressive treatment group had a higher frequency of adverse events, predominantly CMV infections, leukopenia, urinary tract infections, pneumonia, infectious diarrhea, and pneumocystosis.
Progressive treatment had a good response in proteinuria < 1.73g/d (p = 0.016), but not in the >1.73 group (p = 0.215).
CONCLUSION
Aggressive treatment showed better graft survival in CAMR. Supportive treatment was a predictor of graft loss (HR 2.77). Rituximab is a commonly used drug, but it has infections as the main adverse effect. CMV and Pneumocystosis should be considered in this group. Despite having more infections, it did not increase the mortality of transplant patients.
CARLOS TADEU LEONIDIO
2 years ago
Summarise this study and reflect on your practice.
Diagnosis is based on the detection of donor-specific antibodies (DSAs) and specific morphologic lesions, most importantly, microvascular inflammation/injury with or without capillary C4d deposition. METHODS
Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR. The first biopsy was used for statistical analysis if the patient had multiple biopsies. All biopsies were performed for cause and reviewed by a renal pathologist. Biopsies with ABO-incompatable grafts and those with recurrent or de novo glomerulonephritis (GN) and DM nephropathy were excluded. All the patients had negative T and B cell complement-dependent cytotoxicity cross-match (CDC-CMX) result before kidney transplantation. DSA was not performed for every recipients in hospital, because Luminex® technology for HLA antibody detection in organ transplant is expensive in Taiwan
The patients were divided into two groups according to treatment strategy.
END POINTS
The patients were followed up until graft loss or death or the end of 2017. The definition of graft loss included: returned to dialysis, re-transplant, or patient death. The same pathologist evaluated and graded graft biopsies according to Banff 2017 criteria.
RESULTS
From February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified. Three cases were excluded from the analysis owing to short follow up duration (less than 6 months).
Group 1 comprised 59 cases, whereas group 2 comprised 23 cases. There were no statistically significant differences between group 1 and group 2 in terms of age, donor type, transplant duration, follow up duration, percentages of diabetes mellitus, hepatitis B or C, panel reactive antibody (PRA) class I and II titer, percentages of patients who received induction treatment, immunosuppressive regimen (cyclosporine based or tacrolimus based), serum creatinine, proteinuria, and Banff scores.
The main results were:
A- Survival analysis
– A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1 (all for sepsis), and 3/23 (13.04%) in group 2 (two for sepsis). Patient survival at the end of this study was not significantly different between these groups.
B – Predictor of graft loss
– By univariate analysis, the significant predictors of graft loss for CAMR were creatinine, proteinuria, PRA class II, cg ≥ 1, ci + ct ≥ 3, and supportive treatment.
– Supportive treatment (HR 2.86, 95%CI [1.05–7.77]) and proteinuria (HR 1.39, 95% CI [1.06–1.83])were independently associated with graft loss;
C – Adverse events
– Adverse event free survival was significantly better in group 2 (P = 0.002 by log-rank test). The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
D – Subgroup analysis
A Kaplan-Meier analysis was conducted with patients with proteinuria < 1.73 g/d and ≥ 1.73 g/d.
– Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d (p = 0.016 by log rank analysis), but not in patients with proteinuria ≥1.73 g/d (p = 0.215 by log rank analysis). In the subgroup analysis which included patients with proteinuria < 1.73 g/d, there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff scores
DISCUSSION
– aggressive treatment for CAMR patients was associated with better graft survival. However, the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival.
– The factors independently associated with graft loss were proteinuria and supportive treatment
– there was evidence that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury. But, on the contrary, patients with low microvascular injury scores appeared less likely to benefit from antihumoral therapy;
– linical experience of bortezomib in transplantation showed variable results among patients with different disease states and populations.
– Supportive treatment was a predictor of graft loss in the univariate analysis (HR 2.77, 95% CI [1.19–6.41], P = 0.017). After adjustment of proteinuria, creatinine, and cg score, supportive treatment was still an independent risk factor of graft loss
What is the level of evidence?
This is a primary study of unic center. Retrospective study – level 03.
Wael Jebur
2 years ago
A retrospective study was conducted to evaluate the effectiveness of treatment of chronic active antibody mediated rejection CAMR.
82 biopsy proven cases of CAMR in a single center were included from 2009 through 2017. They were followed until graft loss, patients death or end of 2017.
Graft loss means return to Dialysis or retransplantation.
CAMR diagnostic criteria according to Banff 2017 include:
1] Evidence of chronic tissue injury TG, PTCM., chronic interstitial nephritis ci, tubular atrophy ct
2] evidence of recent or current antibody interaction with vascular endothelium.which is MVI or C4d.
3] Presence of DSAs anti HLA or other donor antigens.
C4d staining was a prerequisite for the diagnosis of CAMR as the testing for the expression of validated transcripts / classifiers was not done routinely.
Immunosuppressant protocol:
Induction with either ATG or IL-2 R antagonist {CD25 antagonist}, and maintenance with either Tacrolimus or Cyclosporin based regimen which include in addition MMf and prednisolon.
The cohort of patients were divided into 2 groups:
1] Group 1:Treatment group 59 patients where received DFPP of 1-1,5 plasma volume, and one of the following treatment ,40 patients received Rituximab 375 mg/m , 10 patients received IVIG 2gm/kg , 17 patients received MP , 4 patients received rATG 1-1.5 mg/kg for 3-5 days, and 10 patients received Bortizomib 1.3 mg/m ,
Multiple treatment usually yearly if the repeat biopsy revealed persisient lesion.
2] Group 2: Control group 23 patients received supportive therapy including:
Hypertension control with RAASi.
Control of DM with oral hypoglycemuc or insulin.
hyperuricemia control with Allopurinol or Feboxustat.
Control of Hyperlipidemia with statin or fibrate.
Bicarbonate if acidosis was reported.
these measures were considered in group 1 as well.
Primary point was graft survival after treatment in group 1.
secondary end point includes patient survival .
They were followed for an average of 32.59 months post diagnosis of CAMR
Result of the study:
Loss of allograft
group 1 11/59
group 2 11/23
Graft survival was worse in group 2
Mortality:
group 1 6/59 because of sepsis
group 2 3/23 because of sepsis and hemorrhage.
Patient survival was not statistically different at the end of study between the 2 groups.
Predictors of graft loss:
creatinine and proteinuria
PRA class II
cg more than 1
ci+ct of more than 3
supportive therapy. Adverse events:
group 1 54/59 adverse events
group 2 7/23 adverse events
adverse events in group 1 include:
CMV
PJP
Leukopenia
Urinary tract infection
Pneumonia
Infectious Diarrhoea.
Therefor adverse events free survival was significantly better in group 2 then group 1
CAMR Diagnosis is based on the detection of donor-specific antibodies (DSAs) and specific morphologic lesions, most importantly, micro vascular inflammation/injury with or without capillary C4d deposition.
Treatment strategies included:intravenous immunoglobulin (IVIG), rituximab, proteasome inhibitor-bortezomib, complement inhibitor-eculizumab, and IL-6 receptor blocker. Methods: Patients and graft biopsies:
Renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR.All biopsies were performed for cause and reviewed by a renal pathologist.
Biopsies with ABO-incompatible grafts and those with recurrent or de novo glomerulonephritis (GN) and DM nephropathy were excluded.All the patients had negative cross-match pretransplantation.
Treatment strategies for CAMR:
No treatment.
Methylprednisolone pulse therapy (usually 500 mg of MP for 3 days).
Plasmapheresis.
Rituximab intravenous bolus (375 mg/m2).
Intravenous immunoglobulin (IVIG) (2 g/kg).
Antithymocyte globulin (ATG) (Thymoglobulin 1–1.5 mg/kg for 3–5 days).
Groups (group1 received aggressive treatment group 2 received supportive treatment). End points
Graft loss or death or the end of 2017. Histopathology and diagnosis of CAMR
CAMR, all 3 criteria in the following according to Banff 2017
(1) morphologic evidence of chronic tissue injury,
(2) evidence of current/recent antibody interaction with vascular endothelium,
(3) Serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens).
C4d staining in the biopsy tissue or expression of validated transcripts/classifiers may substitute for DSA. Data analysis
P value of less than 0.05 was considered statistically significant. All statistical analyses were performed by using SPSS software (version 21.0, Chicago, IL, USA).
Results
A total of 22 (26.82%) patients lost their allograft, including11/59 patients (18.64%) in group 1 and 11/23 (47.83%) patients in group 2.
Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1, and 3/23 (13.04%) in group 2.
All of the mortality cases in group 1 died of sepsis and 1 case died of hemorrhagic shock due to hemothorax.
Patient survival at the end of this study was not significantly different between these groups (P = 0.567).
Predictors of graft loss:
Creatinine, proteinuria, PRA class II, cg ≥ 1, ci + ct ≥ 3.
Adverse events:
Total of 54 adverse events in group 1, compared with 7 in group 2.
The most frequent events in aggressive treatment group were CMV, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
Graft survival in patients with proteinuria < 1.73 g/d with aggressive treatment resulted in better graft survival but not in patients with proteinuria ≥1.73 g/d.
Discussion
Aggressive treatment for CAMR patients was associated with better graft survival but higher incidence of adverse events.
Factors independently associated with graft loss were proteinuria and supportive treatment.
The subgroup with transplant glomerulopathy (TG) was associated with a poorer response.
HLA antibodies produced by long-lived plasma cells (LLPCs) are more refractory to proteasome inhibitor therapy. LLPC resistance and immunologic compensatory mechanisms may also play a role in treatment failure.
This study highlights the importance of aggressive treatment in CAMR at an earlier stage and with a higher degree of microvascular injury.
ABO-incompatible kidney transplant recipients who received rituximab had higher incidence of CMV disease (due to the release of TNF-α after administration, which may stimulate cellular nuclear factor кB and viral replication via binding to the promoter region of the CMV immediate-early antigen gene and reduced cytotoxic T cell response thus impaired viral clearance).
The average duration between last rituximab and first infection episode in transplant recipients was about 5 to 6 months.
Limitations of the study; no DSA were performed, and no specific rules for treatment according to every physician decision. Conclusion
Aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome but higher incidence of adverse events.
Level of evidence: 3 (retrospective study).
Reem Younis
2 years ago
. Chronic active antibody-mediated rejection (CAMR) is associated with graft failure.
– Diagnosis is based on the detection of donor-specific antibodies (DSAs) and specific morphologic lesions, most importantly, microvascular inflammation/ injury with or without capillary C4d deposition.
-Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR.
-All the patients had negative T and B cell complement-dependent cytotoxicity
cross-match (CDC-CMX) result before kidney transplantation.
-Thymoglobulin or basiliximab may be prescribed for induction therapy. Maintenance immunosuppression included calcineurin inhibitors (CNIs) tacrolimus or cyclosporine A, mycophenolate, and prednisone.
-One or more of the following treatment strategies were selected for CAMR treatment according to the patient’s clinical condition and the decision of the individual practitioners: no treatment, methylprednisolone (MP) pulse therapy (usually 500 mg of MP for 3 days), double filtration plasmapheresis (DFPP), rituximab intravenous bolus (375 mg/m2 ), intravenous immunoglobulin (IVIG)
(2 g/kg), and rabbit anti thymocyte globulin (ATG) (Thymoglobulin 1–1.5 mg/kg for 3–5 days).
-The patients were followed up until graft loss or death or the end of 2017.
-The definition of graft loss included: returned to dialysis, re-transplant, or patient death.
-Primary endpoint was graft survival after treatment.
-Secondary outcomes included patient survival and the occurrence of major adverse events.
-Aggressive treatment for CAMR patients was associated with better graft survival but had a higher incidence of adverse events and a reduced adverse event-free survival.
-Currently, there are no approved treatments for CAMR.
– Several studies showed:
-IVIG and rituximab significantly reduced or stabilized the progressive
loss of transplant function. However, the subgroup with transplant glomerulopathy (TG) was associated with poorer response.
Another study conducted
– IVIG with rituximab treatment for severe TG in CAMR did not change the
natural history of TG.
– IVIG with rituximab revealed no difference between the treatment and
placebo groups in eGFR decline, increase of proteinuria, and MFI of the immunodominant DSA.
-There was evidence that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury, for example, biopsies
with g ≥ 2 and/or (g + ptc) ≥4 .
-Two cycles of bortezomib had no significant benefit for late-onset DSA-positive ABMR in graft survival and DSA reduction.
– HLA antibodies produced by long-lived plasma cells (LLPCs) are more refractory
to proteasome inhibitor therapy. LLPC resistance and immunologic compensatory mechanisms may also play a role in treatment failure.
-After adjustment of proteinuria, creatinine, and cg score, supportive treatment was still an independent risk factor of graft loss.
– A aggressive treatment for CAMR resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d.
-CMV infection was reported to be associated with Rituximab, ATG, and bortezomib treatment in renal transplant and myeloma patients. ABO-incompatible kidney transplant recipients who received rituximab had higher incidence of CMV disease.
-PCP is a major cause of morbidity and mortality in patients receiving immunosuppressant therapies.
-It is recommended that valganciclovir and trimethoprim-sulfamethoxazole
prophylaxis be given for at least 5~6 months after aggressive anti-rejection therapy.
–Limitations of study :
1.There were no rules for treatment of CAMR in our cohort, and the need
for treatment was determined by each clinical physician.
2. DSA was not performed for every recipients in The hospital, because Luminex® technology for HLA antibody detection in organ transplant is expensive in Taiwan.
CMV prophylaxis should be considered after aggressive Retrospective study level III
Theepa Mariamutu
2 years ago
Treatment of chronic active antibodymediated rejection in renal transplant recipients – a single center retrospective study by Hsien-Fu Chiu
This is a retrospective study evaluate the outcomes of CAMR, comparing graft survival between different treatment regimens
The study period was from February 2009 to December 2017, 85 patients were recruited in the study
The data was taken from the computer records of transplant biopsies with a diagnosis of CAMR, according to Banff’s 2017 diagnostic criteria
The patients were divided into two groups ;
Group 1: received aggressive treatment ( DFPP, and either rituximab, IVIG, ATG, bortezomib, or Methylprednisolone pulse therapy)
Group 2: received supportive therapy
Exclusion criteria: ABOi- grafts, recurrent or de novo GN, DKD
Results
Survival Analysis
Demographic data showed no statistically significant differences between groups 1 and 2 (age, donor type, transplant duration, follow up duration, DM, Hepatitis B,C, PRA, percentage of patients who received induction treatment, IS regimen, s.creatinine, proteinuria, and Banff score)
The patients were followed up for 32.59 months after the diagnosis of CAMR
26.82% patients lost their allograft, including 18.64% in group 1 and 47.83% patients in group 2
Median graft survival for group 1 and group 2 – 6.45 years vs 3.68 years
Death-censored graft survival showed worse survival in group 2
10.97% patients died after diagnosis of CAMR- 10.16% patients in group 1, and 13.04% in group 2
Mortality rate was 10% in group 1 and 13% in group 2
The cause of death in group 1 was mainly sepsis.
Patient survival at the end of this study was not significantly different between these groups
Predictors of graft loss
By multivariate analysis – supportive treatment and proteinuria – independently associated with graft loss
Adverse events
Mean number of adverse events per patient was higher in group 1- CMV, leukopenia, UTI, pneumonia, infectious diarrhoea, and PJP
Adverse event-free survival was significantly better in group 2
Subgroup analysis
Kaplan-Meier analysis – Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d
Patients with proteinuria < 1.73 g/d (Table 4), there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff score
Conclusion:
Aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome in the study.
However, there were higher incidence of adverse events.
Longer duration about 6 months of PCP and CMV prophylaxis should be considered after aggressive treatment for rejection
What is the level of evidence?
Level of evidence 3.
Radwa Ellisy
2 years ago
Background:
Diagnosis of chronic active antibody-mediated rejection based on the presence of DSA and evidence of tissue injury +/- C4d staining
Treatment is still challenging between conservative treatment or more aggressive immunosuppression with their adverse side effects.
This is a retrospective single-center study comparing the conservative TTT vs the aggressive treatment group over 7 years with follow up (2- 4 years) Patients and methods:
– Retrospective through 2009-217 from Taichung Veterans General Hospital
– Biopsies with CAMR (according to Banff 2017) from patients with negative B and T CDC -CMX were collected
– After exclusion of
1- ABO-incompatible grafts
2- recurrent or de novo glomerulonephritis (GN)
3- DM nephropathy
– Patients were divided into two groups: Group A with DFPP and either MP, rituximab, IV Ig, rATG, or bortezomib (and continued yearly) + care for CKD Group B: No treatment group
– The patients were followed up till graft loss (dialysis, re tx, or patient death) or death or the end of 2017.
– patient survival and major adverse events were considered secondary outcomes results:
– better survival was found in group A with mortality attributed to sepsis only in this group
– proteinuria and supportive treatment were independent factors for graft loss
– major adverse events were significantly higher in group A conclusion:
– aggressive Is is better when commenced early before significant tissue injury but with care for CMV and PCP prophylaxis to avoid major adverse events. level of Evidence 3 case-control retrospective study
Study limitation
A retrospective study included a small number of patients
Heterogenicity in antirejection protocols.
The follow-up period is shorter to detect other risk events like increased cancer risk level of Evidence 3 retrospective cohort study my reflection :
In our center, the diagnosis with CAMR is usually delayed for the insidious presentation of CAMR usually creeping creatinine, and also for financial aspects concerning DSA.
I think in absence of consensus treatment for CAMR, treatment should be individualized according to the IFTA score, the time elapsed between presentation and diagnosis, the baseline graft function, and the availability of antirejection treatment.
Among antirejection treatment, only plasma exchange low dose IVIG and methylprednisolone only experienced in our center for ttt of CAMR
Treatment of chronic active antibody mediated rejection in kidney transplant patients remains a dilemma for transplant physicians. Management is always individualized.In this retrospective study by Hsien and colleagues have shared there center experience of treating CAMR.
Methods: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection.
The patients were divided into two groups according to treatment strategy:
Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy)
Group 2 received supportive treatment.
End points
The patients were followed up until graft loss or death or the end of 2017.
The definition of graft loss included: returned to dialysis,
re-transplant,
or patient death.
Primary end point was graft survival after treatment in the 2 groups.
Secondary outcome included patient survival and the occurrence of major adverse events.
Histopathology and diagnosis of CAMR
For CAMR, all 3 criteria in the following were met for diagnosis according to Banff 2017 criteria:
(1) morphologic evidence of chronic tissue injury, (2) evidence of current/recent antibody interaction with vascular endothelium,
(3) serologic evidence of donor-specific antibodies (DSA)
Results
From February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified.
Three cases were excluded from the analysis owing to short follow up duration (less than 6 months).
Group 1 comprised 59 cases,
whereas group 2 comprised 23 cases.
In group 1, besides DFPP, 40 patients had received Rituximab, 10 patients had received IVIG, 10 patients had received bortezomib, whereas 4 patients had received antithymocyte globulin and 17 patients had received MP pulse therapy .
Survival analysis
Patients were followed for a median of 32.59 months after the diagnosis of CAMR. A total of 22 (26.82%) patients lost their allograft, including 11/59 patients (18.64%) in group 1
and 11/23 (47.83%) patients in group 2.
Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
Overall median graft survival was 5.6years. Kaplan-Meier ana- lysis of death-censored graft survival showed worse survival in group 2 (P = 0.015 by log-rank test)
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1
3/23 (13.04%) in group 2.
All of the mortality cases in group 1 died of sepsis. On the other hand, two of those in group 2 died of sepsis, and 1 case died of hemorrhagic shock due to hemothorax. Patient survival at the end of this study was not significantly different between these
Subgroup analysis
They conducted a Kaplan-Meier analysis of graft survival in patients with proteinuria < 1.73 g/d and ≥ 1.73 g/d.
Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d
Adverse Events
There was a total of 54 adverse events in group 1, 7 in group 2.
Mean number of adverse events per patient was higher in group 1 (P < 0.001). Adverse event free survival was significantly better in group 2.
Limitations
Retrospective review
DSA was not done routinely
No standardized treatment
Conclusion
In conclusion, aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome .However, higher incidence of adverse events cannot be overlooked. To mitigate potential life-threatening infections, longer duration of PCP and CMV prophylaxis should be considered after aggressive treatment of rejection.
Level of Evidence III
RETROSPECTIVE
This paper has not shown something extraordinarily new which could effect my practice. I think we should know when not to intervene as effect of those heavy immunosuppressive drugs is seen few months to years later and I feel countries like pakistan where chronic infections like TB is so prevalent we should weigh the risk and benefits before hitting very hard
I. Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single centre retrospective study Summarise this study and reflect on your practice. This is a single center retrospective study of post- kidney transplant patients diagnosed with chronic active AMR on the basis of for-cause biopsy. ABO-i grafts & those with recurrent or de novo GN & DM nephropathy were excluded. CDC-CMX was negative in all patients. Thymoglobulin or basiliximab was for induction. Maintenance IS included CNIs (tacrolimus or cyclosporine A), MMF, & prednisone. Few patients received mTOR-i (sirolimus or everolimus). The patients were divided into 2 groups: Group 1: received aggressive treatment (DFPP & 1 of the following: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy); treated annually, each year using one different agent of the 5 drugs for a wider spectrum of allo-immune blockade. Group 2: received supportive treatment(ideal BP control, blood sugar control, hyper-uricemia control, & avoidance of nephrotoxic drugs). Oral NaHCO3 was prescribed if the patient had metabolic acidosis. Statin/fibrate used to control lipids; ACEI/ARB to control BP. The patients were followed up until graft loss or death or the end of 2017. Primary end point was graft survival after treatment in the 2 groups. Secondary outcome: patient survival & the occurrence of major adverse events (any event associated with death, hospital admission , prolongation of a hospital stay, persistent or significant disability or incapacity, or was otherwise life-threatening in connection with specific treatment). ———————————————————– Histopathology and diagnosis of CAMR Biopsies were examined by LM using silver & PAS stains, IF stains for IgG, IgA, IgM, C3, C4d, C1q, kappa, & lambda light chains, &EM. For diagnosis of CAMR, all 3 criteria in the following were met according to Banff 2017 criteria: (1) morphologic evidence of chronic tissue injury, (2) evidence of current/recent antibody interaction with vascular endothelium, and (3) serologic evidence of DSA, to HLA or other antigens. C4d staining in the biopsy tissue or expression of validated transcripts/classifiers may substitute for DSA. ————————————————– Results A total of 85 (59 in group 1 & 23 in froup2) patients with biopsy-proven CAMR were identified. 3 cases were excluded due to short follow up duration (<6 months). Group 1: besides DFPP, 40 patients received Rituximab, 10 received IVIG, 10 received bortezomib, 4 received ATG, & 17 received MP pulse therapy only. Patients were followed for a median of 32.59 months after the diagnosis of CAMR. A 22 (26.82%) patients lost their allograft: 11/59 (18.64%) in group 1 & 11/23 (47.83%) in group 2. Median graft survival (yrs): 6.45(group1) & 3.68 (group2). Overall median graft survival was 5.6 years. Worse death-censored graft survival in group 2. Nine (10.97%) patients died after diagnosis of CAMR: 6/59 (10.16%) in group 1, & 3/23 (13.04%) in group 2. Sepsis was the cause of all deaths in group 1. Patient survival was not significantly different between these groups. Predictors of graft loss for CAMR were: – creatinine – proteinuria – PRA class II – cg ≥ 1, ci + ct ≥ 3, and – supportive treatment. The most frequent adverse events in aggressive treatment group were: – CMV disease – Leucopenia – urinary tract infection – pneumonia – infectious diarrhea – PJP Median adverse event free survival was 6.0 months in the aggressive treatment group. Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d, but not in patients with proteinuria ≥1.73 g/d. Conclusions: Aggressive treatment for CAMR was associated with better graft survival. Supportive treatment was a predictor of graft loss. Aggressive treatment had higher incidence of adverse events & a reduced adverse event free survival. Proteinuria & supportive treatment were independently associated with graft loss. No approved treatments for CAMR currently exists. This study highlight the importance of aggressive treatment in CAMR at an earlier stage & with a higher degree of micro-vascular injury. The most frequently prescribed anti-humoral agent was rituximab, followed by IVIG, bortezomib, & ATG. ————————————————– Reflection on our practice: We rarely encounter cases of chronic active AMR, probably because we are highly selective in choosing patients for transplantation; highly sensitized patients are usually excluded. Also we infrequently do biopsy in cases of chronic allograft dysfunction. And, if we ever encounter such a case we do not use aggressive treatments. =================================== What is the level of evidence? Level III
Mohamad Habli
3 years ago
This is a retrospective study with level of evidence 3,that included a total of 85 patients with biopsy-proven CAMR From February 2009 to December 2017 in Taiwan.
– Group 1 comprised 59 cases, received different treatment options including DFPP, bortezomib, Rituximab, IVIG, MP pulse and ATG.
– Group 2 comprised 23 cases, received supportive treatment only
End points: graft and patients survival by the end of 2017. Graft loss was defined as: return to dialysis, re-transplant, or patient death.
Diagnosis of CAMR according to Banff 2017 criteria. All 3 criteria were met in all patients.
(1) morphologic evidence of chronic tissue injury
(2) evidence of current/recent antibody interaction with vascular endothelium
(3) serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens).
Survival analysis Patients were followed for a median of 32.59 (IQR 24.01–49.89) months after the diagnosis of CAMR.
Results
A total of 22 patients lost their allograft, including 11/59 patients (18.64%) in group 1 and 11/23 (47.83%) patients in group 2.
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1-all from sepsis, and 3/23 (13.04%) in group 2.
Adverse events
– Adverse event free survival was significantly better in group 2.
– Infectious adverse events were more common in aggressive treatment group included CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
In conclusion, aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome in our series. However, higher incidence of adverse events cannot be overlooked. To mitigate potential life-threatening infections, longer duration of PCP and CMV prophylaxis should be considered after aggressive treatment for rejection
Treatment of chronic AMR is still challenging; as it is associated with a lot of side effects like infections either viral or bacterial, and also associated with blood diseases because of removal of important clotting factors with plasmapheresis.
The treatment is limited to plasmapheresis or immunoadsorption, ivig and rituximab, also proteasome inhibitor (bortezomib), complement inhibitor (eculizumab) , and IL-6 receptor blocker may be used.
Characteristics of CAMR:
1- Chronic tissue injury on tissue biopsy
2- Microvascular inflammation on tissue biopsy with or without c4d deposition
3- Circulating de novo DSA
Aggressive treatment of CAMR can be beneficial but associated with much side effects which can endanger the patient life , on other hand the treatment will no reverse the chronic injury of the kidney so it is beneficial before development of chronicity.
level of evidence cohort retrospective study level 3
in my practice, treatment is based on the extent of chronicity by tissue biopsy , clinical situation, and financial aspect of the patient
Summarise this study and reflect on your practice.
* Chronic active antibody mediated
rejection (CAMR) is the most important causes of renal graft failure.
* Diagnosis of CAMR is depend mainly on the detection of circulating DSAs and presence of microvascular inflammation or injury with or without capillary C4d deposition biopsy finding.
*A variety of treatment strategies have been proven effective for acute antibody mediated rejection.
* The treatment of CAMR is a major challenge, and some studies showed using IVIG plus rituximab, bortezomib, eculizumab and IL-6 receptor blocker have not always turned out to be effective and the adverse effect of these immunosuppressants are important.
*This study investigated the outcomes of CAMR comparing graft survival between
different treatment strategies.
Methods
*In this retrospective study, Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR.
*The exclusion criteria includes ABO incompatible grafts, those with recurrent or de novo (GN) and DM nephropathy.
*All the patients had negative T and B cell (CDC-MX) result before kidney transplantation .
*The patients (82) with CMR were divided into two groups according to treatment strategy:
# Group 1(59) received aggressive treatment (DFPP and one of the
followings: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy)
# Group 2 (23) received supportive treatment; patients received routine medical care for chronic kidney disease including control blood pressure, sugar, UA, lipids and preventing further kidney damage by avoiding drugs affect the kidney.
*The patients were followed up until graft loss or death or the end of 2017.
* The definition of graft loss included: returned to dialysis, re transplant, or patient death.
Results
*There were no significant differences between group 1 and group 2 in (age, donor type, transplant & follow up duration, DM, hepatitis B or C, (PRA) class I and II titer, percentages of patients who received induction treatment, immunosuppressive regimen, serum creatinine, proteinuria, and following Banff scores 2017
*A total of 22 (26.82%) patients lost their allograft, including
11/59 patients (18.64%) in group 1 and 11/23 (47.83%)
patients in group 2.
* Median graft survival was increase in group 1 than group 2.
*The death censored graft survival showed worse survival
in group 2.
* (10.97%) patients died after diagnosis of CAMR, including (10.16%) patients in group 1, and (13.04%) in group 2.
* All of the mortality cases in group 1 due to sepsis, two of those in group 2 died of sepsis, and 1 case died of hemorrhagic shock due to hemothorax.
* Patient survival at the end of this study was not significantly different between these groups (P = 0.567 by log-rank test).
*There was more adverse events in group 1, compared to group 2.
*Aggressive treatment resulted in better graft survival in patients with proteinuria <1.73 g/d.
*In the subgroup analysis of patients with proteinuria < 1.73 g/d there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff scores.
Discussion
*Aggressive treatment for CAMR result better graft survival, but has higher incidence of adverse events.
*Proteinuria and supportive treatment are independent factors that associated with graft loss .
*IVIG and rituximab stabilized the progressive graft loss, but with poor response in (TG).
*Study conducted that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury, but patients with low microvascular injury has less benefit from antihumoral therapy.
*Recently study showed that bortezomib had no significant benefit for
late onset DSA-positive ABMR in graft survival and DSA reduction .
* The most common adverse events is CMV associated with (Rituximab & ATG), UTI, bacterial / PCP pneumonia and infectious diarrhea.
*Adequate valganciclovir prophylaxis may have reduced the mortality rate by 50%
in our patients who received aggressive treatment, so they recommend that valganciclovir and trimethoprim-sulfamethoxazole prophylaxis be given for at least 5 to 6 months after aggressive anti rejection therapy.
Conclusion
*Early and aggressive treatment for CAMR is associated with better graft survival&
outcome, but with higher incidence of adverse events.
*To minimize the risk of life threatening infections, longer duration of PCP and
CMV prophylaxis is essential after aggressive treatment.
*In our practice still there is challennging in managing such patients because the diagnosis is too late, so we do plasmapheresis & IVIG in early presentation and supportive treatment, medical care for chronic kidney disease including control blood pressure, sugar, UA, lipids and preventing further kidney damage by avoiding nephrotoxic drugs in late presentation.
We hope to benefit from these studies in the future
What is the level of evidence?
This is retrospective study/ Level of evidence 3
Chronic active AMR (CAMR) is a major cause of graft failure with no approved treatment.
The aim of the study was to compare between different treatment strategies of CAMR and their effect on graft survival.
The study was retrospective, included 82 patients with allograft biopsy showing CAMR with exclusion of ABOi grafts, recurrent or de novo GN and diabetic nephropathy.
Patients were divided according to treatment strategy into group 1 who received aggressive immunosuppression in the form of double filtration plasmapheresis (DFPP) and one of 5 drugs, rituximab, IVIG, ATG, bortezomib or pulse steroids while group 2 received routine medical care of CKD including control of blood pressure, blood sugar and hyperuricemia with avoidance of nephrotoxic drugs
Patients were followed till graft failure, death or end of 2017.
primary endpoint was graft survival and secondary endpoints were patient survival and adverse events.
The study showed that
Aggressive treatment before advanced tissue injury was associated with better graft survival but with higher incidence of adverse events.
Proteinuria and supportive treatment were significantly associated with graft loss.
It is important to aggressively treat CAMR at early stage especially that with high degree of microvascular inflammation.
Common adverse events of aggressive therapy were CMV disease, UTI, bacterial/PCP pneumonia and infectious diarrhea.
Although there were higher incidence of adverse events in the aggressive treatment group, there was no significant difference in patient survival.
Longer duration of PCP and CMV prophylaxis is needed after aggressive treatment of CAMR.
Limitations:
The decision of either supportive or aggressive treatment was determined by each physician with no rules for choice
DSA wasn’t performed to all patients.
Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single center retrospective study Summaries this study and reflect on your practice.
Chronic active antibodies mediated rejection is a predominant cause of allograft failure is also, Diagnosis is based on serological detection of donor-specific antibodies (DSAs) and morphologic lesions (microvascular inflammation/injury with or without capillary C4d deposition). but the treatment remained a major challenge.
retrospective stud from February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified the study conducted in different therapeutic approaches comparing them with the outcomes of graft survival
Inclusion criteria all cases diagnosed with CAMR.
Exclusion criteria all Biopsies with ABO-incompatible grafts and those with recurrent or de novo glomerulonephritis (GN) and DM nephropathy.
All the patients had negative T and B cell complement-dependent cytotoxicity cross-match (CDC-CMX) result before kidney transplantation.
patients were divided into two groups according to treatment strategy.
Group 1 comprised 59 cases received aggressive treatment besides DFPP, 40 patients had received Rituximab, 10 patients had received IVIG, 10 patients had received bortezomib, whereas 4 patients had received anti thymocyte globulin and 17 patients had received MP pulse therapy, patients were usually treated annually with DFPP plus one of the 5 drugs, but different in each year in order to accomplish a wide blockade of the alloimmunity.
Group 2 comprised 23 cases received supportive treatment.
The patients were followed up until graft loss or death or the end of 2017. Survival analysis
-graft survival showed worse in group 2.
-Patient survival was not significantly different between these groups.
– All of the mortality cases in group 1 died of sepsis. On the other hand, two of those in group 2 died of sepsis, and 1 case died of hemorrhagic shock due to hemothorax.
–There was another subgroup which received DFPP and IV methylprednisolone alone, which had graft outcomes in between those of group 1 and group 2.
The significant predictors for graft loss included supportive treatment, creatinine, proteinuria, PRA class II and histological parameters of cg≥1 and ci+ct≥3. Supportive treatment and proteinuria were independently associated with graft loss.
-Adverse event-free survival was lower in group 1, (The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia Conclusion There are no approved treatments for CAMR.
Aggressive treatment for CAMR patients was associated with better graft survival. However, it had higher incidence of adverse events and a reduced adverse event free survival.
To mitigate potential life-threatening infections, longer duration of PCP and CMV prophylaxis should be considered after aggressive treatment for rejection.
– IVIG and rituximab significantly reduced or stabilized the progressive loss of transplant function. But,TG is associated with a poorer response.
▪︎The combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury. But, patients with low microvascular injury appeared less likely to benefit from it.
▪︎ Bortezomib: had no significant benefit for late onset DSA-positive ABMR in graft survival and DSA reduction. OUR PRACTICE
We are using plasmapheresis (3-5) session in combination of IVIG small dose after each session Level of evidence Its retrospective cohort study level III
Huda Al-Taee
3 years ago
Summarise this study and reflect on your practice
A retrospective study investigated the outcomes of CABMR by comparing graft survival between different treatment strategies.
From February 2009 to December 2017, 85 patients were involved in the study.
The data was taken from the computer records of transplant biopsies with a diagnosis of CABMR.( according to Banff’s 2017 diagnostic criteria).
The patients were divided into two groups based on treatment strategy:
Group 1 (59 cases): received aggressive treatment ( DFPP, and either rituximab, IVIG, ATG, bortezomib, or MP pulse therapy).
Group 2 (23 cases): received supportive therapy.
Exclusion criteria: ABO-incompatible grafts, recurrent or de novo GN, DM nephropathy.
There were no statistically significant differences between groups 1 & 2 in terms of age, donor type, transplant duration, follow up duration, DM, Hepatitis B,C, PRA, percentage of patients who received induction treatment, IS regimen, s.cr, proteinuria, and Banff score.
Follow up duration was 32.59 months after the diagnosis of CABMR.
Median graft survival for group 1 was 6.45 years, while for group 2 it was 3.68 years.
Death-censored graft survival showed worse survival in group 2.
Mortality rate was 10% in group 1 & 13% in group 2.
The cause of death in group 1 was mainly sepsis.
Survival at the end of the study was not significantly different between these groups.
By multivariate analysis, supportive treatment and proteinuria were independently associated with graft loss.
More adverse events are encountered in group 1 such as CMV, leucopenia, UTI, pneumonia, infectious diarrhea, and PJP.
Adverse event-free survival was significantly better in group 2.
Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d.
In a subgroup analysis of patients with proteinuria < 1.73 g/d, there was no significant difference between the aggressive and supportive treatment groups in terms of proteinuria, creatinine, and Banff score.
Conclusion:
Aggressive treatment was associated with better graft outcomes, but a higher incidence of infection. Prophylactic AB is recommended for such patients.
Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single center retrospective study Summarize this study and reflect on your practice.
Abstract:
Chronic active antibody mediated rejection considers one of the common causes of graft loss and till date no standardization of treatment of CABMR and the evidence is limited to retrospective and pilot studies with heterogenicity designs.
Setting, materials and method:
This is a retrospective electronic data collection of 82 biopsy proven CABMR from single center with good fu period of 7 years, the aim of this study to determine the graft survival as primary outcome among the two groups aggressive treatment group1 vs conservative treatment group2, Secondary outcome included patient survival and the incidence of major adverse events.
Aggressive treatment ABMR group1 of 59 patients including the use of annual DFPP plus one of 5 medications named, IVIG, Rituximab, Bortezomib, ATG, PMP.
Group 2 only23 patients with conservative medical therapy with routine medical care for both group 1,2 which consistent of strict sugar and blood pressure control, hyperuricemia and dyslipidemia control and avoid nephrotoxic medications.
All patients have negative XCM, induction either ATG, Basiliximab , with different maintenance triple therapy (CNI, tacrolimus, Ciclosporin, MMF, sirolimus, steroids) Exclusion criteria : includes the ABOi kidney transplant, recurrence or Denovo GN and Diabetic nephropathy cases Short fu duration < 6 months.
Duration of the study 2009-2017 with Follow up till graft loss or death, or end of 2017, (the graft loss defined as back to dialysis or retransplant or patient death).
The histological diagnosis of the CABMR based on banff17 criteria, using IF for C4D staining and IC staining C4D staining one of diagnostic criteria in this study
Patients demographics between two groups almost homogenous but in aggressive treatment group majority received DFPP Plus rituximab (40 cases), Followed by 17 cases received PMP only and 10 Bortezomib, another 10 IVIG and 4 only received ATG. Results: Graft survival as primary outcome.
