I. A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection (BORTEJECT Trial)
- How do you define late AMR?
- Summarise the methodology and the conclusion of this study in your own words.
- How would you prevent and treat late AMR?
Development of acute antibody-mediated rejection (AMR) is associated with graft loss and can occur both early (3 months) post-transplant. Treatment and prognosis differ in early and late AMR. Herein, we present a single-center experience using high-dose intravenous immunoglobulin (IVIg) (2g/kg) for the treatment of late AMR. All kidney recipients with negative T- and B-cell flow crossmatch at transplant and biopsy-proven late AMR were included (2009-2013, n=126). All patients were treated with IVIg at 2g/kg over divided doses and high-dose intravenous methylprednisolone. Variables collected included demographics, Banff 2007 renal allograft biopsy scoring criteria, and laboratory values. Multivariable Cox proportional hazard regression was used to identify factors predictive of graft loss. Median age was 46 years, with 60% male and 47.6% African American. Median time from transplant to rejection was 3.8 years. Baseline serum creatinine was 1.6 mg/dl and median serum creatinine at diagnosis was 2.6 mg/dl. Fifty-eight patients (46%) eventually lost their grafts at a median of 12 months (interquartile range: 4-21) from diagnosis. Serum creatinine >5.3 mg/dl at time of diagnosis was associated with a 94% probability of graft loss, and after controlling for multiple recipient and donor factors, only serum creatinine and urine protein creatinine ratio at diagnosis were predictive of graft loss. Late AMR has a poor prognosis, with 46% graft loss at a median follow-up of 12 months. Serum creatinine was a better predictor of subsequent graft failure than histological characteristics in late AMR. These findings help inform treatment plans as well as prognosis.
The full analysis set consisted of 44 patients who were randomized and
entered the interventional trial. Continuous data were presented as
median and interquartile range, and categorical variables were presented as absolute and relative frequencies. Fisher exact test was used
to compare categorical data, and the Mann–Whitney U test was used
for comparison of continuous data. Kaplan–Meier analysis was applied for calculation of graft and patient survival or AE/SAE-free
survival. Mantel Cox log rank test was used for comparison of survival between groups. GFR trajectories were analyzed using a mixed
linear model, with eGFR values from 0 to 24 months as dependent and time and the interaction of treatment and time as fixed effects.
Furthermore, patient-specific random effects for intercept and slope
were specified. The covariance structure was specified as an autoregressive model of the first order. The null hypothesis that the coefficient of the interaction term treatment and time is zero was tested at a
two-sided significance level of 5%. We conducted additional sensitivity analyses where (1) eGFR after graft loss was set to zero or (2)
eGFR values after 3 months were included in the model.
Prevent late ABMR
Avoid performed DSA.
Good selection of immunosuppression protocol.
Encourage donor exchange
Treat sensitised patients early
Definition of late AMR?
Late AMR had been defined as AMR that occur after 6 months’ post-transplantation, changed to become AMR that occur after one-month post-transplantation. it is due to DSA, or de novo DSA
Summary:
It is a randomized double-blind control study
Aimed at evaluation of the effect of bortezomib in the treatment of late AMR
It started by choosing the recipients according to inclusion criteria then screening them for the presence of DSAs, those who were positive for DSAs underwent graft biopsy. Recipients who were diagnosed to have AMR were randomly divided into two groups by a computerized program.
One group receive bortezomib and the other group receive a placebo.
Then the patient followed up with the measurement of GFR, proteinuria and DSA level at regular intervals, graft biopsy at 24 months.
The primary endpoint was any change in GFR
The secondary endpoint was proteinuria, decrease DSA level, graft and patient survival, and cure in the biopsy.
The study concluded that the bortezomib fail to show any beneficial effect on the GFR, or DSA level, graft function and patient and graft survival. In addition, it was unsafe, with high side effects, especially GIT and hematologic SE.
Prevention of Late AMR
1- Best selection to the donor with a best possible HLA match
2- Avoid preformed DSA presence
3- Treatment of sensitized patients properly, if no other option for him.
4- Encourage donor exchange programs to better select donor
5- education of the patients about the importance of drug adherence and strict follow up
6- good selection to immunosuppressive regime according to patient need with a good dose.
7- For sensitized patients, monitoring of DSA can be of role in early detection of rejection
8- Protocol biopsy individualized could be
9- A high index of suspicion for any sign of rejection.
Q1: Late AMR previously was defined as AMR after 6 month but transplant society had an expert consensus and defined late AMR after 30 days of TX which could be related to preformed DSAs or de novo DSAs.
Q2: This randomized controlled trial (BORTEJECT trial) used two series of bortezomib injection consisting 1.3 mg/m2 for four doses (1, 4, 8, 11) comparing with placebo in prevention of decreasing GFR due to late AMR with positive DSA. Forty-four recipients with late AMR were enrolled in this study. Nineteen had performed DSA and the other de novo DSA. They were randomized in two groups: 21 received bortezomib and 23 placebo. There were no significant difference between two groups in term of decreasing GFR, graft survival, proteinuria MFI of DSAs in 24 – months. So in conclusion bortezomib was not effective preventing GFR decreasing or improving biopsy results in spite of its GI or hematological adverse effects and we still need new treatment in this subject.
Q3: The best option is prevention by proper HLA matching between donor and recipient, suitable immunosuppressant with effective dose, adherence to immunosuppressant drugs, monitoring for DSA and if positive performing allograft biopsy.
There are no definite treatment for late AMR. Steroid/high dose IVIG and rituximab had positive results in few studies, but drugs such as bortezomib, eculizumab, C1 esterase inhibitor or tocilizumab(IL-6 inhibitor) showed no effect.
Define late AMR:
Late Active AMR based on the Banff 2017 classification are:
(1) histological evidence of graft injury via microvascular inflammation
(MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI
(3) the presence of circulating DSA, predominantly anti-HLA antibody
And occurs after 30 days post renal transplantation.
A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection
This was a randomized, placebo controlled, double-blind trial. It is a non-inferiority study
Out of 1165 kidney transplant recipients, 1076 were evaluated for anti HLA antibody presence. 111 had donor specific antibodies (DSA) out of which 86 underwent kidney biopsy.
In the end, only 45 patients had DSA and AMR on biopsy who were randomized into 2 groups:
Group 1: Bortezomib (2 cycles of 4 injections in 2 weeks)
Group 2 Placebo
The patients were followed up with laboratory evaluation at pre-specified intervals for a period of 24 months.
Bortezomib had no effect
-on renal function -eGFR, proteinuria and measured GFR at 2 years on
-on patient and graft survival
-on DSA levels
The trial was not able to show any positive effect of bortezomib use with relation to graft function, graft, and patient survival in patients with late AMR.
Bortezomib group was associated with increased gastrointestinal toxicity (nausea and diarrhoea) as well as hematotoxicity (anaemia, leukopenia, and thrombocytopenia).
How would you prevent and treat late AMR?
Prevention of Late AMR:
Pre-transplant optimal donor selection
Post-transplant management:
Counselling – to avoid non-adherence as well as avoiding iatrogenic sub-optimal immunosuppression
Monitoring of DSA post-transplant according to the risk stratification of the patient:
If DSA is negative, no further testing is required in these 2 groups unless there is change in immunosuppression, graft dysfunction, non-adherence or if the patient is transferred to remote unit.
If DSA is positive, kidney biopsy is done and if it shows AMR, it should be treated.
· high risk group (DSA positive) and very high-risk group (desensitized cross match positive), DSA testing with kidney biopsy should be done during first 3 months. If biopsy shows AMR, treatment should be initiated. If biopsy is negative, but DSA rising, then it should be treated as AMR. If no AMR in biopsy, monitor DSA.
After one year post transplant, routine DSA monitoring is not recommended unless there is change in immunosuppression, graft dysfunction, non-adherence or if the patient is transferred to remote unit.
3) Protocol biopsy: In high-risk patients.
Treatment of AMR (Late)
1) Augmentation of immunosuppression is important, with triple drug immunosuppression (CNI, MMF, steroids). Add steroids, if on a steroid-free regimen.
2) Treatment of Pure Antibody mediated rejection:
· 5 sessions of Plasma exchange followed by IVIG (100-200mg/kg).
· Injection Rituximab 375 mg/m2 following last treatment.
3) Treatment of mixed rejection (both acute cellular rejection and AMR): A combination of therapy to cover both aspects of the rejection. Treatment of cellular rejection component is based on the histological picture:
For Acute T cell mediated rejection:
· Banff Ia: IV methylprednisolone 500 mg/d x 3-5 days
· Banff Ib: If mild graft dysfunction: IV methylprednisolone 500 mg/d x 3-5 days
· Banff Ib: If severe graft dysfunction: rATG 1.5mg/kg/day x 5-7 days or until recovery
· Banff IIa, IIb or III: rATG 1.5mg/kg/day x 5-7 days or until recovery
it is an antibody mediated rejection that occurs after 30 days of transplantation , it is mediated by de novo DSA or pre-existing DSA.
This study is randomized , double blind, placebo controlled trial.
Fist step there was screening of patients for the presence of DSA , then graft biopsy is taken to diagnose ABMR, those who have ABMR is randomized to either receiving bortezomib or placebo . The primary endpoint was change in GFR slope and the secondary end points was the measured GFR at 2 years and DSA level, proteinuria , graft survival at 2 years .
There was no difference between the two groups in the primary or secondary endpoints.
The treatment of ABMR is difficult with varying degree of success and the best way is to maximize efforts to prevent ABMR like better HLA matching and identifying patients at risk to use more aggressive induction treatment and frequent monitoring for DSA level , better adherence with immunosuppressive medication .
Many protocols are used for the treatment of ABMR : high dose IVIG (2gm/kg) or plasmapheresis with low dose IVIG with or without rituximab had been used. Monitoring for DSA after successful treatment is needed as patients who have DSA level decrease by 50% have better outcomes than patients who didn’t.
Many other drugs had been used like bortezomib , IL-6 inhibitors with varying degree of success.