Average graft survival of 5.2 years
Worse survival rate among group 2
longer median survival rate of 6.2 years in aggressive treatment group vs 3.2 years in group 2. with better graft survival in those with less sever proteinuria score < 1.73g/d in aggressive treatment group.
Overall Similar patients’ survival between two groups and more death with sepsis in aggressive treatment group (all death in group 1 due to sepsis) more CMV infection, UTI, bacterial infections pneumonia PJP and infective diarrhea in group1.
Predictors of graft loss
This study emphasizes about the early diagnosis of CABMR with less tg score and more microvascular inflammation, proteinuria < 1.73gm/day consider predictor of better response to aggressive treatment with better graft survival but on the count of more adverse side effects including higher rate of infections, sepsis.
Proteinuria, and supportive treatment associated with lower graft survival. Limitation:
Retrospective design, small size number and heterogenous immunosuppression protocols
No standardization of CABMR treatment, limitation to access to some drugs due to self-paying not covered by medical insurance.
HLA -DSA testing by Luminex not done in all cases due to cost, same for PRA testing.
C4d staining should be positive for the final diagnosis of CAMR which exclude cases of c4d negative CAMBR .
To conclude still we can consider aggressive IS therapy treatment in cases of CABMR with early diagnosis and less advanced chronic graft injuries like TG1 SCORE and more microvascular inflammation and proteinuria < 1-1.5gm with recommendation of longer CMV and antibacterial prophylaxis therapy extension up to 6 months. in our center still we depend on pathological scoring with C4D staining and we don’t have Constant DSA monitoring in most of our cases (more commercial transplant with missing data regarding the donors. again, no standardized protocol for CABMR treatment but we use more the combination of IVIG and rituximab and less use of plasmapheresis also modification of the maintenance triple IS like change cyclosporine to tacrolimus and MMF instead azathioprine in addition to strict control of other medical condition like BP , DM , dyslipidemia ,hyperuricemia and proteinuria with ACEI , and ARBS , regular infections screen like BKV , CMV ,UTI.
– ATG ,bortezomib and PMP not part of our CABMR treatment protocol due to high infections rate especially with bortezomib.
What is the level of evidence?
Level 111 retrospective cohort study.
Thank You Saja I like this structured summary. This is how it should be. Well done
Amit Sharma
3 years ago
I. Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single centre retrospective study
Summarise this study and reflect on your practice.
One of the most common causes of graft loss is chronic active antibody mediated rejection (CAMR). The optimal treatment for CMR eludes consensus. This was a retrospective study from 2009 to 2017 to evaluate the effect of aggressive treatment versus supportive treatment in patients with CAMR by collecting the computerized patient records. A total of 82 patients with CAMR were included in the study and followed up until graft loss or death or the end of 2017. They were divided in 2 groups: Group1: Included 59 patients treated with double filtration plasmapaheresis (DFPP) with at least one of the 5 drugs namely methylprednisolone pulse, rituximab, IVIG, ATG or bortezomib. Group 2: Included 23 patients treated with supportive management including glycemic and blood pressure control. The graft loss was 26.82% in group 1 as compared to 57.83% in group 2 with increased median graft survival in group 1. Death censored graft survival was worse in group 2. Patient survival was 89.84% in group 1 and 86.96% in group 2, indicating no significant difference. All the deaths in group were due to sepsis (50% due to CMV), while two-thirds of the deaths in group 2 were due to sepsis. There was another subgroup which received DFPP and IV methylprednisolone alone, which had graft outcomes in between those of group 1 and group 2. The significant predictors for graft loss included supportive treatment, creatinine, proteinuria, PRA class II and histological parameters of cg≥1 and ci+ct≥3. Supportive treatment and proteinuria were independently associated with graft loss. Group 1 had higher adverse events, mostly due to infections including CMV disease, pneumonia, UTI, infectious diarrhoea, pneumocystis pneumonia and leukopenia. The adverse event free survival was lower in group 1. Hence it was advised to prolong the prophylactic antivirals and anti-pneumocystis drugs for at least 5-6 months after anti-rejection treatment. In group 1, patients with proteinuria less than 1.73g/d had better graft survival than those with increased proteinuria. CAMR was diagnosed at an early stage in the study and had higher degree of microvascular injury in the study, increasing the response rate to aggressive treatment. Limitations of the study included: retrospective, single-centre study, lack of DSA levels in all the patients and no defined protocol for treatment of CAMR, with financial issues also playing a role in the line of treatment opted. In conclusion, aggressive treatment of CAMR in early stages with higher degree of microvascular injury and proteinuria less than 1.73 g/day is associated with better graft outcomes while there is no effect on patient survival. But aggressive treatment is associated with increased infections and hence there should be adequately prolonged (at least 5-6 months post treatment) antiviral and anti-pneumocystis prophylactic treatment in such patients.
What is the level of evidence?
The level of evidence is Level III: retrospective cohort study.
The presence of chronic ABMR is one of the most prevalent factors that contribute to graft failure.
The current study is a retrospective study (level of evidence III) addressing the difference between the aggressive and conservative treatment of chronic ABMR in terms of graft, patient survival, and major adverse events in 82 patients with biopsy-proven chronic ABMR done between 2009 and 2017 in a single centre in Taiwan. The patients all had biopsy-proven chronic ABMR. The study was carried out between 2009 and 2017.
Difference between aggressive and conservative treatment outcomes.
According to the treatment plan, the patients were separated into two groups. Group 1 got aggressive treatment (DFPP plus one of the following: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy); group 2 received supportive treatment (routine medical care for chronic kidney disease, including ideal blood pressure control, blood sugar control, hyperuricemia control, and preventing further kidney damage.
Degree of CABMR
According to Banff 2017 standards, all three of the following criteria were satisfied for CAMR diagnosis: (1) indication of chronic tissue damage morphology, (2) evidence of current/recent antibody interaction with vascular endothelium, and (3) serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens). DSA may be replaced by C4d staining in biopsy tissue or expression of approved transcripts/classifiers.
In this study, they involve CAMR was diagnosed at a relatively early stage (median cg score: 1.0, ci + ct: 2.0).
After intensive anti-rejection treatment, valganciclovir and trimethoprim-sulfamethoxazole prophylaxis were administered for at least 5-6 months. As The most common adverse events in our patients were CMV disease, urinary tract infection, bacterial/ PCP pneumonia, and infectious diarrhoea.
Conclusion
In conclusion, vigorous therapy for CAMR before advanced tissue damage is still related to superior graft success in our dataset. This was shown to be the case when comparing identical grafts. It is impossible to ignore the fact that there was a greater frequency of adverse occurrences. After rigorous therapy for rejection, a prolonged term of PCP and CMV prophylaxis may be explored as a means of mitigating the risk of potentially life-threatening infections.
Treatment of chronic active antibody mediated rejection in renal transplant recipients – a single center retrospective study.
=It is a single retrospective study which collected data for patients renal biopsies which diagnosed as chronic active anti-body mediated rejection based on BANFF criteria 2017 from February 2009 to December 2017. =Total number of patients was 82 and divided into 2group according to treatment strategy. Group 1 comprised of 59 cases which treated by aggressive protocol included ((double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy). Group 2 comprised of 23 cases which treated by supportive treatment. Result showed : -Death-censored graft survival showed a significantly worse survival in supportive treatment group. -Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. -Proteinuria and supportive treatment were independent risk factors for graft loss. -Patient survival at the end of this study was not significantly different between these groups . -Aggressive treatment for CAMR patients was associated with better graft survival specially here in this study a relatively early stage (median cg score: 1.0, ci + ct: 2.0) -The aggressive treatment group also had higher incidence of adverse events. Reflect on your practice: Overall the treatment of chronic active antibody mediated rejection is still not clearly evidenced and depends mainly on the grade of active tissue injuries and need more randomized control trial looking for the best consensus which will led to good graft and patient survival. Retrospective study level evidence III.
Summary Treatment of chronic active antibody- mediated rejection in renal transplant recipients introduction
CAMR is associated with graft failure although the treatment has still a major challenge.
Therapeutic approach for CAMR are based on retrospective studies and pilot trials, including IVIG, plus rituximab ,bortezomib ,eculizumab and IL6-receptor blocker but still the result of these studies not always be effective and side effects of these thearpy of great concern.
this study investigated the outcome of CAMR comparing graft survival between different treatment strategies in this centre. methods Retrospective study- Computerised record from Taichung Veterans Hospital over 7 years for biopsies performed for CAMR was collected. The patients were divided into two groups according to treatment strategy:
1)group1 received aggressive treatment in form of :DFPP plus one of the following:
Rituximab ,IVIG ,ATG ,bortezomib or MP pluse therapy.
2)group2 received supportive treatment including BP controlling, sugar, lipid, uric acid and avoid nephrotoxic medication and preventing further progression of ckd. Result
all patients were followed up until graft loss or death or the end of 2017.
graft survival in this study was significantly better in the aggressive treatment group compared to the supportive group.
higher incidence of adverse events in aggressive treatment group
in depend graft loss factors were proteinuria>1.73g/d and supportive treatment.
despite the significantly higher rate of adverse events in the aggressive treatment group there was no significant difference in patients survival.
limitation of this study
no rules for treatment of CAMR in this cohort study.
DSA not done for every patients as its expensive.
small size sample. conclusion
aggressive treatment for CAMR before advanced tissue injury is associated with better graft outcome.
higher incidence of adverse event in aggressive treatment group1is a challenge to apply this treatment.
aggressive treatment for rejection should receive longer duration of PCP,CMV prophylaxis as to avoid life threatening infection.
level of evidence :retrospective studies level 3
(those who received MP pulse with DFPP only were excluded)
These patients had graft survival between aggressive treatment and supportive treatment group
Chronic antibody mediated rejection (CAMR) is an important entity leading to graft loss. Diagnosis of CAMR depends on presence of DSA and biopsy showing micro vascular inflammation with or without C4d deposition in capillary. Treatment of CAMR is a challenge. options include IVIG plus Rituximab, bortezomib, eculizumab, and IL6 receptor blocker. There have been retrospective studies on outcome but the results have not always turned out to be effective. This study investigated the graft outcome in between different treatment strategies.
Methods.
Retrospective study- Computerised record from Taichung Veterans Hospital over 7 years for biopsies performed for CAMR was collected. Biopsies of ABOI grafts, recurrent or denovo golmerulonephritis and Diabetic nephropathy were excluded. All patients had negative T and B cell CDC cross match . Total patient no-82. Two groups were made-
Group 1 – Aggressive treatment Group
This group received double filter PP and one of either Rituximab, IVIG, ATG Boretezomib, or Pulse steroids
Group 2- Conservative treatment-
Good control of medical conditions and avoidance of nephrotoxics
Results-
Aggressive treatment had good outcome if patient had less advanced disease, proteinuria <1.73gm, micro vascular injury While those with TG had worse outcome. This group had higher incidence of infections like UTI , Diarrhoea, CMV. Patient received 1 month of prophylaxis for PCP and CMV
No difference was noted in survival between two groups. Boretezomab did not offer additional advantage in those with positive DSA.
Limitations.
No rules for treatment of CAMR
DSA was not performed for every patient
Retrospective and small sample.
Conclusion
Aggressive treatment of CAMR has better outcome
There is higher incidence of life threatening infections.
Longer duration (6 moths) of PCP and CMV prophylaxis should be given before aggressive therapy
Chronic active antibody mediated rejection(CAMR) is now considered an important risk factor for allograft dysfunction and ultimately graft failure. Diagnosis is based on presence of DSA, morphologic evidence of chronic tissue injury, microvascular inflammation with or without C4d deposition in capillaries. Treatment of CAMR really a big challenge for the transplant physicians as treatment not always effective & no proper recommendations available and also associated with high incidence of side effects. Current management for CAMR includes intravenous immunoglobulin (IVIG) plus rituximab ,proteasome inhibitor-bortezomib , complement inhibitor(eculizumab) and IL-6 receptor blocker .This retrospective study conducted from February 2009 to December 2017 included 82 patients with biopsy-proven CAMR aimed at assessing the outcome of CAMR by comparing allograft survival between those who received aggressive therapy(double filtration plasmapheresis(DFPP) and one of the followings: rituximab, IVIG, ATG, bortezomib, or methylprednisolone pulse therapy)and those who received conservative or supportive therapy. CONCLUSION:
Aggressive treatment for CAMR leads to better graft survival but on the other hand is associated with higher incidence of adverse events. The most common adverse events seen were UTI, CMV infection, bacterial or PCP pneumonia, and infectious diarrhea. Proteinuria >1.73 g/d and supportive treatment were independently associated with graft loss. IVIG plus rituximab was seen to be favorable for patients with increased microvascular injury, while transplant glomerulopathy patients did not benefit from this treatment specifically. Bortezomib did not appear to have significant advantage in treating patients who were DSA positive. There was no difference in survival between the two groups. Adequate valganciclovir prophylaxis may have reduced the mortality rate by 50% and it is recommend that valganciclovir and trimethoprim-sulfamethoxazole prophylaxis be given for at least 5-6 months after aggressive anti-rejection therapy due to increased risk of major adverse effects.
You have covered most of the salient features. The discussion could have been a little more organized
Last edited 3 years ago by Hemant Sharma
Sherif Yusuf
3 years ago
Chronic ABMR constitutes one of the most common causes of graft failure
The current study is a retrospective study (level of evidence III) addressing the difference between the aggressive and conservative treatment of chronic ABMR in terms of graft, patient survival, and major adverse events in 82 patients with biopsy proven chronic ABMR done between 2009 and 2017 in a single center in Taiwan
Aggressive treatment was defined as the use of double filtration plasmapheresis and one of the following: Rituximab, IVIG, ATG, Bortezumab or pulse methylprednisolone
Diagnosis of chronic ABMR was based in this study on the presence of histologic features of chronic ABMR and the presence of C4d since the detection of DSA using luminex is expensive and thus not done in these cases
Conclusions
1- Aggressive treatment of chronic ABMR offer better outcome only in the following patients
Patients with early, less advanced disease with cg of 1
Patients with lesser degree of proteinuria < 1.73 gm
Patients with evident microvascular injury (median g score of 2, g+ ptc score of 3.5)
2- Aggressive treatment was associated with a higher incidence of infections including PCP, CMV infections, infectious diarrhea, and UTI which was evident in the first 6 months after treatment with Rituximab, ATG or Bortezumab. Patients in this study received PCP and CMV prophylaxis for only 1 month after treatment so the authors recommend 6 months prophylactic treatment after aggressive treatment
Dear all in order to make full use of this article please address the following points:
Degree of CABMR
Difference between aggressive and conservative treatment outcomes.
Effect of aggressive treatment on infectious complications
Indication to prolong antiviral treatment.
Chronic active antibody mediated rejection(CAMR) is now considered an important risk factor for allograft dysfunction and loss. Unfortunately therapeutic decisions for treatment of CAMR is hampered by lack large RCT comparing the efficacy of individual treatment. The available data were informed by retrospective studies (4,5). This retrospective from February 2009 to December 2017 aimed at evaluating the outcomes of CAMR by comparing allograft survival between those who received aggressive therapy and those who received conservative or supportive therapy.
Methods ;
Retrospective analysis of electronic record was performed at Taichung Veterans General Hospital
Total number of 82 recipients with evidence of biopsy proven CAMR in the last 7 years were evaluated and patients were divided into two groups( group1 & group2)
Group1 ; Treated with intensive immune-suppression plus double filtration plasma phersis. The immuno-suppression consist of one of these drugs ; IVIG, RTX, ATG, bortezomib, or IV methyprednisolone
Group2 ; Managed by supportive care including controlling BP, sugar, lipid, uric acid, avoid nephrotoxic medications and preventing further progression of CKD.
Results ;
Death-censored graft survival was worse in group2 compared with group1
Adverse event-free survival was lower in group1 compared with group2
Proteinuria >1.73 g/d and conservative were independently associated with graft loss
There was no difference in survival between the two groups
Limitations ;
No guidelines for treatment of CAMR, it was left at the physician discretion
DSAs was not done for financial reasons
Retrospective analysis
single center
small sample size
Conclusion ;
Early aggressive treatment of CAMR may be associated with better outcomes than supportive care. This is not true with late or advanced injuries associated with CAMR such as a transplant glomerulopathy(TG).
However, one must keep in mind the high risk of adverse events related to aggressive immune-suppression namely infectious complications
Therefore, prophylactic antibiotics should always be considered the group of the patients who candidates for aggressive treatment of CAMR
Level of evidence ; This is retrospective study, and therefore the level of evidence is 3
The core of this article is concerned with treatment of CAMR or chronic active antibody mediated rejection in renal transplant recipients. Diagnosis is based on three major markers, listed below :
DSA
specific morphological lesions
microvascular inflammation with or without C4d deposition in capillaries.
Different treatment strategies that were attempted in renal transplant recipients were collected from records in this trial and its results were compared with respect to graft survival and patient outcome. The treatment strategies involved were IVIG plus rituximab, proteasome inhibitor – Bortezomib, complement inhibitor – eculizumab, IL – 6 receptor blocker. These medications were used in two groups of patients – one for aggressive treatment and one for supportive therapy.
Computerized records collected from the past 7 years of biopsies from one particular center have been used as the baseline material in this publication.
Since graft survival is the ultimate marker in this study, we mention the definition of graft loss according to the authors of this publication – graft loss included patients who returned to dialysis, re-transplant, or patients who died.
Major adverse event was defined by any event that was associated with death, admission to hospital, prolongation, persistent or significant disability or incapacity, or was otherwise life threatening in connection with specific treatment.
This study found that CAMR patients had better rates of graft survival with aggressive treatment. The downside to this, however, was that aggressive treatment also meant more chances of major adverse events. The most common adverse events seen were UTI, CMV infection, bacterial or PCP pneumonia, and infectious diarrhea.
Graft loss was found to be associated with supportive therapy alone and proteinuria.
Outcomes related to specific treatment regimen :
IVIG plus rituximab was seen to be favorable for patients with increased microvascular injury, while transplant glomerulopathy patients did not benefit from this treatment specifically.
Bortezomib did not appear to have significant advantage in treating patients who were DSA positive.
Aggressive treatment of CAMR has a good response if done at an early stage and in patients with higher microvascular inflammation, and proteinuria below 1.7 g/dL. Above this level of proteinuria, aggressive treatment does not appear to have significant benefit.
Due to increased risk of major adverse events with employment of aggressive therapy, CMV and PCP prophylaxis is recommended.
LEVEL OF EVIDENCE :
This is a retrospective study with level of evidence 3.
☆Treatment of chronic active antibodymediated rejection in renal transplant recipients – a single center retrospective study
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
Background:
_____________
▪︎CAMR is a major etiology of graft failure in renal transplant recipients.
▪︎Diagnosis is based on the presence of DSAs and specific histological lesions, most importantly, microvascular inflammation/ injury +/- capillary C4d deposition.
▪︎Treatment for CAMR has remained a major challenge and the current therapeutic stratigies are based on retrospective studies and pilot trials, including: IVIG plus rituximab, proteasome inhibitor-bortezomib, complement inhibitor-eculizumab, and IL-6 receptor blocker..
☆Methods:
__________
▪︎From Taichung Veterans General Hospital a computerized records were collected to identify renal transplant biopsies performed in the past 7 years with CAMR.
▪︎The patients were divided into two groups according to treatment approach:
1. Group 1 received aggressive treatment
(double filtration plasmapheresis(DFPP) and one of the followings: rituximab, IVIG, ATG, bortezomib, or methylprednisolone pulse therapy).
2. Group 2 received supportive treatment.
▪︎End points:
The patients were followed up until graft loss or death or the end of 2017.
▪︎The definition of graft loss included: returned to dialysis, re-transplant, or patient death.
▪︎Histopathology and diagnosis of CAMR:
All renal graft biopsies were performed using US guided percutaneous technique (two~three cores per biopsy; 16~18 gauge needle).
▪︎Graft biopsies were examined by LM, IF studies for IgG, IgA, IgM, C3, C4d, C1q, kappa, and lambda light chains, and EM.
▪︎C4d staining was performed on all biopsies by direct IF on frozen sections.
▪︎All of the following 3 criteria were met for diagnosis of CAMR according to Banff 2017 criteria:
(1) Morphologic evidence of chronic tissue injury,
(2) Evidence of current/recent antibody interaction with vascular endothelium
(3) Serologic evidence of DSA, to HLA or other antigens.
▪︎C4d staining should be positive for the
definite diagnosis of CAMR if DSA is not performed.
☆Results:
__________
▪︎From February 2009 to December 2017, a total of 82 patients with biopsy-proven CAMR were identified.
▪︎Exclusion criteria: Biopsies with ABO-incompatable grafts and those with
recurrent or denovo GN & DM nephropathy.
▪︎ All the patients had neg T and B cell CDC-CMX result before kidney transplantation
▪︎Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2.
▪︎Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different.
▪︎Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis.
☆Discussion:
______________
▪︎Aggressive treatment for CAMR patients was associated with better graft survival, higher incidence of adverse events and a reduced adverse event free survival.
▪︎ Proteinuria and supportive treatment .
were independently associated with graft loss.
▪︎ There are no approved treatments for CAMR.
▪︎ IVIG and rituximab significantly reduced or stabilized the progressive loss of transplant function. But,TG is associated with a poorer response.
▪︎The combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury. But, patients with low microvascular injury appeared less likely to benefit from it.
▪︎ Bortezomib: had no significant benefit for late onset DSA-positive ABMR in graft survival and DSA reduction.
▪︎ HLA antibodies produced by long-lived plasma cells are more refractory to proteasome inhibitor therapy.
▪︎Patients with CAMR are more likely to respond to antihumoral therapy when diagnosed early with prominent microvascular injury
▪︎Aggressive treatment for CAMR resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d.
▪︎ In this study the most frequently prescribed antihumoral agents are rituximab, followed by IVIG, bortezomib, and ATG. The most common adverse events were CMV disease, UTI, bacterial / PCP pneumonia, and infectious diarrhea.
▪︎Adequate valganciclovir prophylaxis may have reduced the mortality rate by 50% and it is recommend that valganciclovir and trimethoprim-sulfamethoxazole prophylaxis be given for at least 5~6 months after aggressive anti-rejection therapy.
☆Limitations of the study:
___________________________
1) No rules for treatment of CAMR.
2) DSA was not performed for every recipients.
●Level of the study: Level III ( a retrospective cohort study )
-Summary Background
Chronic active antibody mediated rejection CAMR is diagnosed by the presence of donor-specific antibodies (DSAs) and biopsy finding of microvascular inflammation/injury with or without capillary C4d deposition .
Current management for CAMR includes
intravenous immunoglobulin (IVIG) plus
rituximab ,
proteasome inhibitor-bortezomib ,
complement inhibitor-eculizumab and
IL-6 receptor blocker . Methods
Included patients were retrospectively collected for 7 years
The cases had negative T and B cell complement-dependent cytotoxicity cross-match (CDC-CMX) result before kidney transplantation.
Thymoglobulin or basiliximab were given for induction therapy. For maintenance immunosuppression calcineurin inhibitors (CNIs) tacrolimus or cyclosporine A, mycophenolate, and prednisone were given.
mTOR inhibitor, either sirolimus or everolimus, was taken in some cases.
Patients were divided into group 1 receiving aggressive CAMR treatment which was double filtration plasmapheresis( DFPP) and one of the followings: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy; and group 2 receiving supportive therapy.
Diagnosis of CAMR in the graft biopsy was done according to Banff 2017 criteria:
-morphologic evidence of chronic tissue injury
-evidence of current/recent antibody interaction with vascular endothelium
– serologic evidence of donor-specific antibodies .
-C4d staining in the biopsy tissue if DSA was negative Results
The important predictors of graft loss were Creatinine, proteinuria, PRA class II, transplant glomerulopathy, interstitial fibrosis, tubular atrophy, mesangial matrix increase, glomerulitis, peritubular capillary inflammation and supportive treatment.
Mean number of adverse events was higher in group 1.
The most common adverse events group 2 were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d. Discussion
Aggressive treatment for CAMR lead to better graft survival but on the other hand is associated with higher incidence of adverse events.
Independent factors for graft loss were proteinuria and supportive treatment.
Studies showed that IVIG and rituximab can stabilize the progression of graft loss but not with severe TG.
Other study revealed that anti humoral therapy was beneficial in cases with biopsies with high levels of microvascular injury.
Bortezomib usage in a study did not give favourable outcomes for late onset DSA-positive ABMR regarding graft survival and DSA reduction.
Current study emphasised the significance of aggressive treatment in CAMR at an earlier stage and with a higher degree of microvascular injury.
CMV infection was associated with Rituximab, ATG, and bortezomib treatment in renal transplant cases.
It is recommended to administer valganciclovir and trimethoprim-sulfamethoxazole prophylaxis for at least 5 to 6 months after aggressive anti-rejection therapy as in this study 3 of 6 died of CMV disease. Conclusion
Aggressive treatment early for CAMR is associated with better graft survival meanwhile adverse events are associated with such therapy therefore PCP and CMV prophylaxis for long periods will be essential for such cases.
Summery:
CAMR is an important risk factor of graft loss & its treatment is a big challenge.
All types of treatment( IVIG+ rituximab, bortezomib, eculizumab, & IL-6 receptor blockers) that tried among CAMR patients was based on retrospective study or pilot trial. These studies show that treatment wasn’t always effective & was associated with high incidence of side effects.
Retrospective study include all patient ( Feb2009-Dec2017) with proved CAMR by graft biopsy changes & negative CDC-XM. Patients with ABOi graft, recurrent or de novo GN or DM were excluded from analysis.
All patient were induced by ATG or basiliximab, & maintained on CNI, MMF, steroid or mTOR-I.
The patients divided into 2 groups. Group1(59 patients) treated aggressively with DFPP & at least one of the following: IVIG+ rituximab, ATG, bortezuman, or only pulsed MP. Group 2(23 patients) receive supportive therapy. Both groups receive standard treatment ( good control of blood pressure, blood sugar & hyperuricemia).
The patient are followed up until the end of 2017, graft loss( return to dialysis, retransplant or patient death), or death. CAMR diagnosed according Banff 2017 classification ( all 3 criteria):
morphological evidence of chronic tissue injury
evidence of current/ recent antibody interaction with vascular endothelium.
serological evidence of DSA.
Study results show that aggressive treatment of CAMR was associated with better graft survival in spite of increased incidence of adverse events. This finding was similar to other studies e.g. Billing et al, & different from others e.g. Bachelet et al who found that aggressive treatment of TG in CAMR didn’t alter natural history of TG.
The conflict in result may be due to enrollment of patients with advance TG, & low microvascular injury score. It was proven that using of rituximab + IVIG was associated with improved graft survival in patients with high microvascular injury score, early stage of CAMR & proteinuria <1.73g/day.
Another finding of this study was increasing incidence of CMV, UTI, CPC pneumonia, & infectious diarrhea among patient treated aggressively. So it was recommended to extend prophylaxis 5-6 months or longer after using of aggressive regime.
Limitation of the study:
non standardized CAMR treatment.
DSA didn’t performed for all patients.
Conclusion:
Aggressive treatment in early chronic tissue injury associated with good graft survival & adverse events can be reduced by using longer duration of prophylaxis.
Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single centre retrospective study.
This is a retrospective study with level III evidence.
Mechanism of chronic allograft injury
1. Immunological causes
2. Recurrence of primary glomerular diseases.
3. Infection. CMV, BKV.
4. CNI Toxicity.
5. Urinary tract obstruction.
6. Renal artery stenosis.
Diagnostic strategies
Careful history for the primary disease for end stage renal failure, any previous history of rejection. Induction protocol and immunosuppressants. Blood pressure and sugar control.
Urinalysis help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively.
A kidney ultrasound may exclude mechanical obstruction of urinary tract.
Protocol kidney biopsy should be performed in the majority of patients with dysfunction and red flag features such as significant proteinuria or cellular casts are present.
Protein and mRNA levels of CXCL9 is a great predictor of rejection (AUC 0.88) with an elevation in levels detected 30 days before a biopsy-proven rejection.
A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection (AUC 0.85).
High NKG2A+ cells after kidney transplantation correlated with the presence of DSA, cABMR and worse graft function.
Treatment strategies
Desensitization with plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients . Potential alternatives to rituximab to reduce antibody production include bortezomib .
Eculizumab is indicated in severe ABMR, IT inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy. Plasmapheresis, IV IG , IV Rituximab are among the suggested therapy for ABMR. The FDA currently has no approved therapy for chronic ABMR and mechanistic interventional clinical trials are needed to address the safety and efficacy of B cell and DSA depleting strategies for chronic rejection. It is important to treat the recurrence of primary diseases.
In conclusion, chronic allograft injury can significantly affect long-term renal allograft survival. Therefore, preventive measures are significant to ensure good renal allograft outcome.
It is a retrospective cohort study with level 2 of evidence
Although chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies.
Diagnosis of CAMR is based on presence of DSA, morphologic findings consist of microvascular inflammation/injury with or without capillary C4d deposition. Therapeutic approach in different studies consist of intravenous immunoglobulin (IVIG) plus rituximab, proteasome inhibitor-bortezomib, complement inhibitor-eculizumab, and IL-6 receptor blocker. All of these treatments don’t show effectiveness and are correlated with various adverse effects.
Pathologic findings based on Banff 2017 criteria including Glomerulitis (g), peritubular capillaritis (ptc), transplant glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and mesangial matrix (mm) scores were assigned in each case. Criteria for CAMR consists of morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens) were meet.
In this study, a total of 82 patients with biopsy proven chronic antibody-mediated rejection divided in 2 groups base on treatment strategies. Group 1 was treated with (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, anti-thymocyte globulin, bortezomib, or methylprednisolone pulse therapy, and group 2 received supportive therapy.
Aggressive treatment for CAMR patients was associated with better graft survival and with treatment higher incidence of adverse events and a reduced adverse event free survival, whereas patient survival was not significantly different. The worst survival was shown in patients who were on supportive therapy.
Proteinuria and supportive treatment were independent risk factors for graft loss.
In other studies, transplant glomerulopathy was associated with poor response to therapy. On the other hand, high levels of microvascular injury, for example biopsies with g ≥ 2 and/or (g + ptc) ≥ 4 were correlated with better response to IVIG and rituximab.
Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events deserves personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.
The aggressive treatment for CAMR patients was associated with better graft survival. However, the aggressive treatment group also had higher incidence
of adverse events and a reduced adverse event free survival. The factors independently associated with graft loss were proteinuria and supportive treatment.
Currently, there are no approved treatments for CAMR.
CMV infection was reported to be associated with Rituximab, ATG, and bortezomib treatment in renal transplant and myeloma patient.
Despite the significantly higher rate of adverse events in the aggressive treatment group, there was no significant difference in patient survival (Fig. 2), implying that
the patients still could have a reasonable chance of survival if these complications can be treated judiciously.
There are limitations in our study. Firstly, there were no rules for treatment of CAMR in our cohort, and the need for treatment was determined by each clinical physician.
Second, DSA was not performed for every recipients in our hospital, because Luminex® technology for HLA antibody detection in organ transplant is expensive in Taiwan.
retrospective study evidence III
Chronic ABMR is one of the contributory factor for graft loss. For diagnosis of chronic ABMR, DSA level is needed beside morphological evidence of injury with or without C4d deposition in the PTC.
The article is about a retrospective study conducted over 7 years in Taichung Veterans General Hospital, assessing treatment outcome among patients with biopsy proven chronic ABMR. Patients were put on 2 categories, one who received aggressive therapy(DFPP plus one of ituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy) , the other group only received supportive therapy. Banff 2017 criteria for diagnosis of CAMR were met in all patients:
Patients were followed up to an end point of the study (Graft loss, Death and end of the study time 2017). Predictors of graft loss in this study were; creatinine, proteinuria, PRA class II, cg ≥ 1, ci + ct ≥ 3, and supportive treatment. The study revealed that aggressive treatment was associated with better graft survival although serious adverse events were also related to aggressive therapy.
Level of evidence: 3a
CAMR is one of the major causes of graft loss.CAMR is diagnosed by the presence of DSAsand evidence of tissue injury plus +/-C4d staining.the treatment for CAMR has remained a major challenge.
This retrospective study is done to investigate the outcomes of CAMR by comparing graft survival between different treatment strategies.
From February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified. Three cases were excluded from the analysis owing to short follow up duration (less than 6).
The patients were divided in two groups according the treatment strategies:
Group 1 included 59 patients who received aggressive treatment, besides double filtration plasmapheresis (DFPP), 40 patients had received Rituximab, 10 patients had received IVIG, 10 patients had received bortezomib, whereas 4 patients had received antithymocyte globulin and 17 patients had received MP pulse therapy only.
Group 2 received no treatment or supportive treatment
After follow up for a median of 32.59 months after the diagnosis of CAMR. A total of 22 (26.82%) patients lost their allograft, including 11/59 patients (18.64%) in group 1 and 11/23 (47.83%) patients in group 2. Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively. Overall median graft survival was 5.6 years. Kaplan-Meier analysis of death-censored graft survival showed worse survival in group 2
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1, and 3/23 (13.04%) in group 2. All of the mortality cases in group 1 died of sepsis. Patient survival at the end of this study was not significantly different between these groups
Creatinine, proteinuria, PRA class II and supportive treatment were significant predictors of graft loss for CAMR .Supportive treatment and proteinuria were independently related to graft loss
There was a total of 54 adverse events in group 1, compared with 7 in group 2. Mean number of adverse events per patient was higher in group 1 (P < 0.001). Adverse
event free survival was significantly better in group 2 . The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia (PCP). Median adverse event free survival was 6.0 months in the aggressive treatment group.
Aggressive treatment resulted in better graft survival inpatients with proteinuria < 1.73 g/d , but not in patients with proteinuria ≥1.73 g/d
Conclusion : Aggressive treatment for CAMR patients was associated with better graft survival. However, the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival.The factors independently associated with graft loss were proteinuria and supportive treatment.
limitation of study :
Firstly, there were no rules for treatment of CAMR
Second, DSA was not performed for every recipients.
Level of evidence: Retrospective study level III
Summary
• Treatment of chronic active ABMR is still mater of debate. However, the current study concluded that it improves the long term graft and recipient survival.
• Diagnosis:
o Is based on combined presence of histo-pathological graft damage (immune mediated and chronic changes) plus detection of circulating DSA (evidence of antibody mediated graft damage) plus evidence of antibody interaction with tissue (+ve c4d).
o At least, one of DSA or c4d must be positive to diagnose chronic active ABMR.
o Pathology was revised by the same pathologist and staged according to the Banff 2017.
• Treatment of chronic active ABMR:
o No available RCT, all are retrospective studies.
o Available therapies include pulse steroids, plasmapheresis, IVIG, Rituximab, Bortezomib, ATG and Ecluizimab.
• Outcomes of treatment
o Assessment of graft outcome is evaluated by GFR and the degree of proteinuria as main indictors or predictors of graft function.
o Aggressive immunosuppressive therapy used increases risk of infections and malignancy.
o Infections as UTI, gastroenteritis, pneumonia and skin infections are increased so prophylaxis against PJP by trimethoprim-sulfamethoxazole is essential after treatment of each rejection episode.
o CMV infection is common especially with Rituximab, Bortezomib and ATG. Hence, Valganciclovir prophylaxis is mandatory for at least 6 months after antirejection therapy.
o The risk further increased in those who received prior aggressive immunosuppresses as in desensitization in ABO I transplantation and highly sensitized recipients.
o Appropriate treatment of these infections can lead to good graft and patient outcomes.
Level of evidence: retrospective cohort (level III).
Chronic active antibody mediated rejection ;CAMR, frequently leads to graft failure.
A retrospective study; evidence III, It included:
* Group I :included 59patients ,with different treatment modalities including, bortezomib, Rituximab, IVIG, pulse steroid and ATG.
–*Group II included 23 cases, with supportive treatment.
Graft and patients survival at the end of 2017 was the endpoint.
Diagnosis of CAMR according to Banff 2017 criteria. All 3 criteria were there :
1-Evidence of chronic tissue injury
2- evidence of antibody interaction with vascular endothelium
3-DSA.
Patients survival was followed for a median of 32.59 (IQR 24.01–49.89) months following diagnosis of CAMR.
Results revealed total of 22 patients had allograft loss, including 18.64% in group I and 47.83% patients in group II.10.97% patients died after diagnosis of CAMR, including 10.16% patients in group I; due to sepsis, and13.04%in group II.
– Survival without adverse events was significantly better in group II.
– Infectious diseases were more common group with aggressive treatment included CMV disease, leucopenia, uti, pneumonia, infectious diarrhea, and Pneumocystis pneumonia.
Conclusion: CAMR treated aggressively before advanced tissue injury is associated with better graft outcome ,but with higher incidence of adverse events. Appropriate PCP and CMV prophylaxis must be implemented following aggressive treatment for rejection
Type of study :Retrospective study grade III
This study done at Taichung Veterans General Hospital.
Data collected from 2009 to 2017 from 82 patients with biopsy showing CAMR
and divided into 2 groups:
Group 1:
this group contains 59 patients receiving aggressive treatment as DFPP beside one of the following: ATG , IVIG, rituximab, bortezomab and MP pulse
Group 2:
containing 23 patients on supportive therapy
All biopsies were examined by LM , IF , EM and classified according to Banff critria
To diagnose CAMR, the following must be present :
-evidence of chronic tissue injury
-evidence of recent or current interaction between antibodies and vascular endothelium .
-presence of DSA
End points of the study:
Death or Graft loss or end of 2017
Results and Discussion:
Group 1 with aggressive treatment showed better graft survival but infection as CMV , UTI , PCP Pneumonia
Evidence 3
Treatment-of-chronic-active-antibody-mediated-rejection-in-renal-transplant-recipients-–-a-single-center-retrospective-study
It’s retrospective study done in single centre between 2009 to 2017 focus on outcome of CABR with different immunosuppressive protocols.
CABR defined as presence of circulating DSA and morphological changes of chronic micro vascular damage with or without C4d staining.
All transplant patients to avoid graft loss should receive induction therapy of intravenous ATG or Basiliximab and maintenance therapy of tacrolimus/ mycophenolate / prednisone.