How do you define late AMR?
some litertures defined the Late AMR usually occur after 6 months of transplantation(2).
according to the new calssification the cutoff of 30days and above for late AMR with dn DSA , or preexsiting performed DSAs , as its indolunet progressive type of rejection(1).
Summarize the method:
BORTEJECT Trial (randomized, placebo-controlled trial) double blinded
The objective of this trial is to evaluate the effect of the proteasome inhibitor bortezomibon the course of late ABM by assessing the change in slope of e GFR over fu period as primary outcome and secondary outcome compare the graft survival
Two steps of randomizations
First step is Part A, cross-sectional Screening period from 2013-2015,1076 recipients fit the HLA ABS Screening with the key inclusion criteria All adults above 18 years, more than 180 months post transplantation, with GFR >20ml/min, all with histological finding of ABMR, TCMR covariates(minimization)
Exclusion of 389 (53.7%) patients due to detectable HLA class I and/or II antibody reactivity
Another 111 (15%) recipients were DSA positive, and 86 of them were underwent a protocol biopsy. Twenty-five patients did not undergo biopsy because of either a lack of consent or other exclusionCriteria, so only 44 kidney transplant recipients included in part B the interventional stage
Key inclusion criteria
were the detection of HLA class1 and/or II DSA and an index biopsy showing at least one of the morphologic features suggestive of ABMR
Exclusion criteria for part B: biopsy-proven acute rejection within 1 month before screening; acute deterioration of graft function suspicious of acute rejection. TCMR Banff classification > garde1,thrombocytopenia < 30gm/l, de novo or recurrent severe thrombotic microangiopathy,polyoma virus nephropathy, de novo or recurrent GN, neutrophil count ,1 g/L, or peripheral neuropathy greater than or equal to grade 2, Active infection, pregnancy, bortezomib intolerance performed DSAs was found in 19 patients, one recipient withdrew consent shortly after randomization Twenty-three patients received placebo, and 21 patients received bortezomib(1-1 ratio )Two patients died during follow-up in bortizemab arm , and the other 42 recipients completed the study after 24 months of randomization.
limitaions:
less MMF dosing in bortezomib arm , lower baseline GFR and more vascular and advanced tissue injury in the bortezomib group, may explain in part the resistant to treatment more side effect in bortezomib in combination with valaciclovir treatment and bortezomib given as IV infusion not Sc route which know to have less side effects also the trial was very short to maintain the inhibitory effect of bortezomib and also short duration to assess the outcome (24 months) , another limitation small sample size and using GFR decline as a surrogate of graft survival, heterogenicity in the maintenance IS protocal this is another limitation,Variation In the definition of ABMR which affect the inclusion and exclusion criteria
In conclusion:
its negative study the results with bortezomib treatment failed to show improvement in the graft function, the graft survival, histologic or molecular rejection phenotypes, and reduction in DSA, yet bortezomib treatment associated with more gastrointestinal and hematologic toxicity.
to date, findings of studies using bortezomib have been inconsistent. Most are small studies with small sample size using different drugs in combination with bortezomib, so far, it’s in effective in AMR and we need more studies with better design like large prospective studies to confirm its role in AMR prevention and treatment.
How would you prevent and treat late AMR?
The prevention and treatment of late AMR should target the B cells inhibition , development,maturation, and activity,so far no consensus regarding the best treatment option of AMR.
based on the available limited evidence from different studies, still the use of combination therapy is preferred ,as late AMR associated with poor graft and patient survival ,also increase the risk of chronic Active AMR and chronic rejection and graft loss.
Prevention of late AMR :
-Identify the patients at risk of AMR, by detection of performed DSA, Dn DSA group prior to transplantation, those with positive crossmatch and more mismatch in LD program preferred to allocated KPD (Kidney paired donation) , desensitization with plex , IVIG, rituximab for highly sensitized group
-Use induction therapy with ATG, or alemtuzumab in high immunological risk
– Monitor DSA s and addressing nonadherence and underimmunosuppression upon FU protocol biopsies ( center preferences )
Treatments of late AMR:
in general the treatment target to remove the preformed or preexist DSAs by plasmapheresis, IVIG to suppress further production of ABS and rituximab as B cell depleting agents followed by optimizing the maintenance IS with triple IS including Tacrolimus, MMF, Steroids with frequent monitoring of DSAs level by using lumniex SAB assay,Some drugs used as rescue therapy as second line like eculizumab ( anti C5 monoclonal Abs) , ANTI c1q abs inhibitors , ANTI 1l-6 Iinhibitors combination of eculizumab and splenectomy ,proteasome inhibitor(bortezomib) all shows in consistent results from small studies and thier use dependes on avialablity of the drugs ,cost ,safety profile and longterm efficacy.
during the treatment all patients should recieved CMVpropylaxis and PJP prophylaxis , antifungal , strict sugar and BP control .
references:
1-Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group, transplantion , may 2020
2- uptodate medicine , kidneytransplantion in adults:prevention and treatment of antibody-mediatedrejectionof the renalallgraft , accessed 2021.
Late AMR:
There is no consensus on the time point for late AMR. Many authors stated 3-6 months after the Tx. The Transplantation Society working group defined late AMR >30 days post-transplant.
A Randomized Trial of Bortezomib in Late AMR (BORTEJECT Trial)
-This was a randomized, placebo controlled, double-blind trial.
Out of 1165 kidney transplant recipients, 1076 were evaluated for anti HLA antibody presence. 111 had DSA out of which 86 underwent kidney biopsy. Finally ,45 patients had DSA and AMR on biopsy who were randomized into 2 groups. One group received bortezomib while the other group received placebo.
The trial didn’t show any positive effect of bortezomib use regarding the graft function, graft and patient survival in patients. As well as associated with increased gastrointestinal toxicity as well as hematotoxicity .
Prevention and ttt of Late AMR:
Prevention of late AMR has 2 aspects – Pre-transplant optimal donor selection (better HLA matching, absent pre-transplant DSA) and post-transplant management.
Post-transplant management for prevention of AMR includes:
*Regular monitoring of DSA post-transplant
*Protocol biopsy: In high risk patients.
Treatment of Late AMR:
-Intensification of immuno-suppression CNI, MMF, steroids.
-Treatment of Antibody mediated rejection:
5-7 sessions of Plasma exchange followed by IVIG (100-200mg/kg).
Rituximab 375 mg/m2 following last treatment.
-Treatment of mixed rejection:
For Acute T cell mediated rejection:
Banff Ia: IV methylprednisolone 500 mg/d x 3-5 days
Ib: If mild graft dysfunction: IV methylprednisolone 500 mg/d x 3-5 days
Ib: If severe graft dysfunction: rATG 1.5mg/kg/day for 5-7 days
IIa, IIb or III: rATG 1.5mg/kg/day for 5-7 days
-Prophylaxis for infection prevention: CMV prophylaxis needs to be given.
Late AMR is by definition > 30 days posttransplant. This means there is early AMR which findings < 30 days posttransplant criteria for AMR(DSA, microcirculation inflammation/injury, +/- C4d in peritubular capillaries or glomerular capillaries)
-How do you define late AMR? The Transplantation Society working group defined late AMR as one presenting >30 days post-transplant. .
Summarise the methodology and the conclusion of this study in your own words. This study done to evaluate the effect bortezomib on treatment of late ABMR . It was randomized, double-blind, placebo-controlled, parallel group. 1165 kidney transplant recipients, 1076 were evaluated for anti HLA antibody presence. 111 had donor specific antibodies (DSA) out of which 86 underwent kidney biopsy. 45 patients had DSA and AMR on biopsy ,were randomized into 2 groups. One group received bortezomib ( 2 cycles of 4 injections in 2 weeks) while the other group received placebo.
The patients were followed for 24 months. The effect of bortezomib on renal function on patient and graft survival and on DSA levels was evaluated which was found to be not statistically different from placebo.
Conclusion: The trial failed to show any effect of bortezomib use in the graft function, graft and patient survival in patients with late AMR. Additionally, the bortezomib group was associated with increased gastrointestinal toxicity (nausea and diarrhea) as well as hematotoxicity (anemia, leukopenia and thrombocytopenia).
.
How would you prevent and treat late AMR?
Prevention : Good HLA matching ,no DSA and Improved medication adherence .MMF , TAC treatment In high risk group monitoring DSA level and doing protocol biopsies .
Treatment : Late antibody –mediated rejection (ABMR) is a major cause of graft failure , for which there is no proven effective treatment .
optimization of immunosuppression therapy, Pulse steroids, PP , IV IG and Rituximab may be effective .Anti C5 antibody eculizumab which is very expensive .
How do you define late AMR? This study defined it as AMR occurring after 6 month from transplant. Other study define it as AMR which occur after >3 months post-transplant .
Agarwal G, Diskin CD, Williams TA, Kumar V. Late Antibody-Mediated Rejection in Kidney Transplant Recipients: Outcomes after Intravenous Immunoglobulin Therapy. Clin Transpl. 2016;32:111-118. PMID: 28564528.
Summarise the methodology and the conclusion of this study in your own words
BORTEJECT is a randomized, placebo-controlled trial which is a prospective, double blind , randomized controlled trial , of 2 parts (parts A and B).
Part A (screening phase) which is a cross sectional of 1165 kidney transplant recipients and it ended with only 45 patients after fulfilling the sequential criteria for phase B which are (age >18 years old, >180 days post transplantation, eGFR >20 ml/min per 1.73 m2, detectable HLA class I and/or II DSA, subjected to a protocol biopsy showing at least one of : glomerulitis, peritubular capillaritis, transplant glomerulopathy, C4d staining along peritubular capillaries, or MLPTC on electron microscopy.
part B (intervention trial) One recipient withdrew and so only 44 recipients entered randomized in a 1:1 ratio by computer .21 received bortezomib and 23 received placebo and both were assessed during 24 months
The primary outcome was the slope of eGFR, which was not significantly different in both groups and so were urinary protein excretion, and graft survival
Secondary result were not significantly different between both groups including the percentage DSA MFI changes, 24 months measured GFR , ABMR diagnosis and biopsy findings
How would you prevent and treat late AMR?