In this study patients with chronic changes receiving pulse therapy of steroid and double filtration plasma exchange with intravenous rituximab and Iv ATG.
The patients divided into 2 groups: first group receive aggressive treatment and second group receive supportive treatment by control blood pressure and sugar/ control lipid and avoid nephrotoxic agents.
The end points of this study are returning to dialysis, retransplant, death or end of 2017.
To diagnosing CABR the biopsy done and classified according to banff 2017 and C4d staining done.
Criteria of diagnosis are presence of circulating DSA and morphological chronic changes of micro vascular inflammation and tubular atrophy and antibodies reactions between endothelial vessels and C4d staining.
The group who received aggressive treatment ( Intravenous rituximab and intravenous immunoglobulin), have good outcome of graft but high risk of infection like CMV and urinary tract infection and infected diarrhoea, leukopenia and pneumocystic carinii pneumonia.
Conclusion:
Chronic antibodies mediated rejection with aggressive immunosuppressive therapy responded with good graft outcome but still risk of opportunity infection.
the importance of aggressive treatment in CAMR at an earlier stage and with a higher
degree of microvascular injury.
The most common adverse events in our patients were CMV disease, urinary
tract infection, bacterial / PCP pneumonia, and infectious
diarrhea.
PCP is a major cause of morbidity and mortality in patients receiving immunosuppressant
therapies. Previous CMV
infection, acute graft rejection and intensity of immunosuppressive therapy had been
reported as risk factors
for PCP in kidney transplant recipients
Despite the significantly higher rate of adverse events in the aggressive treatment group,
there was no significant
difference in patient survival , implying that the patients still could have a
reasonable chance of survival if these complications can be treated judiciously.
aggressive treatment for CAMR before advanced tissue injury is still
associated with better graft outcome in our series. However,
higher incidence of adverse events cannot be overlooked.
To mitigate potential life-threatening infections, longer
duration of PCP and CMV
prophylaxis should be considered after aggressive treatment for rejection.
Chronic active antibody-mediated rejection ( CAMR ) is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies.this retrospective study was designed to compare graft survival and patient survival according to the treatment strategy for CAMR
Methods: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection.
The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte
globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment.
Results: From February 2009 to December 2017, a total of 82 patients with biopsy-proven CAMR were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2
Although group 1 showed better graft survival but on conditiuon that proteinuria is less htan 1.73 g/d , which concludes that proteinuria is an independant predictor for graft loss
. Adverse event-free survival was lower in group 1 where infections & sepsis wrer more common in the form of ( CMV , UTI , leucopenia , pneumonia , PCP , infectious diarrhea ) whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis.
Conclusions: Appropriate prophylactic antibiotics ( TMP , Valganciclovir ) are recommended for longer period (5-6 months ) inpatients undergoing aggressive treatment.
reflectoin on my practice : its results encourages the institution of aggrressive treatment strategy should CAMR be diagnosed by a protocol or ofor cause biopsy with attention toward the high incidence of serious infections and considering the adherence to the prophylactic antimicrobials routinely prescribed .
Level of evidence : level III
This is a retrospective single center study at Taichung Veterans General Hospital from February 2009 to December 2017. This is a level 3 evidence study. The main objective of this study is to assess the outcome of biopsy proven Chronic active antibody mediated rejection (CAMR) among kidney transplant recipients of the center. A total of 82 patients recruited of which 59 patients ( Group 1) received aggressive immunosuppressive therapy and 23 patients ( Group 2 ) were on supportive therapy following CAMR diagnosis. The follow up period was 32.59 months (IQR 24.01–49.89). Graft survival more favorable for group 1 which is statistically significant. The median graft survival was 6.45 years for group 1 and 3.68 years in group 2. On the other hands, adverse event-free survival was lower in group 1 but patient survival was not significantly different between these two groups. Multivariate analysis shown that proteinuria and conservative management were independent risk factors associated with graft loss. The limitation of this study include no standardize consensus on the treatment protocol for CAMR. Besides, DSA not performed for all kidney transplant recipients and PRA only done one a year. In conclusion, we need to personalize the management of CAMR
This is a retrospective study from Taichung Veterans General Hospital.
Computerized data for 7 years(2009-2017) were collected from 82 patients with biopsy diagnosis of chronic active antibody mediated rejection(CAMR), using Kaplan-Meir analysis of death-censored graft survival between 2 groups.
Chronic active antibody mediated rejection(CAMR) is one of the major causes graft loss, despite this no presence of agreemental universal treatment
Group 1:
59 patients received aggressive treatment of DFPP and one of the followings: rituximab, IVIG, ATG, bortezomib or MP pulse therapy.
Group 2:
23 patients received supportive treatment.
All renal biopsies were examined by light microscopy, IF and EM and graded according to Banff criteria. for Glomerulitis(g), peritubular cappillaritis(ptc), transplant glomerulopathy(cg), interstitial fibrosis(ci), tubular atrophy(ct) and mesangial matrix(mm).
The diagnosis was done due to presence of all of the following:
1- Morphological changes of chronic tissue injury.
2- Evidence of current/recent antibody interaction with vascular endothelium.
3- Presence of DSA.
End points:
The patient were followed until graft loss or death or end of 2017.
Results and Discussion:
No statistical difference between the 2 groups regarding age, donor type, treatment duration, follow up, DM or hepatitis B or C, PRA, class1&2 titer percentages of patients who received induction treatment, immunosuppressive regimen, serum creatinine, proteinuria and Banff criteria scores.
Aggressive treatment group showed better graft survival in patients with proteinuria or equal 1.37 g/d.
Higher incidence of adverse effect and infection in the 1st group mainly: CMV disease, bacterial pneumonia, UTI, infectious diarrhea and leukopenia.
In the 1st group 3 of them died due to sepsis.
In the 2nd group one died of sepsis and the second died of hemorrhagic shock due to hemothorax.
Conclusion:
Aggressive treatment of CAMR before advanced tissue injury has a better graft survival but increased risk of life threatening infections.
Appropriate prophylaxis duration for PCP and CMV is needed.
This study is level 3 evidence.
-This is a retrospective study addressing different protocols of mangment of Chronic active antibody mediated rejection.
Level of evidence III
-Chronic active antibody mediated rejection (CAMR) is one of the major causes of graft failure.
– it is Diagnosed by presence of DSAs and specific morphologic lesions( microvascular inflammation/injury,with or without capillary C4d deposition).
– treatment for CAMR remains a major challenge.
-this is a study of 82 patients with biopsy-proven chronic antibody mediated rejection
in 7 years duration.
The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis with one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment.
-Results
*Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
*Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2.
* Adverse event-free survival was lower in group 1.
*Proteinuria was independent risk factors for graft loss in multivariate analysis.
*The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia (PCP)
*All of the mortality cases in group 1 died of sepsis. On the other hand, two of those in group 2 died of sepsis.
*Patient survival at the end of this study was not significantly different between these groups
*Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d.
*patients with proteinuria < 1.73 g/d , there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff scores.
-Conclusion of the study
aggressive treatment for CAMR patients was associated with better graft survival.
the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival.
The factors independently associated with graft loss were proteinuria and supportive treatment.
Currently, there are no approved treatments for CAMR.
it was reported that IVIG and rituximab significantly reduced or stabilized the progressive loss of transplant function
But it still controversial.
randomized double-blind clinical trial for evaluation the efficacy and safety of IVIG with rituximab also revealed no difference .
there was evidence that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury, for example biopsies with g ≥ 2 and/or (g + ptc) ≥ 4.
On the contrary, patients with low microvascular injury scores appeared less likely to benefit from antihumoral therapy.
*limitations of thestudy
-no rules for treatment of CAMR .
-the need for treatment was determined by each clinical physician.
-DSA was not performed for every recipients.
Summarise this study and reflect on your practice :
1- the 1st group received aggressive treatment including double filtration plasmapharesis and one of the following : Rituximab, IVIG, ATG, Bortezomab, pulse steroids.
2- the 2nd group received only supportive treatment.
1- graft survival was better in patients of the 1st group. however, there was a higher incidence of adverse events related to intensive immunosuppression.
2- patient survival wasn’t significantly different in both groups of patients.
What is the level of evidence?
This paper is a single-center retrospective study (level 3 evidence) evaluating proposed treatments for chronic active antibody-mediated rejection. Data were collected over a period of seven years.
Several strategies have been used, but there is still no evidence of which would be the most effective method. The strategies were: 1. no treatment; 2. pulse therapy with methylprednisolone for three days; 3. double filtration plasmapheresis; 4. rituximab; 5. intravenous immunoglobulin (IVIG); and rATG. Graft loss criteria include return to dialysis, retransplantation, or patient death.
CAMR criteria are morphological evidence of chronic tissue damage, evidence of active interaction between antibody and endothelium, evidence of DSA. C4d deposit is also considered.
1. Survival Analysis
There was no difference in survival between patients, but the graft was lost in 18.64% in Group 1 versus 47.83% in Group 2 (p = 0.015).
2. Predictors of graft loss
Creatinine, proteinuria, PRA Class II, and supportive care were markers of graft loss. Supportive treatment HR 2.86 and proteinuria HR 1.39 were independent predictors of graft loss.
3. Adverse Events
The aggressive treatment group had a higher frequency of adverse events, predominantly CMV infections, leukopenia, urinary tract infections, pneumonia, infectious diarrhea, and pneumocystosis.
Progressive treatment had a good response in proteinuria < 1.73g/d (p = 0.016), but not in the >1.73 group (p = 0.215).
CONCLUSION
Aggressive treatment showed better graft survival in CAMR. Supportive treatment was a predictor of graft loss (HR 2.77). Rituximab is a commonly used drug, but it has infections as the main adverse effect. CMV and Pneumocystosis should be considered in this group. Despite having more infections, it did not increase the mortality of transplant patients.
Diagnosis is based on the detection of donor-specific antibodies (DSAs) and specific morphologic lesions, most importantly, microvascular inflammation/injury with or without capillary C4d deposition.
METHODS
Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR. The first biopsy was used for statistical analysis if the patient had multiple biopsies. All biopsies were performed for cause and reviewed by a renal pathologist. Biopsies with ABO-incompatable grafts and those with recurrent or de novo glomerulonephritis (GN) and DM nephropathy were excluded. All the patients had negative T and B cell complement-dependent cytotoxicity cross-match (CDC-CMX) result before kidney transplantation. DSA was not performed for every recipients in hospital, because Luminex® technology for HLA antibody detection in organ transplant is expensive in Taiwan
The patients were divided into two groups according to treatment strategy.
END POINTS
The patients were followed up until graft loss or death or the end of 2017. The definition of graft loss included: returned to dialysis, re-transplant, or patient death. The same pathologist evaluated and graded graft biopsies according to Banff 2017 criteria.
RESULTS
From February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified. Three cases were excluded from the analysis owing to short follow up duration (less than 6 months).
Group 1 comprised 59 cases, whereas group 2 comprised 23 cases. There were no statistically significant differences between group 1 and group 2 in terms of age, donor type, transplant duration, follow up duration, percentages of diabetes mellitus, hepatitis B or C, panel reactive antibody (PRA) class I and II titer, percentages of patients who received induction treatment, immunosuppressive regimen (cyclosporine based or tacrolimus based), serum creatinine, proteinuria, and Banff scores.
The main results were:
A- Survival analysis
– A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1 (all for sepsis), and 3/23 (13.04%) in group 2 (two for sepsis). Patient survival at the end of this study was not significantly different between these groups.
B – Predictor of graft loss
– By univariate analysis, the significant predictors of graft loss for CAMR were creatinine, proteinuria, PRA class II, cg ≥ 1, ci + ct ≥ 3, and supportive treatment.
– Supportive treatment (HR 2.86, 95%CI [1.05–7.77]) and proteinuria (HR 1.39, 95% CI [1.06–1.83])were independently associated with graft loss;
C – Adverse events
– Adverse event free survival was significantly better in group 2 (P = 0.002 by log-rank test). The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
D – Subgroup analysis
A Kaplan-Meier analysis was conducted with patients with proteinuria < 1.73 g/d and ≥ 1.73 g/d.
– Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d (p = 0.016 by log rank analysis), but not in patients with proteinuria ≥1.73 g/d (p = 0.215 by log rank analysis). In the subgroup analysis which included patients with proteinuria < 1.73 g/d, there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff scores
DISCUSSION
– aggressive treatment for CAMR patients was associated with better graft survival. However, the aggressive treatment group also had higher incidence of adverse events and a reduced adverse event free survival.
– The factors independently associated with graft loss were proteinuria and supportive treatment
– there was evidence that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury. But, on the contrary, patients with low microvascular injury scores appeared less likely to benefit from antihumoral therapy;
– linical experience of bortezomib in transplantation showed variable results among patients with different disease states and populations.
– Supportive treatment was a predictor of graft loss in the univariate analysis (HR 2.77, 95% CI [1.19–6.41], P = 0.017). After adjustment of proteinuria, creatinine, and cg score, supportive treatment was still an independent risk factor of graft loss
This is a primary study of unic center. Retrospective study – level 03.
A retrospective study was conducted to evaluate the effectiveness of treatment of chronic active antibody mediated rejection CAMR.
82 biopsy proven cases of CAMR in a single center were included from 2009 through 2017. They were followed until graft loss, patients death or end of 2017.
Graft loss means return to Dialysis or retransplantation.
CAMR diagnostic criteria according to Banff 2017 include:
1] Evidence of chronic tissue injury TG, PTCM., chronic interstitial nephritis ci, tubular atrophy ct
2] evidence of recent or current antibody interaction with vascular endothelium.which is MVI or C4d.
3] Presence of DSAs anti HLA or other donor antigens.
C4d staining was a prerequisite for the diagnosis of CAMR as the testing for the expression of validated transcripts / classifiers was not done routinely.
Immunosuppressant protocol:
Induction with either ATG or IL-2 R antagonist {CD25 antagonist}, and maintenance with either Tacrolimus or Cyclosporin based regimen which include in addition MMf and prednisolon.
The cohort of patients were divided into 2 groups:
1] Group 1:Treatment group 59 patients where received DFPP of 1-1,5 plasma volume, and one of the following treatment ,40 patients received Rituximab 375 mg/m , 10 patients received IVIG 2gm/kg , 17 patients received MP , 4 patients received rATG 1-1.5 mg/kg for 3-5 days, and 10 patients received Bortizomib 1.3 mg/m ,
Multiple treatment usually yearly if the repeat biopsy revealed persisient lesion.
2] Group 2: Control group 23 patients received supportive therapy including:
Hypertension control with RAASi.
Control of DM with oral hypoglycemuc or insulin.
hyperuricemia control with Allopurinol or Feboxustat.
Control of Hyperlipidemia with statin or fibrate.
Bicarbonate if acidosis was reported.
these measures were considered in group 1 as well.
Primary point was graft survival after treatment in group 1.
secondary end point includes patient survival .
They were followed for an average of 32.59 months post diagnosis of CAMR
Result of the study:
Loss of allograft
group 1 11/59
group 2 11/23
Graft survival was worse in group 2
Mortality:
group 1 6/59 because of sepsis
group 2 3/23 because of sepsis and hemorrhage.
Patient survival was not statistically different at the end of study between the 2 groups.
Predictors of graft loss:
creatinine and proteinuria
PRA class II
cg more than 1
ci+ct of more than 3
supportive therapy.
Adverse events:
group 1 54/59 adverse events
group 2 7/23 adverse events
adverse events in group 1 include:
CMV
PJP
Leukopenia
Urinary tract infection
Pneumonia
Infectious Diarrhoea.
Therefor adverse events free survival was significantly better in group 2 then group 1
Its retrospective study with level of evidence 3
Background:
CAMR Diagnosis is based on the detection of donor-specific antibodies (DSAs) and specific morphologic lesions, most importantly, micro vascular inflammation/injury with or without capillary C4d deposition.
Treatment strategies included: intravenous immunoglobulin (IVIG), rituximab, proteasome inhibitor-bortezomib, complement inhibitor-eculizumab, and IL-6 receptor blocker.
Methods:
Patients and graft biopsies:
Renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR. All biopsies were performed for cause and reviewed by a renal pathologist.
Biopsies with ABO-incompatible grafts and those with recurrent or de novo glomerulonephritis (GN) and DM nephropathy were excluded. All the patients had negative cross-match pretransplantation.
Treatment strategies for CAMR:
No treatment.
Methylprednisolone pulse therapy (usually 500 mg of MP for 3 days).
Plasmapheresis.
Rituximab intravenous bolus (375 mg/m2).
Intravenous immunoglobulin (IVIG) (2 g/kg).
Antithymocyte globulin (ATG) (Thymoglobulin 1–1.5 mg/kg for 3–5 days).
Groups (group1 received aggressive treatment group 2 received supportive treatment).
End points
Graft loss or death or the end of 2017.
Histopathology and diagnosis of CAMR
Ultrasound guided biopsies percutaneous technique.
CAMR, all 3 criteria in the following according to Banff 2017
(1) morphologic evidence of chronic tissue injury,
(2) evidence of current/recent antibody interaction with vascular endothelium,
(3) Serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens).
C4d staining in the biopsy tissue or expression of validated transcripts/classifiers may substitute for DSA.
Data analysis
P value of less than 0.05 was considered statistically significant. All statistical analyses were performed by using SPSS software (version 21.0, Chicago, IL, USA).
Results
A total of 22 (26.82%) patients lost their allograft, including11/59 patients (18.64%) in group 1 and 11/23 (47.83%) patients in group 2.
Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1, and 3/23 (13.04%) in group 2.
All of the mortality cases in group 1 died of sepsis and 1 case died of hemorrhagic shock due to hemothorax.
Patient survival at the end of this study was not significantly different between these groups (P = 0.567).
Predictors of graft loss:
Creatinine, proteinuria, PRA class II, cg ≥ 1, ci + ct ≥ 3.
Adverse events:
Total of 54 adverse events in group 1, compared with 7 in group 2.
The most frequent events in aggressive treatment group were CMV, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
Graft survival in patients with proteinuria < 1.73 g/d with aggressive treatment resulted in better graft survival but not in patients with proteinuria ≥1.73 g/d.
Discussion
Aggressive treatment for CAMR patients was associated with better graft survival but higher incidence of adverse events.
Factors independently associated with graft loss were proteinuria and supportive treatment.
The subgroup with transplant glomerulopathy (TG) was associated with a poorer response.
HLA antibodies produced by long-lived plasma cells (LLPCs) are more refractory to proteasome inhibitor therapy. LLPC resistance and immunologic compensatory mechanisms may also play a role in treatment failure.
This study highlights the importance of aggressive treatment in CAMR at an earlier stage and with a higher degree of microvascular injury.
ABO-incompatible kidney transplant recipients who received rituximab had higher incidence of CMV disease (due to the release of TNF-α after administration, which may stimulate cellular nuclear factor кB and viral replication via binding to the promoter region of the CMV immediate-early antigen gene and reduced cytotoxic T cell response thus impaired viral clearance).
The average duration between last rituximab and first infection episode in transplant recipients was about 5 to 6 months.
Limitations of the study; no DSA were performed, and no specific rules for treatment according to every physician decision.
Conclusion
Aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome but higher incidence of adverse events.
Level of evidence: 3 (retrospective study).
. Chronic active antibody-mediated rejection (CAMR) is associated with graft failure.