Prevention: In pre transplant work up, avoid HLA mismatch, preformed DSA. After transplant: measures to optimize medication trough level include better compliance and adherence of treating personnel to the recommended levels.
Treatment: options are : apheresis (plasmapheresis, immunoadsorption), intravenous immunoglobulin (IVIG), CD20 antibody rituximab, proteasome inhibitor bortezomib, and anti-C5 antibody eculizumab
Böhmig, G.A., Eskandary, F., Doberer, K. and Halloran, P.F. (2019), The therapeutic challenge of late antibody-mediated kidney allograft rejection. Transpl Int, 32: 775-788. https://doi.org/10.1111/tri.13436
Summarise the methodology and the conclusion of this study in your own words.
-It prospective ,randomized ,double-blind,placebo,single –center trial.
-It is evaluated bortezomib in late ABMR.
-Inclusion criteria: age˃18 years old,˃180 days post-transplant, eGFR ˃20ml/min per1,73m2.
-1076 recipients fulfilled inclusion criterias.741recipient underwent HLA –screening.
-111 recipients were DSA positive and 86 subject to protocol biopsy.
-44 recipients entered the interventional trial.
-Patients were randomly assigned to receive cycles of either bortezomib (1.3mg/m2, IV twice weekly) or placebo(0.9 % normal saline) at 3-month intervals in double-blinded fashion.
-Tacrolimus adjusted to trough level 7-10 and cyclosporine 50-100 ng/ml.
-Patients followed for 2 years.
-The trial failed to show that bortezomib retards the decline in eGFR.There was also no significant difference in measured GFR, urinary protein level, DSA, or the morphological and molecular features of disease activity in follow-up biopsies.
How do you define late AMR?
Late ABMR occurs ˃30 days –post-transplant. It is either due to preexisting DSA or de novo DSA. It may be associated with allograft dysfunction and proteinuria. Graft loss can occur within months to years.
How would you prevent and treat late AMR?
-plasma exchange ,IVIG ±rituxmab and corticosteroid .
-Optimizing immunosuppression and medical treatment (BP, glucose, lipids).
-Screening and follow-up for DSA level.
A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection (BORTEJECT Trial)
1. How do you define late AMR?
Antibody mediated rejection that is caused by anti-donor-specific antibodies, mostly anti-HLA antibodies [1]. Some non-HLA antibodies, not related to a certain time after transplantation , thus diagnosed by detection of circulating DSA.
Renal biopsy showing certain characteristic histological lesions ( C4d stainingcapillary basement membrane, , and serum DSA detection. C4d, microcirculating inflammation)
With no morphologic evidence of chronic tissue injury such as glomerular double contours compatible with transplant glomerulopathy, peritubular capillary basement membrane multilayering, interstitial fibrosis/tubular atrophy, and fibrous arterial intimal thickening.
2. Summarise the methodology and the conclusion of this study in your own words.
Methodology
placebo-controlled trial
No. of patients: 44 Ktx patients with DSA-positive ABMR morphology were cross sectionally choosen among 741 patients within a period of 5 years post transplantation
Then randomly divided into two goups of patients, one assigned to receive bortezomib (n=21) , (two cycles of bortezomib, (eachcycle:1.3mg/m2intravenouslyondays1,4,8,and11) the other is placebo (n=23).
Patients were followed for 24 months. follow up parameters: serial eGFR measurement (at 0,6,12,18,and24months , urinary protein levels , DSA levels, protocol and indicated Biopsy for morphologic characteristics, and molecular rejection phenotypes , assessment of toxicity and side effects associated with the use of Bortezomib
Conclusion:
trial showed that despite Toxicity and side effects bortezomib failed to prevents GFR loss, improve DSA levels or graft survival
Adverse events include :, gastrointestinal toxicity, (nausea and diarrhea) Infectious, peripheral neuropathy, malignant disease. Among other AEs, headache and fatigue were most frequent as well as anemia, thrombocytopenia, and leukocytopenia.
3. How would you prevent and treat late AMR?
prevention: through HLA typing for both Donor and Recepient, DSA profiling , better outcomes achieved through less mismatches and in the absence of preformed DSA.
Treatment:
(1) IV Ig: targeting Allogenic AB
(2) Bortizomib : antiproteosome , Trgeting plasma cells producing AB
(3) Tosilizomib ( anti IL6): Targetin IL6 receptors that helps in B cell differentiation into plasma cells
(4) Rituximab (anti Cd20) : Monoclonal Ab targeting B cells
(5) Eculizumab : Anticomplement (terminal C5) locks activation into C5a and C5b
References:
1. R. B. Colvin, “Antibody-mediated renal allograft rejection: diagnosis and pathogenesis,” Journal of the American Society of Nephrology, vol. 18, no. 4, pp. 1046–1056, 2007.View at: Publisher Site | Google Scholar
It is a phenotype of AMR occurring after 30 days of transplant, may occur with pre existing or de novo DSA.
The features of AMR according to Banff 2017 classification are histological evidence f graft injury, histological evidence of antibody endothelial interaction (C4d positive or moderate microvascular interaction) and presence of circulating DSA.
It is associated with patterns of gene expression and molecular data
It leads to graft loss within months to years
It is a randomized placebo-controlled trial
45 patients were eligible for inclusion:
age >18 years, >180 days post transplant, eGFR>20ml/min/1.73m2, had class I and/or II reactivity, DSA detected in serum and features of AMR in biopsy.
patients were randomized into 2 groups, one group received 2 cycle IV bortezomib with oral valacyclovir and the other group received IV and oral placebo treatment
the 2 groups were followed up for 24 months.
primary outcome was the difference in slope of eGFR (eGFR at 0,6,12,18 and 24 months)
secondary outcomes were course of DSA, rejection phenotype and measured GFR after 2 years follow up
conclusion:
Bortezomib didn’t prevent progression of graft dysfunction due to late antibody mediated rejection and several adverse events were observed with its use
Prevention:
Donor-recipient HLA matching especially HLA-DR and DQ to decrease risk of de novo DSA post transplant
avoiding preformed DSA through kidney paired donation or desensitization
maintaining adequate immunosuppression including CNI in adequate doses to prevent TCMR and de novo DSA formation
treatment:
In preformed DSA and active AMR without chronic features:
plasmapheresis, IVIG and steroids with or without rituximab should be considered
Chronic active AMR:
Is differentiated from late AMR by the histological evidence of chronic tissue injury as transplant glomerulopathy (with no evidence of TMA), chronic recurrent or de novo glomerulonephritis, severe peritubular capillary basemen membrane multilayering in EM or arterial intimal fibrosis of new onset
supportive treatment (control of blood pressure, blood glucose and lipid control) with optimization of immunosuppression to stabilize and decrease the rate of decline in GFR, proteinuria and histological injury
De novo DSA with active and chronic active AMR
Usually due to under-immunosuppression and has concomitant TCMR (mixed AR)
Optimization of immunosuppression with managing of medication non adherence
Treatment of TCMR is mandatory in all cases with methylprednisolone pulses then oral prednisone but the dose, duration, taper and decision to use thymoglobulin are variable.
Plasmapheresis and IVIG with or without rituximab are of low evidence.
Nickerson PW. What have we learned about how to prevent and treat antibody‐mediated rejection in kidney transplantation?. American Journal of Transplantation. 2020 Jun;20:12-22.
Ho J, Okoli GN, Rabbani R, Lam OL, Reddy VK, Askin N, Rampersad C, Trachtenberg A, Wiebe C, Nickerson P, Abou‐Setta AM. Effectiveness of T cell‐mediated rejection therapy: A systematic review and meta‐analysis. American Journal of Transplantation. 2021 Dec 3.
Schinstock CA, Mannon RB, Budde K, Chong AS, Haas M, Knechtle S, Lefaucheur C, Montgomery RA, Nickerson P, Tullius SG, Ahn C. Recommended treatment for antibody-mediated rejection after kidney transplantation: The 2019 expert consensus from the transplantation society working group. Transplantation. 2020 May;104(5):911.
1. Late ABMR is a leading cause of kidney allograft failure, manifesting as a continuous and often clinically silent alloimmune process.
Its diagnosis is based on detection of DSAs and distinct morphological lesions, particularly inflammation and injury of microcirculation and finding of C4d deposit which is non-mandatory.
A major trigger of ABMR is the formation of antibodies against HLA class I, and particularly in chronic rejection against HLA class II.
Diagnostic criteria are the detection of typical morphological lesions in the microcirculation, which include glomerulitis (g), peritubular capillaritis (ptc), transplant glomerulopathy (cg), serological evidence of circulating DSA and/or the finding of C4d as a specific marker of DSA-triggered complement activation in the microvasculature.
In addition, the innovative diagnostic tool of gene expression analysis using validated platforms, such as the Molecular Microscope Diagnostic system (MMDx), has been included in the Banff scheme to further increase diagnostic precision.
Late ABMR, is commonly defined by its diagnosis beyond 6 months post transplantation, is often associated with anti-HLA DSA, sometimes in the context of underimmunosuppression (minimization) or nonadherence. Late ABMR is commonly associated with de novo DSA (also referred to as type 2 rejection).
2. First, cross sectional ABMR screening of 741 kidney transplant recipients identified 45 patients eligible for inclusion in the interventional part of the trial. Ultimately, 23 patients receive placebo (2 cycles placebo intravenously and peroral placebo) and 21 patients received bortezomib (2 cycles bortezomib intravenously and peroral valacyclovir.
This study is a randomized placebo-controlled trial that evaluated the impact of Bortezomib on the course of late ABMR compared to placebo. A difference in the slope of GFR, phenotypes of rejection, courses of DSA were outcomes evaluated.
For increasing precision, gene expression analysis has been evaluated in addition to protocol biopsies.
Most of participants in this study had DSA against HLA class II antigens, mostly HLA-DQ.