– Diagnosis is based on the detection of donor-specific antibodies (DSAs) and specific morphologic lesions, most importantly, microvascular inflammation/ injury with or without capillary C4d deposition.
-Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR.
-All the patients had negative T and B cell complement-dependent cytotoxicity
cross-match (CDC-CMX) result before kidney transplantation.
-Thymoglobulin or basiliximab may be prescribed for induction therapy. Maintenance immunosuppression included calcineurin inhibitors (CNIs) tacrolimus or cyclosporine A, mycophenolate, and prednisone.
-One or more of the following treatment strategies were selected for CAMR treatment according to the patient’s clinical condition and the decision of the individual practitioners: no treatment, methylprednisolone (MP) pulse therapy (usually 500 mg of MP for 3 days), double filtration plasmapheresis (DFPP), rituximab intravenous bolus (375 mg/m2 ), intravenous immunoglobulin (IVIG)
(2 g/kg), and rabbit anti thymocyte globulin (ATG) (Thymoglobulin 1–1.5 mg/kg for 3–5 days).
-The patients were followed up until graft loss or death or the end of 2017.
-The definition of graft loss included: returned to dialysis, re-transplant, or patient death.
-Primary endpoint was graft survival after treatment.
-Secondary outcomes included patient survival and the occurrence of major adverse events.
-Aggressive treatment for CAMR patients was associated with better graft survival but had a higher incidence of adverse events and a reduced adverse event-free survival.
-Currently, there are no approved treatments for CAMR.
– Several studies showed:
-IVIG and rituximab significantly reduced or stabilized the progressive
loss of transplant function. However, the subgroup with transplant glomerulopathy (TG) was associated with poorer response.
Another study conducted
– IVIG with rituximab treatment for severe TG in CAMR did not change the
natural history of TG.
– IVIG with rituximab revealed no difference between the treatment and
placebo groups in eGFR decline, increase of proteinuria, and MFI of the immunodominant DSA.
-There was evidence that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury, for example, biopsies
with g ≥ 2 and/or (g + ptc) ≥4 .
-Two cycles of bortezomib had no significant benefit for late-onset DSA-positive ABMR in graft survival and DSA reduction.
– HLA antibodies produced by long-lived plasma cells (LLPCs) are more refractory
to proteasome inhibitor therapy. LLPC resistance and immunologic compensatory mechanisms may also play a role in treatment failure.
-After adjustment of proteinuria, creatinine, and cg score, supportive treatment was still an independent risk factor of graft loss.
– A aggressive treatment for CAMR resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d.
-CMV infection was reported to be associated with Rituximab, ATG, and bortezomib treatment in renal transplant and myeloma patients. ABO-incompatible kidney transplant recipients who received rituximab had higher incidence of CMV disease.
-PCP is a major cause of morbidity and mortality in patients receiving immunosuppressant therapies.
-It is recommended that valganciclovir and trimethoprim-sulfamethoxazole
prophylaxis be given for at least 5~6 months after aggressive anti-rejection therapy.
–Limitations of study :
1.There were no rules for treatment of CAMR in our cohort, and the need
for treatment was determined by each clinical physician.
2. DSA was not performed for every recipients in The hospital, because Luminex® technology for HLA antibody detection in organ transplant is expensive in Taiwan.
CMV prophylaxis should be considered after aggressive
Retrospective study level III
Treatment of chronic active antibodymediated rejection in renal transplant recipients – a single center retrospective study by Hsien-Fu Chiu
The patients were divided into two groups ;
Exclusion criteria: ABOi- grafts, recurrent or de novo GN, DKD
Results
Survival Analysis
Predictors of graft loss
By multivariate analysis – supportive treatment and proteinuria – independently associated with graft loss
Adverse events
Conclusion:
What is the level of evidence?
Level of evidence 3.
Background:
Diagnosis of chronic active antibody-mediated rejection based on the presence of DSA and evidence of tissue injury +/- C4d staining
Treatment is still challenging between conservative treatment or more aggressive immunosuppression with their adverse side effects.
This is a retrospective single-center study comparing the conservative TTT vs the aggressive treatment group over 7 years with follow up (2- 4 years)
Patients and methods:
– Retrospective through 2009-217 from Taichung Veterans General Hospital
– Biopsies with CAMR (according to Banff 2017) from patients with negative B and T CDC -CMX were collected
– After exclusion of
1- ABO-incompatible grafts
2- recurrent or de novo glomerulonephritis (GN)
3- DM nephropathy
– Patients were divided into two groups:
Group A with DFPP and either MP, rituximab, IV Ig, rATG, or bortezomib (and continued yearly) + care for CKD
Group B: No treatment group
– The patients were followed up till graft loss (dialysis, re tx, or patient death) or death or the end of 2017.
– patient survival and major adverse events were considered secondary outcomes
results:
– better survival was found in group A with mortality attributed to sepsis only in this group
– proteinuria and supportive treatment were independent factors for graft loss
– major adverse events were significantly higher in group A
conclusion:
– aggressive Is is better when commenced early before significant tissue injury but with care for CMV and PCP prophylaxis to avoid major adverse events.
level of Evidence 3 case-control retrospective study
Study limitation
A retrospective study included a small number of patients
Heterogenicity in antirejection protocols.
The follow-up period is shorter to detect other risk events like increased cancer risk
level of Evidence 3 retrospective cohort study
my reflection :
In our center, the diagnosis with CAMR is usually delayed for the insidious presentation of CAMR usually creeping creatinine, and also for financial aspects concerning DSA.
I think in absence of consensus treatment for CAMR, treatment should be individualized according to the IFTA score, the time elapsed between presentation and diagnosis, the baseline graft function, and the availability of antirejection treatment.
Among antirejection treatment, only plasma exchange low dose IVIG and methylprednisolone only experienced in our center for ttt of CAMR
Thank You
Thank You
Summarise this study and reflect on your practice
Background:
Chronic active antibody mediated rejection (CAMR) is one of the most frequently
encountered etiologies associated with graft failure.
Treatment for CAMR has remained a major challenge.
Study investigated the outcomes of CAMR in center by comparing graft survival between
different treatment strategies.
Methods Patients and graft biopsies:
Records from Taichung Veterans General Hospital were collected to identify renal
transplant biopsies performed in the past 7 years with a diagnosis of CAMR.
All the patients had negative T and B CDC-CMX.
Induction therapy: Thymoglobulin or basiliximab may be prescribed.
Maintenance immunosuppression: included CNIs t, mycophenolate, and prednisone.
MTOR inhibitor, Either Sirolimus or Everlimus, was prescribed in few patients.
Treatment strategies divided into two groups were selected for CAMR treatment:
Group 1: 59 patient, received aggressive treatment (DFPP and one of the followings:
rituximab, IVIG, ATG, Bortezomib, or MP pulse therapy). group 1, patients were usually
treated annually with DFPP plus one of the 5 drugs, but different in each year in order to
accomplish a wide blockade of the alloimmunity.
Group 2: 24 patient received supportive treatment.
Both received regular medical care for chronic kidney.
End points:
The patients were followed up until graft loss or death or the end of 2017.
Primary end point was graft survival after treatment in the 2 groups.
Secondary outcome included patient survival and the occurrence of major adverse
events.
Histopathology and diagnosis of CAMR:
3 criteria in the following were met for diagnosis according to Banff 2017 criteria:
(1) Morphologic evidence of chronic tissue injury.
(2) Evidence of current/recent antibody interaction with vascular endothelium, and
(3) Serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens).
C4d staining in the biopsy tissue or expression of validated transcripts/classifiers may
substitute for DSA.
Data analysis:
All statistical analyses were performed by using SPSS software.
Results Comparison of patient’s:
Group 1, besides DFPP, 40 patients had received Rituximab, 10 patients had received
IVIG, 10 patients had received Bortezomib, whereas 4 patients had received
antithymocyte globulin and 17 patients had received MP pulse therapy only.
Survival analysis:
Patients were followed for a median of 32.59 months from diagnosis of CABMR.
22 (26.82%) patients lost their allograft.
Including 11 patients (18.64%) in group 1 and 11(47.83%) patients in group 2.
Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
Overall median graft survival was 5.6 years.
Death-censored graft survival showed worse survival in group 2.
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6(10.16%) patients
in group 1, and 3 (13.04%) in group 2.
All of the mortality cases in group 1 died of sepsis.
Predictors of graft loss:
The significant predictors of graft loss for CAMR were creatinine, proteinuria, PRA class
II, cg ≥ 1, ci + ct ≥ 3, and supportive treatment.
Adverse events:
The most frequent adverse events in aggressive treatment group were CMV disease,
leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis
carinii pneumonia, more in group2
.
Discussion;
Found aggressive treatment for CAMR patients was associated with better graft survival
compared to the supportive treatment group, Supportive treatment was a predictor of
graft loss in the univariate analysis.
A subgroup analysis revealed that aggressive treatment for CAMR resulted in better graft
survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73
g/d.
Study highlight the importance of aggressive treatment in CAMR at an earlier stage and
with a higher degree of microvascular.
Despite the significantly higher rate of adverse events in the aggressive treatment group,
there was no significant difference in patient survival, implying that the patients still
could have a reasonable chance of survival if these complications can be treated
judiciously.
Conclusion:
Aggressive treatment for CAMR before advanced tissue injury is still associated with
better graft However, higher incidence of adverse events cannot be overlooked.
To mitigate potential life-threatening infections, longer duration of PCP and CMV
prophylaxis should be considered after aggressive treatment for rejection.
limitations of the study:
Firstly, there were no rules for treatment of CAMR i and the need for
treatment was determined by each clinical physician.
Second, DSA was not performed for every recipients .
reflect on your practice:
Most of the time we use plasmapheresis , IVIG plus methylprednisolone or
plasmapheresis ,IVIG plus ATG.
We will consider rituximab protocol also and more prophylactic against infection to
reduce side effect and sepsis risk.
Level of evidence 3.
Excellent
Treatment of chronic active antibody mediated rejection in kidney transplant patients remains a dilemma for transplant physicians. Management is always individualized.In this retrospective study by Hsien and colleagues have shared there center experience of treating CAMR.
Methods: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection.
The patients were divided into two groups according to treatment strategy:
Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy)
Group 2 received supportive treatment.
End points
The patients were followed up until graft loss or death or the end of 2017.
The definition of graft loss included: returned to dialysis,
re-transplant,
or patient death.
Primary end point was graft survival after treatment in the 2 groups.
Secondary outcome included patient survival and the occurrence of major adverse events.
Histopathology and diagnosis of CAMR
For CAMR, all 3 criteria in the following were met for diagnosis according to Banff 2017 criteria:
(1) morphologic evidence of chronic tissue injury, (2) evidence of current/recent antibody interaction with vascular endothelium,
(3) serologic evidence of donor-specific antibodies (DSA)
Results
From February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified.
Three cases were excluded from the analysis owing to short follow up duration (less than 6 months).
Group 1 comprised 59 cases,
whereas group 2 comprised 23 cases.
In group 1, besides DFPP, 40 patients had received Rituximab, 10 patients had received IVIG, 10 patients had received bortezomib, whereas 4 patients had received antithymocyte globulin and 17 patients had received MP pulse therapy .
Survival analysis
Patients were followed for a median of 32.59 months after the diagnosis of CAMR. A total of 22 (26.82%) patients lost their allograft, including 11/59 patients (18.64%) in group 1
and 11/23 (47.83%) patients in group 2.
Median graft survival was 6.45 and 3.68 years for group 1 and group 2, respectively.
Overall median graft survival was 5.6years. Kaplan-Meier ana- lysis of death-censored graft survival showed worse survival in group 2 (P = 0.015 by log-rank test)
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1
3/23 (13.04%) in group 2.
All of the mortality cases in group 1 died of sepsis. On the other hand, two of those in group 2 died of sepsis, and 1 case died of hemorrhagic shock due to hemothorax. Patient survival at the end of this study was not significantly different between these
Subgroup analysis
They conducted a Kaplan-Meier analysis of graft survival in patients with proteinuria < 1.73 g/d and ≥ 1.73 g/d.
Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d
Adverse Events
There was a total of 54 adverse events in group 1, 7 in group 2.
Mean number of adverse events per patient was higher in group 1 (P < 0.001). Adverse event free survival was significantly better in group 2.
Limitations
Retrospective review
DSA was not done routinely
No standardized treatment
Conclusion
In conclusion, aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome .However, higher incidence of adverse events cannot be overlooked. To mitigate potential life-threatening infections, longer duration of PCP and CMV prophylaxis should be considered after aggressive treatment of rejection.
Level of Evidence III
RETROSPECTIVE
This paper has not shown something extraordinarily new which could effect my practice. I think we should know when not to intervene as effect of those heavy immunosuppressive drugs is seen few months to years later and I feel countries like pakistan where chronic infections like TB is so prevalent we should weigh the risk and benefits before hitting very hard
Thank You
I. Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single centre retrospective study
Summarise this study and reflect on your practice.
This is a single center retrospective study of post- kidney transplant patients diagnosed with chronic active AMR on the basis of for-cause biopsy.
ABO-i grafts & those with recurrent or de novo GN & DM nephropathy were excluded. CDC-CMX was negative in all patients.
Thymoglobulin or basiliximab was for induction.
Maintenance IS included CNIs (tacrolimus or cyclosporine A), MMF, & prednisone. Few patients received mTOR-i (sirolimus or everolimus).
The patients were divided into 2 groups:
Group 1: received aggressive treatment (DFPP & 1 of the following: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy); treated annually, each year using one different agent of the 5 drugs for a wider spectrum of allo-immune blockade.
Group 2: received supportive treatment(ideal BP control, blood sugar control, hyper-uricemia control, & avoidance of nephrotoxic drugs).
Oral NaHCO3 was prescribed if the patient had metabolic acidosis.
Statin/fibrate used to control lipids; ACEI/ARB to control BP.
The patients were followed up until graft loss or death or the end of 2017.
Primary end point was graft survival after treatment in the 2 groups.
Secondary outcome: patient survival & the occurrence of major adverse events (any event associated with death, hospital admission , prolongation of a hospital stay, persistent or significant disability or incapacity, or was otherwise life-threatening in connection with specific treatment).
———————————————————–
Histopathology and diagnosis of CAMR
Biopsies were examined by LM using silver & PAS stains, IF stains for IgG, IgA, IgM, C3, C4d, C1q, kappa, & lambda light chains, &EM.
For diagnosis of CAMR, all 3 criteria in the following were met according to Banff 2017 criteria:
(1) morphologic evidence of chronic tissue injury,
(2) evidence of current/recent antibody interaction with vascular endothelium, and
(3) serologic evidence of DSA, to HLA or other antigens. C4d staining in the
biopsy tissue or expression of validated transcripts/classifiers may
substitute for DSA.
————————————————–
Results
A total of 85 (59 in group 1 & 23 in froup2) patients with biopsy-proven CAMR were identified. 3 cases were excluded due to short follow up duration (<6 months).
Group 1: besides DFPP, 40 patients received Rituximab, 10 received IVIG, 10 received bortezomib, 4 received ATG, & 17 received MP pulse therapy only.
Patients were followed for a median of 32.59 months after the diagnosis of CAMR.
A 22 (26.82%) patients lost their allograft: 11/59 (18.64%) in group 1 & 11/23 (47.83%) in group 2.
Median graft survival (yrs): 6.45(group1) & 3.68 (group2).
Overall median graft survival was 5.6 years.
Worse death-censored graft survival in group 2.
Nine (10.97%) patients died after diagnosis of CAMR: 6/59 (10.16%) in group 1, & 3/23 (13.04%) in group 2.
Sepsis was the cause of all deaths in group 1.
Patient survival was not significantly different between these groups.
Predictors of graft loss for CAMR were:
– creatinine
– proteinuria
– PRA class II
– cg ≥ 1, ci + ct ≥ 3, and
– supportive treatment.
The most frequent adverse events in aggressive treatment group were:
– CMV disease
– Leucopenia
– urinary tract infection
– pneumonia
– infectious diarrhea
– PJP
Median adverse event free survival was 6.0 months in the aggressive treatment group.
Aggressive treatment resulted in better graft survival in
patients with proteinuria < 1.73 g/d, but not in patients with proteinuria ≥1.73 g/d.
Conclusions:
Aggressive treatment for CAMR was associated with better graft survival.
Supportive treatment was a predictor of graft loss.
Aggressive treatment had higher incidence of adverse events & a reduced adverse event free survival.
Proteinuria & supportive treatment were independently associated with graft loss.
No approved treatments for CAMR currently exists.
This study highlight the importance of aggressive treatment in CAMR at an earlier stage & with a higher degree of micro-vascular injury.
The most frequently prescribed anti-humoral agent was rituximab, followed by IVIG, bortezomib, & ATG.
————————————————–
Reflection on our practice:
We rarely encounter cases of chronic active AMR, probably because we are highly selective in choosing patients for transplantation; highly sensitized patients are usually excluded.
Also we infrequently do biopsy in cases of chronic allograft dysfunction.
And, if we ever encounter such a case we do not use aggressive treatments.
===================================
What is the level of evidence?
Level III
This is a retrospective study with level of evidence 3,that included a total of 85 patients with biopsy-proven CAMR From February 2009 to December 2017 in Taiwan.
– Group 1 comprised 59 cases, received different treatment options including DFPP, bortezomib, Rituximab, IVIG, MP pulse and ATG.
– Group 2 comprised 23 cases, received supportive treatment only
End points: graft and patients survival by the end of 2017. Graft loss was defined as: return to dialysis, re-transplant, or patient death.
Diagnosis of CAMR according to Banff 2017 criteria. All 3 criteria were met in all patients.
(1) morphologic evidence of chronic tissue injury
(2) evidence of current/recent antibody interaction with vascular endothelium
(3) serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens).
Survival analysis Patients were followed for a median of 32.59 (IQR 24.01–49.89) months after the diagnosis of CAMR.
Results
A total of 22 patients lost their allograft, including 11/59 patients (18.64%) in group 1 and 11/23 (47.83%) patients in group 2.
A total of 9 (10.97%) patients died after diagnosis of CAMR, including 6/59 (10.16%) patients in group 1-all from sepsis, and 3/23 (13.04%) in group 2.
Adverse events
– Adverse event free survival was significantly better in group 2.
– Infectious adverse events were more common in aggressive treatment group included CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
In conclusion, aggressive treatment for CAMR before advanced tissue injury is still associated with better graft outcome in our series. However, higher incidence of adverse events cannot be overlooked. To mitigate potential life-threatening infections, longer duration of PCP and CMV prophylaxis should be considered after aggressive treatment for rejection
Excellent
Treatment of chronic AMR is still challenging; as it is associated with a lot of side effects like infections either viral or bacterial, and also associated with blood diseases because of removal of important clotting factors with plasmapheresis.
The treatment is limited to plasmapheresis or immunoadsorption, ivig and rituximab, also proteasome inhibitor (bortezomib), complement inhibitor (eculizumab) , and IL-6 receptor blocker may be used.