There were no significant differences with respect to eGFR slope, in percentage MFI changes, DSA, and urinary protein between two groups.
Patient and graft survival was not significantly different between two groups, although a death due to infection happened in the bortezomib group.
There were no significant differences in terms of ABMR diagnosis and its categories, Banff single lesion, glomerulitis and peritubular capilaritis sum score, and MLPTC. In addition, there were no significant differences in molecular ABMR, T cell–mediated rejection, all rejection, and atrophy/fibrosis scores, however, a change in rejection phenotypes was described.
The absence of an effect of Bortezomib on DSA and rejection is expected. Although bortezomib promotes apoptosis of plasma cells, their vulnerability to this agent is dependent on the rate of IgG production.
Bortezomib may also deplete normal antibody-producing plasma cells. Plasma cells conditions in ABMR may make them less responsible to this drug. The process of humoral compensation due to B cell proliferation and antibody production shortly after treatment may be the cause of unresponsiveness.
Adverse effects of Bortezomib include gastrointestinal, hematologic, and neurologic events, most prominently nausea, diarrhea, and hematologic toxicity that may lead to a decrease in average daily doses of MMF.
Although adverse events and severe adverse events and hospitalization were more frequent in the Bortezomib group, differences were not significant and there was a trend toward lower severe adverse events free survival. Leukopenia, anemia and thrombocytopenia were significantly higher in the bortezomib group.
An interesting strategy to enhance Bortezomib role on plasma cell inhibition is combinational therapy for example in combination with plasmapheresis or Rituximab in desensitization protocols.
Some studies have reported no benefit of Bortezomib and Rituximab in late ABMR and TG.
In conclusion, this study demonstrated that bortezomib has no significant effect on preventing the progression of kidney dysfunction and reduction in disease activity in late ABMR. This, in addition to more adverse effects of Bortezomib don’t support the use of this agent in the treatment of ABMR.
3. Adequate levels of immunosuppression help prevent acute, subclinical, and/or chronic immunologic rejection, thereby providing some protection against the development of late ABMR.
Early detection and successful treatment of cellular rejection and active ABMR may prevent progression to chronic ABMR.
If donor-specific antibodies are detected, either preformed or de novo, close clinical surveillance as well as serial titration and protocol biopsy may identify the earliest stages and potentially prevent progression.
Triple maintenance immunosuppressive therapy with CNIs, MMF, and prednisolone for prevention of TG is recommended.
Better protection from chronic allograft dysfunction with a tacrolimus-based regimen than with a cyclosporine-based regimen has been reported.
Numerous therapeutic concepts, amongst them apheresis (plasmapheresis, immunoadsorption), intravenous immunoglobulin (IVIG), CD20 antibody rituximab, proteasome inhibitor bortezomib, and anti-C5 antibody eculizumab have been evaluated in the treatment of ABMR. Levels of evidence, however, have remained low.
Only three distinct therapies (IVIG/rituximab, bortezomib and eculizumab) have now been tested systematically in the specific context of late/chronic ABMR, but results of RCTs are disappointing.
1. How do you define late AMR?
Late ABMR, the latter being commonly defined by its diagnosis beyond 6 months post‐
transplantation, often associated with anti‐HLA DSA, sometimes in the context of under
immunosuppression or nonadherence.
Diagnostic criteria are the detection of typical morphological lesions in the
microcirculation, which include glomerulitis, peritubular capillaritis, transplant
glomerulopathy, serological evidence of circulating DSA and/or the finding of C4d as a
specific marker of DSA‐triggered complement activation in the microvasculature.
1. Summaries the methodology and the conclusion of this study in your own words.
This randomized, placebo-controlled trial.
BORTEJECT] Trial, Bortezomib in Late Antibody Mediated Kidney Transplant Rejection
investigated whether two cycles of Bortezomib (each cycle: 1.3 mg/m2 intravenously on
days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-
specific antibody positive ABMR.
Treatment was associated with gastrointestinal and hematologic toxicity.
There was no significant effect on kidney function, donor specific antibody levels,
rejection phenotypes, or graft survival.
Bortezomib as a single agent may not ameliorate the progression of late rejection.
1. How would you prevent and treat late AMR?
ABMR to high dose steroids and IVIG or steroids and IVIG/rituximab (one dose of
375 mg/m2).
Late AMR is diagnosed after 6 month post transplant.
The borteject trial
Included 2 phases A and B .
Phase A in which 1165 patient at transplant outpatient clinics became filtered according to the inclusion criteria of the Trial , to be 741 patient
Phase B ,
Upon Screening 741 transplant patients for DSAs, only 45 patients were eligible for randomization
1 patient withdrew from the trial .
Total no. Of patients became 44 , 23 of them received placebo , 21 received bortezomib , 2 patients died during follow up
The study was double-blind trial , the bortezomib patients received 2 cycles of bortezomib in the form of 1.3 mg twice weekly ,
Placebo patients received normal saline at same intervals
Patients were followed up for 24 months
They concluded that bortezomib failed to control late AMR as represented with eGFR levels at 6,12,18 and 24 months ,
Besides it’s side effects , it also failed to control 2ry measures outcomes through the trial , including protein excretion, DSA MFI levels .