Characteristics of CAMR:
1- Chronic tissue injury on tissue biopsy
2- Microvascular inflammation on tissue biopsy with or without c4d deposition
3- Circulating de novo DSA
Aggressive treatment of CAMR can be beneficial but associated with much side effects which can endanger the patient life , on other hand the treatment will no reverse the chronic injury of the kidney so it is beneficial before development of chronicity.
level of evidence cohort retrospective study level 3
in my practice, treatment is based on the extent of chronicity by tissue biopsy , clinical situation, and financial aspect of the patient
Thank You, but it is very short summary Riham
Summarise this study and reflect on your practice.
* Chronic active antibody mediated
rejection (CAMR) is the most important causes of renal graft failure.
* Diagnosis of CAMR is depend mainly on the detection of circulating DSAs and presence of microvascular inflammation or injury with or without capillary C4d deposition biopsy finding.
*A variety of treatment strategies have been proven effective for acute antibody mediated rejection.
* The treatment of CAMR is a major challenge, and some studies showed using IVIG plus rituximab, bortezomib, eculizumab and IL-6 receptor blocker have not always turned out to be effective and the adverse effect of these immunosuppressants are important.
*This study investigated the outcomes of CAMR comparing graft survival between
different treatment strategies.
Methods
*In this retrospective study, Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of CAMR.
*The exclusion criteria includes ABO incompatible grafts, those with recurrent or de novo (GN) and DM nephropathy.
*All the patients had negative T and B cell (CDC-MX) result before kidney transplantation .
*The patients (82) with CMR were divided into two groups according to treatment strategy:
# Group 1(59) received aggressive treatment (DFPP and one of the
followings: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy)
# Group 2 (23) received supportive treatment; patients received routine medical care for chronic kidney disease including control blood pressure, sugar, UA, lipids and preventing further kidney damage by avoiding drugs affect the kidney.
*The patients were followed up until graft loss or death or the end of 2017.
* The definition of graft loss included: returned to dialysis, re transplant, or patient death.
Results
*There were no significant differences between group 1 and group 2 in (age, donor type, transplant & follow up duration, DM, hepatitis B or C, (PRA) class I and II titer, percentages of patients who received induction treatment, immunosuppressive regimen, serum creatinine, proteinuria, and following Banff scores 2017
*A total of 22 (26.82%) patients lost their allograft, including
11/59 patients (18.64%) in group 1 and 11/23 (47.83%)
patients in group 2.
* Median graft survival was increase in group 1 than group 2.
*The death censored graft survival showed worse survival
in group 2.
* (10.97%) patients died after diagnosis of CAMR, including (10.16%) patients in group 1, and (13.04%) in group 2.
* All of the mortality cases in group 1 due to sepsis, two of those in group 2 died of sepsis, and 1 case died of hemorrhagic shock due to hemothorax.
* Patient survival at the end of this study was not significantly different between these groups (P = 0.567 by log-rank test).
*There was more adverse events in group 1, compared to group 2.
*Aggressive treatment resulted in better graft survival in patients with proteinuria <1.73 g/d.
*In the subgroup analysis of patients with proteinuria < 1.73 g/d there was no significant difference between aggressive treatment and supportive treatment group in terms of proteinuria, creatinine, and Banff scores.
Discussion
*Aggressive treatment for CAMR result better graft survival, but has higher incidence of adverse events.
*Proteinuria and supportive treatment are independent factors that associated with graft loss .
*IVIG and rituximab stabilized the progressive graft loss, but with poor response in (TG).
*Study conducted that the combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury, but patients with low microvascular injury has less benefit from antihumoral therapy.
*Recently study showed that bortezomib had no significant benefit for
late onset DSA-positive ABMR in graft survival and DSA reduction .
* The most common adverse events is CMV associated with (Rituximab & ATG), UTI, bacterial / PCP pneumonia and infectious diarrhea.
*Adequate valganciclovir prophylaxis may have reduced the mortality rate by 50%
in our patients who received aggressive treatment, so they recommend that valganciclovir and trimethoprim-sulfamethoxazole prophylaxis be given for at least 5 to 6 months after aggressive anti rejection therapy.
Conclusion
*Early and aggressive treatment for CAMR is associated with better graft survival&
outcome, but with higher incidence of adverse events.
*To minimize the risk of life threatening infections, longer duration of PCP and
CMV prophylaxis is essential after aggressive treatment.
*In our practice still there is challennging in managing such patients because the diagnosis is too late, so we do plasmapheresis & IVIG in early presentation and supportive treatment, medical care for chronic kidney disease including control blood pressure, sugar, UA, lipids and preventing further kidney damage by avoiding nephrotoxic drugs in late presentation.
We hope to benefit from these studies in the future
What is the level of evidence?
This is retrospective study/ Level of evidence 3
Thank You
Chronic active AMR (CAMR) is a major cause of graft failure with no approved treatment.
The aim of the study was to compare between different treatment strategies of CAMR and their effect on graft survival.
The study was retrospective, included 82 patients with allograft biopsy showing CAMR with exclusion of ABOi grafts, recurrent or de novo GN and diabetic nephropathy.
Patients were divided according to treatment strategy into group 1 who received aggressive immunosuppression in the form of double filtration plasmapheresis (DFPP) and one of 5 drugs, rituximab, IVIG, ATG, bortezomib or pulse steroids while group 2 received routine medical care of CKD including control of blood pressure, blood sugar and hyperuricemia with avoidance of nephrotoxic drugs
Patients were followed till graft failure, death or end of 2017.
primary endpoint was graft survival and secondary endpoints were patient survival and adverse events.
The study showed that
Limitations:
The decision of either supportive or aggressive treatment was determined by each physician with no rules for choice
DSA wasn’t performed to all patients.
Level of evidence: 3
Thank You
Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single center retrospective study
Summaries this study and reflect on your practice.
Chronic active antibodies mediated rejection is a predominant cause of allograft failure is also, Diagnosis is based on serological detection of donor-specific antibodies (DSAs) and morphologic lesions (microvascular inflammation/injury with or without capillary C4d deposition). but the treatment remained a major challenge.
retrospective stud from February 2009 to December 2017, a total of 85 patients with biopsy-proven CAMR were identified the study conducted in different therapeutic approaches comparing them with the outcomes of graft survival
Inclusion criteria all cases diagnosed with CAMR.
Exclusion criteria all Biopsies with ABO-incompatible grafts and those with recurrent or de novo glomerulonephritis (GN) and DM nephropathy.
All the patients had negative T and B cell complement-dependent cytotoxicity cross-match (CDC-CMX) result before kidney transplantation.
patients were divided into two groups according to treatment strategy.
Group 1 comprised 59 cases received aggressive treatment besides DFPP, 40 patients had received Rituximab, 10 patients had received IVIG, 10 patients had received bortezomib, whereas 4 patients had received anti thymocyte globulin and 17 patients had received MP pulse therapy, patients were usually treated annually with DFPP plus one of the 5 drugs, but different in each year in order to accomplish a wide blockade of the alloimmunity.
Group 2 comprised 23 cases received supportive treatment.
The patients were followed up until graft loss or death or the end of 2017.
Survival analysis
-graft survival showed worse in group 2.
-Patient survival was not significantly different between these groups.
– All of the mortality cases in group 1 died of sepsis. On the other hand, two of those in group 2 died of sepsis, and 1 case died of hemorrhagic shock due to hemothorax.
– There was another subgroup which received DFPP and IV methylprednisolone alone, which had graft outcomes in between those of group 1 and group 2.
The significant predictors for graft loss included supportive treatment, creatinine, proteinuria, PRA class II and histological parameters of cg≥1 and ci+ct≥3. Supportive treatment and proteinuria were independently associated with graft loss.
-Adverse event-free survival was lower in group 1, (The most frequent adverse events in aggressive treatment group were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia
Conclusion
There are no approved treatments for CAMR.
Aggressive treatment for CAMR patients was associated with better graft survival. However, it had higher incidence of adverse events and a reduced adverse event free survival.
To mitigate potential life-threatening infections, longer duration of PCP and CMV prophylaxis should be considered after aggressive treatment for rejection.
– IVIG and rituximab significantly reduced or stabilized the progressive loss of transplant function. But,TG is associated with a poorer response.
▪︎The combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury. But, patients with low microvascular injury appeared less likely to benefit from it.
▪︎ Bortezomib: had no significant benefit for late onset DSA-positive ABMR in graft survival and DSA reduction.
OUR PRACTICE
We are using plasmapheresis (3-5) session in combination of IVIG small dose after each session
Level of evidence
Its retrospective cohort study level III
A retrospective study investigated the outcomes of CABMR by comparing graft survival between different treatment strategies.
From February 2009 to December 2017, 85 patients were involved in the study.
The data was taken from the computer records of transplant biopsies with a diagnosis of CABMR.( according to Banff’s 2017 diagnostic criteria).
The patients were divided into two groups based on treatment strategy:
Group 1 (59 cases): received aggressive treatment ( DFPP, and either rituximab, IVIG, ATG, bortezomib, or MP pulse therapy).
Group 2 (23 cases): received supportive therapy.
Exclusion criteria: ABO-incompatible grafts, recurrent or de novo GN, DM nephropathy.
There were no statistically significant differences between groups 1 & 2 in terms of age, donor type, transplant duration, follow up duration, DM, Hepatitis B,C, PRA, percentage of patients who received induction treatment, IS regimen, s.cr, proteinuria, and Banff score.
Follow up duration was 32.59 months after the diagnosis of CABMR.
Median graft survival for group 1 was 6.45 years, while for group 2 it was 3.68 years.
Death-censored graft survival showed worse survival in group 2.
Mortality rate was 10% in group 1 & 13% in group 2.
The cause of death in group 1 was mainly sepsis.
Survival at the end of the study was not significantly different between these groups.
By multivariate analysis, supportive treatment and proteinuria were independently associated with graft loss.
More adverse events are encountered in group 1 such as CMV, leucopenia, UTI, pneumonia, infectious diarrhea, and PJP.
Adverse event-free survival was significantly better in group 2.
Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d.
In a subgroup analysis of patients with proteinuria < 1.73 g/d, there was no significant difference between the aggressive and supportive treatment groups in terms of proteinuria, creatinine, and Banff score.
Conclusion:
Aggressive treatment was associated with better graft outcomes, but a higher incidence of infection. Prophylactic AB is recommended for such patients.
Retrospective study: level of evidence III.
Thank You
Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single center retrospective study
Summarize this study and reflect on your practice.
Abstract:
Chronic active antibody mediated rejection considers one of the common causes of graft loss and till date no standardization of treatment of CABMR and the evidence is limited to retrospective and pilot studies with heterogenicity designs.
Setting, materials and method:
This is a retrospective electronic data collection of 82 biopsy proven CABMR from single center with good fu period of 7 years, the aim of this study to determine the graft survival as primary outcome among the two groups aggressive treatment group1 vs conservative treatment group2, Secondary outcome included patient survival and the incidence of major adverse events.
Aggressive treatment ABMR group1 of 59 patients including the use of annual DFPP plus one of 5 medications named, IVIG, Rituximab, Bortezomib, ATG, PMP.
Group 2 only23 patients with conservative medical therapy with routine medical care for both group 1,2 which consistent of strict sugar and blood pressure control, hyperuricemia and dyslipidemia control and avoid nephrotoxic medications.
All patients have negative XCM, induction either ATG, Basiliximab , with different maintenance triple therapy (CNI, tacrolimus, Ciclosporin, MMF, sirolimus, steroids)
Exclusion criteria : includes the ABOi kidney transplant, recurrence or Denovo GN and Diabetic nephropathy cases Short fu duration < 6 months.
Duration of the study 2009-2017 with Follow up till graft loss or death, or end of 2017, (the graft loss defined as back to dialysis or retransplant or patient death).
The histological diagnosis of the CABMR based on banff17 criteria, using IF for C4D staining and IC staining C4D staining one of diagnostic criteria in this study
Patients demographics between two groups almost homogenous but in aggressive treatment group majority received DFPP Plus rituximab (40 cases), Followed by 17 cases received PMP only and 10 Bortezomib, another 10 IVIG and 4 only received ATG.
Results:
Graft survival as primary outcome.
Average graft survival of 5.2 years
Worse survival rate among group 2
longer median survival rate of 6.2 years in aggressive treatment group vs 3.2 years in group 2. with better graft survival in those with less sever proteinuria score < 1.73g/d in aggressive treatment group.
Overall Similar patients’ survival between two groups and more death with sepsis in aggressive treatment group (all death in group 1 due to sepsis) more CMV infection, UTI, bacterial infections pneumonia PJP and infective diarrhea in group1.
Predictors of graft loss
This study emphasizes about the early diagnosis of CABMR with less tg score and more microvascular inflammation, proteinuria < 1.73gm/day consider predictor of better response to aggressive treatment with better graft survival but on the count of more adverse side effects including higher rate of infections, sepsis.
Proteinuria, and supportive treatment associated with lower graft survival.
Limitation:
Retrospective design, small size number and heterogenous immunosuppression protocols
No standardization of CABMR treatment, limitation to access to some drugs due to self-paying not covered by medical insurance.
HLA -DSA testing by Luminex not done in all cases due to cost, same for PRA testing.
C4d staining should be positive for the final diagnosis of CAMR which exclude cases of c4d negative CAMBR .
To conclude still we can consider aggressive IS therapy treatment in cases of CABMR with early diagnosis and less advanced chronic graft injuries like TG1 SCORE and more microvascular inflammation and proteinuria < 1-1.5gm with recommendation of longer CMV and antibacterial prophylaxis therapy extension up to 6 months. in our center still we depend on pathological scoring with C4D staining and we don’t have Constant DSA monitoring in most of our cases (more commercial transplant with missing data regarding the donors. again, no standardized protocol for CABMR treatment but we use more the combination of IVIG and rituximab and less use of plasmapheresis also modification of the maintenance triple IS like change cyclosporine to tacrolimus and MMF instead azathioprine in addition to strict control of other medical condition like BP , DM , dyslipidemia ,hyperuricemia and proteinuria with ACEI , and ARBS , regular infections screen like BKV , CMV ,UTI.
– ATG ,bortezomib and PMP not part of our CABMR treatment protocol due to high infections rate especially with bortezomib.
What is the level of evidence?
Level 111 retrospective cohort study.
Thank You Saja
I like this structured summary. This is how it should be. Well done
I. Treatment of chronic active antibody- mediated rejection in renal transplant recipients – a single centre retrospective study
One of the most common causes of graft loss is chronic active antibody mediated rejection (CAMR). The optimal treatment for CMR eludes consensus. This was a retrospective study from 2009 to 2017 to evaluate the effect of aggressive treatment versus supportive treatment in patients with CAMR by collecting the computerized patient records.
A total of 82 patients with CAMR were included in the study and followed up until graft loss or death or the end of 2017. They were divided in 2 groups:
Group1: Included 59 patients treated with double filtration plasmapaheresis (DFPP) with at least one of the 5 drugs namely methylprednisolone pulse, rituximab, IVIG, ATG or bortezomib.
Group 2: Included 23 patients treated with supportive management including glycemic and blood pressure control.
The graft loss was 26.82% in group 1 as compared to 57.83% in group 2 with increased median graft survival in group 1. Death censored graft survival was worse in group 2. Patient survival was 89.84% in group 1 and 86.96% in group 2, indicating no significant difference. All the deaths in group were due to sepsis (50% due to CMV), while two-thirds of the deaths in group 2 were due to sepsis.
There was another subgroup which received DFPP and IV methylprednisolone alone, which had graft outcomes in between those of group 1 and group 2.
The significant predictors for graft loss included supportive treatment, creatinine, proteinuria, PRA class II and histological parameters of cg≥1 and ci+ct≥3. Supportive treatment and proteinuria were independently associated with graft loss.
Group 1 had higher adverse events, mostly due to infections including CMV disease, pneumonia, UTI, infectious diarrhoea, pneumocystis pneumonia and leukopenia. The adverse event free survival was lower in group 1. Hence it was advised to prolong the prophylactic antivirals and anti-pneumocystis drugs for at least 5-6 months after anti-rejection treatment.
In group 1, patients with proteinuria less than 1.73g/d had better graft survival than those with increased proteinuria.
CAMR was diagnosed at an early stage in the study and had higher degree of microvascular injury in the study, increasing the response rate to aggressive treatment.
Limitations of the study included: retrospective, single-centre study, lack of DSA levels in all the patients and no defined protocol for treatment of CAMR, with financial issues also playing a role in the line of treatment opted.
In conclusion, aggressive treatment of CAMR in early stages with higher degree of microvascular injury and proteinuria less than 1.73 g/day is associated with better graft outcomes while there is no effect on patient survival. But aggressive treatment is associated with increased infections and hence there should be adequately prolonged (at least 5-6 months post treatment) antiviral and anti-pneumocystis prophylactic treatment in such patients.
The level of evidence is Level III: retrospective cohort study.
Thank Amit
The presence of chronic ABMR is one of the most prevalent factors that contribute to graft failure.
The current study is a retrospective study (level of evidence III) addressing the difference between the aggressive and conservative treatment of chronic ABMR in terms of graft, patient survival, and major adverse events in 82 patients with biopsy-proven chronic ABMR done between 2009 and 2017 in a single centre in Taiwan. The patients all had biopsy-proven chronic ABMR. The study was carried out between 2009 and 2017.
Difference between aggressive and conservative treatment outcomes.
According to the treatment plan, the patients were separated into two groups. Group 1 got aggressive treatment (DFPP plus one of the following: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy); group 2 received supportive treatment (routine medical care for chronic kidney disease, including ideal blood pressure control, blood sugar control, hyperuricemia control, and preventing further kidney damage.
Degree of CABMR
According to Banff 2017 standards, all three of the following criteria were satisfied for CAMR diagnosis: (1) indication of chronic tissue damage morphology, (2) evidence of current/recent antibody interaction with vascular endothelium, and (3) serologic evidence of donor-specific antibodies (DSA, to HLA or other antigens). DSA may be replaced by C4d staining in biopsy tissue or expression of approved transcripts/classifiers.
In this study, they involve CAMR was diagnosed at a relatively early stage (median cg score: 1.0, ci + ct: 2.0).
After intensive anti-rejection treatment, valganciclovir and trimethoprim-sulfamethoxazole prophylaxis were administered for at least 5-6 months. As The most common adverse events in our patients were CMV disease, urinary tract infection, bacterial/ PCP pneumonia, and infectious diarrhoea.
Conclusion
In conclusion, vigorous therapy for CAMR before advanced tissue damage is still related to superior graft success in our dataset. This was shown to be the case when comparing identical grafts. It is impossible to ignore the fact that there was a greater frequency of adverse occurrences. After rigorous therapy for rejection, a prolonged term of PCP and CMV prophylaxis may be explored as a means of mitigating the risk of potentially life-threatening infections.
Thank You
Very structured summary
Treatment of chronic active antibody mediated rejection in renal transplant recipients – a single center retrospective study.
=It is a single retrospective study which collected data for patients renal biopsies which diagnosed as chronic active anti-body mediated rejection based on BANFF criteria 2017 from February 2009 to December 2017.
=Total number of patients was 82 and divided into 2group according to treatment strategy.
Group 1 comprised of 59 cases which treated by aggressive protocol included ((double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy).
Group 2 comprised of 23 cases which treated by supportive treatment.
Result showed :
-Death-censored graft survival showed a significantly worse survival in supportive treatment group.
-Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different.
-Proteinuria and supportive treatment were independent risk factors for graft loss.
-Patient survival at the end of this study was not significantly different between these groups .
-Aggressive treatment for CAMR patients was associated with better graft survival specially here in this study a relatively early stage (median cg score: 1.0, ci + ct: 2.0)
-The aggressive treatment group also had higher incidence of adverse events.
Reflect on your practice:
Overall the treatment of chronic active antibody mediated rejection is still not clearly evidenced and depends mainly on the grade of active tissue injuries and need more randomized control trial looking for the best consensus which will led to good graft and patient survival.
Retrospective study level evidence III.
Thank You. I agree with your reflection
Summary Treatment of chronic active antibody-
mediated rejection in renal transplant recipients
introduction
CAMR is associated with graft failure although the treatment has still a major challenge.
Therapeutic approach for CAMR are based on retrospective studies and pilot trials, including IVIG, plus rituximab ,bortezomib ,eculizumab and IL6-receptor blocker but still the result of these studies not always be effective and side effects of these thearpy of great concern.
this study investigated the outcome of CAMR comparing graft survival between different treatment strategies in this centre.
methods
Retrospective study- Computerised record from Taichung Veterans Hospital over 7 years for biopsies performed for CAMR was collected.
The patients were divided into two groups according to treatment strategy:
1)group1 received aggressive treatment in form of :DFPP plus one of the following:
Rituximab ,IVIG ,ATG ,bortezomib or MP pluse therapy.
2)group2 received supportive treatment including BP controlling, sugar, lipid, uric acid and avoid nephrotoxic medication and preventing further progression of ckd.
Result
all patients were followed up until graft loss or death or the end of 2017.
graft survival in this study was significantly better in the aggressive treatment group compared to the supportive group.
higher incidence of adverse events in aggressive treatment group
in depend graft loss factors were proteinuria>1.73g/d and supportive treatment.
despite the significantly higher rate of adverse events in the aggressive treatment group there was no significant difference in patients survival.
limitation of this study
no rules for treatment of CAMR in this cohort study.
DSA not done for every patients as its expensive.
small size sample.
conclusion
aggressive treatment for CAMR before advanced tissue injury is associated with better graft outcome.
higher incidence of adverse event in aggressive treatment group1is a challenge to apply this treatment.
aggressive treatment for rejection should receive longer duration of PCP,CMV prophylaxis as to avoid life threatening infection.
level of evidence :retrospective studies level 3
Good effort. Do you know what happened to the cohort of patients that received methylprednisolone pulse therapy with plasmapheresis only?
(those who received MP pulse with DFPP only were excluded)
These patients had graft survival between aggressive treatment and supportive treatment group
Thank You Dr Manal for your structured summary
Chronic antibody mediated rejection (CAMR) is an important entity leading to graft loss. Diagnosis of CAMR depends on presence of DSA and biopsy showing micro vascular inflammation with or without C4d deposition in capillary. Treatment of CAMR is a challenge. options include IVIG plus Rituximab, bortezomib, eculizumab, and IL6 receptor blocker. There have been retrospective studies on outcome but the results have not always turned out to be effective. This study investigated the graft outcome in between different treatment strategies.
Methods.
Retrospective study- Computerised record from Taichung Veterans Hospital over 7 years for biopsies performed for CAMR was collected. Biopsies of ABOI grafts, recurrent or denovo golmerulonephritis and Diabetic nephropathy were excluded. All patients had negative T and B cell CDC cross match . Total patient no-82. Two groups were made-
Group 1 – Aggressive treatment Group
This group received double filter PP and one of either Rituximab, IVIG, ATG Boretezomib, or Pulse steroids
Group 2- Conservative treatment-
Good control of medical conditions and avoidance of nephrotoxics
Results-
Aggressive treatment had good outcome if patient had less advanced disease, proteinuria <1.73gm, micro vascular injury While those with TG had worse outcome. This group had higher incidence of infections like UTI , Diarrhoea, CMV. Patient received 1 month of prophylaxis for PCP and CMV
No difference was noted in survival between two groups. Boretezomab did not offer additional advantage in those with positive DSA.
Limitations.
No rules for treatment of CAMR
DSA was not performed for every patient
Retrospective and small sample.
Conclusion
Aggressive treatment of CAMR has better outcome
There is higher incidence of life threatening infections.
Longer duration (6 moths) of PCP and CMV prophylaxis should be given before aggressive therapy
Retrospective study- Level of Evidence -111
Decent review. Nice effort.
Chronic active antibody mediated rejection(CAMR) is now considered an important risk factor for allograft dysfunction and ultimately graft failure. Diagnosis is based on presence of DSA, morphologic evidence of chronic tissue injury, microvascular inflammation with or without C4d deposition in capillaries. Treatment of CAMR really a big challenge for the transplant physicians as treatment not always effective & no proper recommendations available and also associated with high incidence of side effects. Current management for CAMR includes intravenous immunoglobulin (IVIG) plus rituximab ,proteasome inhibitor-bortezomib , complement inhibitor(eculizumab) and IL-6 receptor blocker .This retrospective study conducted from February 2009 to December 2017 included 82 patients with biopsy-proven CAMR aimed at assessing the outcome of CAMR by comparing allograft survival between those who received aggressive therapy(double filtration plasmapheresis(DFPP) and one of the followings: rituximab, IVIG, ATG, bortezomib, or methylprednisolone pulse therapy)and those who received conservative or supportive therapy.
CONCLUSION:
Aggressive treatment for CAMR leads to better graft survival but on the other hand is associated with higher incidence of adverse events. The most common adverse events seen were UTI, CMV infection, bacterial or PCP pneumonia, and infectious diarrhea. Proteinuria >1.73 g/d and supportive treatment were independently associated with graft loss. IVIG plus rituximab was seen to be favorable for patients with increased microvascular injury, while transplant glomerulopathy patients did not benefit from this treatment specifically. Bortezomib did not appear to have significant advantage in treating patients who were DSA positive. There was no difference in survival between the two groups. Adequate valganciclovir prophylaxis may have reduced the mortality rate by 50% and it is recommend that valganciclovir and trimethoprim-sulfamethoxazole prophylaxis be given for at least 5-6 months after aggressive anti-rejection therapy due to increased risk of major adverse effects.
Level of evidence:III as it is a retrospective study
You have covered most of the salient features. The discussion could have been a little more organized
Chronic ABMR constitutes one of the most common causes of graft failure
The current study is a retrospective study (level of evidence III) addressing the difference between the aggressive and conservative treatment of chronic ABMR in terms of graft, patient survival, and major adverse events in 82 patients with biopsy proven chronic ABMR done between 2009 and 2017 in a single center in Taiwan
Aggressive treatment was defined as the use of double filtration plasmapheresis and one of the following: Rituximab, IVIG, ATG, Bortezumab or pulse methylprednisolone
Diagnosis of chronic ABMR was based in this study on the presence of histologic features of chronic ABMR and the presence of C4d since the detection of DSA using luminex is expensive and thus not done in these cases
Conclusions
1- Aggressive treatment of chronic ABMR offer better outcome only in the following patients
2- Aggressive treatment was associated with a higher incidence of infections including PCP, CMV infections, infectious diarrhea, and UTI which was evident in the first 6 months after treatment with Rituximab, ATG or Bortezumab. Patients in this study received PCP and CMV prophylaxis for only 1 month after treatment so the authors recommend 6 months prophylactic treatment after aggressive treatment
Very nicely summarized. Good effort
Dear all in order to make full use of this article please address the following points:
Degree of CABMR
Difference between aggressive and conservative treatment outcomes.
Effect of aggressive treatment on infectious complications
Indication to prolong antiviral treatment.
Comment on combination of ATG and Retuximab
Introduction ;
Chronic active antibody mediated rejection(CAMR) is now considered an important risk factor for allograft dysfunction and loss. Unfortunately therapeutic decisions for treatment of CAMR is hampered by lack large RCT comparing the efficacy of individual treatment. The available data were informed by retrospective studies (4,5). This retrospective from February 2009 to December 2017 aimed at evaluating the outcomes of CAMR by comparing allograft survival between those who received aggressive therapy and those who received conservative or supportive therapy.
Methods ;
Results ;
Limitations ;
Conclusion ;
Level of evidence ; This is retrospective study, and therefore the level of evidence is 3
Excellent
Thnxs prof
SUMMARY :
The core of this article is concerned with treatment of CAMR or chronic active antibody mediated rejection in renal transplant recipients. Diagnosis is based on three major markers, listed below :
Different treatment strategies that were attempted in renal transplant recipients were collected from records in this trial and its results were compared with respect to graft survival and patient outcome. The treatment strategies involved were IVIG plus rituximab, proteasome inhibitor – Bortezomib, complement inhibitor – eculizumab, IL – 6 receptor blocker. These medications were used in two groups of patients – one for aggressive treatment and one for supportive therapy.
Computerized records collected from the past 7 years of biopsies from one particular center have been used as the baseline material in this publication.
Since graft survival is the ultimate marker in this study, we mention the definition of graft loss according to the authors of this publication – graft loss included patients who returned to dialysis, re-transplant, or patients who died.
Major adverse event was defined by any event that was associated with death, admission to hospital, prolongation, persistent or significant disability or incapacity, or was otherwise life threatening in connection with specific treatment.
This study found that CAMR patients had better rates of graft survival with aggressive treatment. The downside to this, however, was that aggressive treatment also meant more chances of major adverse events. The most common adverse events seen were UTI, CMV infection, bacterial or PCP pneumonia, and infectious diarrhea.
Graft loss was found to be associated with supportive therapy alone and proteinuria.
Outcomes related to specific treatment regimen :
IVIG plus rituximab was seen to be favorable for patients with increased microvascular injury, while transplant glomerulopathy patients did not benefit from this treatment specifically.
Bortezomib did not appear to have significant advantage in treating patients who were DSA positive.
Aggressive treatment of CAMR has a good response if done at an early stage and in patients with higher microvascular inflammation, and proteinuria below 1.7 g/dL. Above this level of proteinuria, aggressive treatment does not appear to have significant benefit.
Due to increased risk of major adverse events with employment of aggressive therapy, CMV and PCP prophylaxis is recommended.
LEVEL OF EVIDENCE :
This is a retrospective study with level of evidence 3.
Very good and comprehensive
☆Treatment of chronic active antibodymediated rejection in renal transplant recipients – a single center retrospective study
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
Background:
_____________
▪︎CAMR is a major etiology of graft failure in renal transplant recipients.
▪︎Diagnosis is based on the presence of DSAs and specific histological lesions, most importantly, microvascular inflammation/ injury +/- capillary C4d deposition.
▪︎Treatment for CAMR has remained a major challenge and the current therapeutic stratigies are based on retrospective studies and pilot trials, including: IVIG plus rituximab, proteasome inhibitor-bortezomib, complement inhibitor-eculizumab, and IL-6 receptor blocker..
☆Methods:
__________
▪︎From Taichung Veterans General Hospital a computerized records were collected to identify renal transplant biopsies performed in the past 7 years with CAMR.
▪︎The patients were divided into two groups according to treatment approach:
1. Group 1 received aggressive treatment
(double filtration plasmapheresis(DFPP) and one of the followings: rituximab, IVIG, ATG, bortezomib, or methylprednisolone pulse therapy).
2. Group 2 received supportive treatment.
▪︎End points:
The patients were followed up until graft loss or death or the end of 2017.
▪︎The definition of graft loss included: returned to dialysis, re-transplant, or patient death.
▪︎Histopathology and diagnosis of CAMR:
All renal graft biopsies were performed using US guided percutaneous technique (two~three cores per biopsy; 16~18 gauge needle).
▪︎Graft biopsies were examined by LM, IF studies for IgG, IgA, IgM, C3, C4d, C1q, kappa, and lambda light chains, and EM.
▪︎C4d staining was performed on all biopsies by direct IF on frozen sections.
▪︎All of the following 3 criteria were met for diagnosis of CAMR according to Banff 2017 criteria:
(1) Morphologic evidence of chronic tissue injury,
(2) Evidence of current/recent antibody interaction with vascular endothelium
(3) Serologic evidence of DSA, to HLA or other antigens.
▪︎C4d staining should be positive for the
definite diagnosis of CAMR if DSA is not performed.
☆Results:
__________
▪︎From February 2009 to December 2017, a total of 82 patients with biopsy-proven CAMR were identified.
▪︎Exclusion criteria: Biopsies with ABO-incompatable grafts and those with
recurrent or denovo GN & DM nephropathy.
▪︎ All the patients had neg T and B cell CDC-CMX result before kidney transplantation
▪︎Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2.
▪︎Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different.
▪︎Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis.
☆Discussion:
______________
▪︎Aggressive treatment for CAMR patients was associated with better graft survival, higher incidence of adverse events and a reduced adverse event free survival.
▪︎ Proteinuria and supportive treatment .
were independently associated with graft loss.
▪︎ There are no approved treatments for CAMR.
▪︎ IVIG and rituximab significantly reduced or stabilized the progressive loss of transplant function. But,TG is associated with a poorer response.
▪︎The combination of IVIG and rituximab appeared to be beneficial in patients with high levels of microvascular injury. But, patients with low microvascular injury appeared less likely to benefit from it.
▪︎ Bortezomib: had no significant benefit for late onset DSA-positive ABMR in graft survival and DSA reduction.
▪︎ HLA antibodies produced by long-lived plasma cells are more refractory to proteasome inhibitor therapy.
▪︎Patients with CAMR are more likely to respond to antihumoral therapy when diagnosed early with prominent microvascular injury
▪︎Aggressive treatment for CAMR resulted in better graft survival in patients with proteinuria < 1.73 g/d but not in patients with proteinuria ≥1.73 g/d.
▪︎ In this study the most frequently prescribed antihumoral agents are rituximab, followed by IVIG, bortezomib, and ATG. The most common adverse events were CMV disease, UTI, bacterial / PCP pneumonia, and infectious diarrhea.
▪︎Adequate valganciclovir prophylaxis may have reduced the mortality rate by 50% and it is recommend that valganciclovir and trimethoprim-sulfamethoxazole prophylaxis be given for at least 5~6 months after aggressive anti-rejection therapy.
☆Limitations of the study:
___________________________
1) No rules for treatment of CAMR.
2) DSA was not performed for every recipients.
●Level of the study: Level III ( a retrospective cohort study )
Comprehensive but could be more concise
Ok, thanks prof Dawlat
-Summary
Background
Chronic active antibody mediated rejection CAMR is diagnosed by the presence of donor-specific antibodies (DSAs) and biopsy finding of microvascular inflammation/injury with or without capillary C4d deposition .
Current management for CAMR includes
intravenous immunoglobulin (IVIG) plus
rituximab ,
proteasome inhibitor-bortezomib ,
complement inhibitor-eculizumab and
IL-6 receptor blocker .
Methods
Included patients were retrospectively collected for 7 years
The cases had negative T and B cell complement-dependent cytotoxicity cross-match (CDC-CMX) result before kidney transplantation.
Thymoglobulin or basiliximab were given for induction therapy. For maintenance immunosuppression calcineurin inhibitors (CNIs) tacrolimus or cyclosporine A, mycophenolate, and prednisone were given.
mTOR inhibitor, either sirolimus or everolimus, was taken in some cases.
Patients were divided into group 1 receiving aggressive CAMR treatment which was double filtration plasmapheresis( DFPP) and one of the followings: rituximab, IVIG, ATG, bortezomib, or MP pulse therapy; and group 2 receiving supportive therapy.
Diagnosis of CAMR in the graft biopsy was done according to Banff 2017 criteria:
-morphologic evidence of chronic tissue injury
-evidence of current/recent antibody interaction with vascular endothelium
– serologic evidence of donor-specific antibodies .
-C4d staining in the biopsy tissue if DSA was negative
Results
The important predictors of graft loss were Creatinine, proteinuria, PRA class II, transplant glomerulopathy, interstitial fibrosis, tubular atrophy, mesangial matrix increase, glomerulitis, peritubular capillary inflammation and supportive treatment.
Mean number of adverse events was higher in group 1.
The most common adverse events group 2 were CMV disease, leucopenia, urinary tract infection, pneumonia, infectious diarrhea, and Pneumocystis carinii pneumonia.
Aggressive treatment resulted in better graft survival in patients with proteinuria < 1.73 g/d.
Discussion
Aggressive treatment for CAMR lead to better graft survival but on the other hand is associated with higher incidence of adverse events.
Independent factors for graft loss were proteinuria and supportive treatment.
Studies showed that IVIG and rituximab can stabilize the progression of graft loss but not with severe TG.
Other study revealed that anti humoral therapy was beneficial in cases with biopsies with high levels of microvascular injury.
Bortezomib usage in a study did not give favourable outcomes for late onset DSA-positive ABMR regarding graft survival and DSA reduction.
Current study emphasised the significance of aggressive treatment in CAMR at an earlier stage and with a higher degree of microvascular injury.
CMV infection was associated with Rituximab, ATG, and bortezomib treatment in renal transplant cases.
It is recommended to administer valganciclovir and trimethoprim-sulfamethoxazole prophylaxis for at least 5 to 6 months after aggressive anti-rejection therapy as in this study 3 of 6 died of CMV disease.
Conclusion
Aggressive treatment early for CAMR is associated with better graft survival meanwhile adverse events are associated with such therapy therefore PCP and CMV prophylaxis for long periods will be essential for such cases.
-Level of evidence is III
Very good
Retrospective study, level 3.
Summery:
CAMR is an important risk factor of graft loss & its treatment is a big challenge.
All types of treatment( IVIG+ rituximab, bortezomib, eculizumab, & IL-6 receptor blockers) that tried among CAMR patients was based on retrospective study or pilot trial. These studies show that treatment wasn’t always effective & was associated with high incidence of side effects.
Retrospective study include all patient ( Feb2009-Dec2017) with proved CAMR by graft biopsy changes & negative CDC-XM. Patients with ABOi graft, recurrent or de novo GN or DM were excluded from analysis.
All patient were induced by ATG or basiliximab, & maintained on CNI, MMF, steroid or mTOR-I.
The patients divided into 2 groups. Group1(59 patients) treated aggressively with DFPP & at least one of the following: IVIG+ rituximab, ATG, bortezuman, or only pulsed MP. Group 2(23 patients) receive supportive therapy. Both groups receive standard treatment ( good control of blood pressure, blood sugar & hyperuricemia).
The patient are followed up until the end of 2017, graft loss( return to dialysis, retransplant or patient death), or death. CAMR diagnosed according Banff 2017 classification ( all 3 criteria):
Study results show that aggressive treatment of CAMR was associated with better graft survival in spite of increased incidence of adverse events. This finding was similar to other studies e.g. Billing et al, & different from others e.g. Bachelet et al who found that aggressive treatment of TG in CAMR didn’t alter natural history of TG.
The conflict in result may be due to enrollment of patients with advance TG, & low microvascular injury score. It was proven that using of rituximab + IVIG was associated with improved graft survival in patients with high microvascular injury score, early stage of CAMR & proteinuria <1.73g/day.
Another finding of this study was increasing incidence of CMV, UTI, CPC pneumonia, & infectious diarrhea among patient treated aggressively. So it was recommended to extend prophylaxis 5-6 months or longer after using of aggressive regime.
Limitation of the study:
Conclusion:
Aggressive treatment in early chronic tissue injury associated with good graft survival & adverse events can be reduced by using longer duration of prophylaxis.
Very good
Thank you