Regarding treatment of late ABMR Currently, there is no treatment proven to be effective in late and/or chronic ABMR.
Trials include bortezomib , complement inhibitors ,but both failed to demonstrate efficacy
Other options include IL6 inhibitors, Blymphocyte stimulatory block , C1 inhibitors, co stimulation block and others .
Many authors preferred the use of high dose IVIG combined with rituximab as a treatment of late ABMR.
37Billing H, Rieger S, Ovens J, et al. Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. Transplantation 2008; 86: 1214.
Dear all, what is the most critical conclusion of this study?
trial failed to show that bortezomib retards the decline in eGFR, a surrogate end point
for long-term graft survival.
no significant differences in measured GFR, urinary protein levels, DSA, or the
morphologic and molecular features of disease activity in follow-up biopsies.
Despite toxicity( GI & hematological), bortezomib fails to reduce GFR decline or improve the histological and molecular features of rejection or reduce DSA level or graft survival
All our friends, who have defined late AMR > 6 months, please see this paper and modulate your answer.
https://journals.lww.com/transplantjournal/fulltext/2020/05000/recommended_treatment_for_antibody_mediated.11.aspx
they put time land mark as one month ,late after one month(LAR) in their criteria?
1. How do you define late AMR?
Acute rejection occurring in late period of post-transplantation are known as late acute rejection. There is no consensus on the time point for diving the rejections into early versus late. Most of the authors use a period ranging from 3 to 6 months post-transplant after which if a rejection presents then it is defined as late rejection. The Transplantation Society working group, in their consensus guidelines published in 2020, defined late AMR as one presenting >30 days post-transplant. (1,2)
Late rejection can be either a cellular or antibody mediated or a mixed rejection.
Late acute rejections are a consequence of under-immunosuppression, non-adherence, infections and formation of de-novo DSAs. These, as compared to early acute rejections have been shown to have poorer graft outcomes and are associated with class I MHC incompatibility.
2. Summarise the methodology and the conclusion of this study in your own words.
A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection (BORTEJECT Trial)
Methodology: This was a randomized, placebo controlled, double-blind trial.
Out of 1165 kidney transplant recipients, 1076 were evaluated for anti HLA antibody presence. 111 had donor specific antibodies (DSA) out of which 86 underwent kidney biopsy. Finally 45 patients had DSA and AMR on biopsy who were randomized into 2 groups. One group received bortezomib ( 2 cycles of 4 injections in 2 weeks) while the other group received placebo.
The patients were followed up with laboratory evaluation at pre-specified intervals for a period of 24 months. The effect of bortezomib on renal function (by looking at eGFR, proteinuria and measured GFR at 2 years), on patient and graft survival and on DSA levels was evaluated which was found to be not statistically different from placebo.
Conclusion: The trial was not able to show any positive effect of bortezomib use with relation to graft function, graft and patient survival in patients with late AMR. Additionally, the bortezomib group was associated with increased gastrointestinal toxicity (nausea and diarrhea) as well as hematotoxicity (anemia, leukopenia and thrombocytopenia).
3. How would you prevent and treat late AMR?
Prevention of Late AMR: Prevention of late AMR has 2 aspects – Pre-transplant optimal donor selection (better HLA matching, absent pre-transplant DSA) and post-transplant management.
Post-transplant management for prevention of AMR includes:
1) Counselling of the patient to avoid non-adherence as well as avoiding iatrogenic sub-optimal immunosuppression, which may happen due to side effects of the drugs (for example leukopenia leading to dose reduction or withdrawal of antimetabolites) or due to minimization protocols. Immunosuppression management should be individualized with close monitoring of drug trough levels.
2) Regular monitoring of DSA post-transplant according to the risk stratification of the patient: (3)
In low risk group (first transplant, no desensitization, no DSA pre transplant): Check DSA at least once in first 3 to 12 months post transplant.
In Intermediate risk group (DSA negative, but prior history of DSA presence): Check DSA in first month post transplant
If DSA is negative, no further testing is required in these 2 groups unless there is change in immunosuppression, graft dysfunction, non-adherence or if the patient is transferred to remote unit.
If DSA is positive, kidney biopsy is done and if it shows AMR, it should be treated.
In high risk group (DSA positive) and very high risk group (desensitized cross match positive), DSA testing with kidney biopsy should be done during first 3 months. If biopsy shows AMR, treatment should be initiated. If biopsy is negative, but DSA rising, then it should be treated as AMR. If no AMR in biopsy, monitor DSA.
After one year post transplant, routine DSA monitoring is not recommended except if there is change in immunosuppression, graft dysfunction, non-adherence or if the patient is transferred to remote unit.
But a recent paper (Crespo et al, Transplantation 2020) recommends DSA monitoring in low risk group at least once in 12 to 24 months and in other groups annually. (4)
3) Protocol biopsy: In high risk patients.
Treatment of Late AMR: Treatment of AMR in late post-transplant period involves multipronged approach. Detailed history, especially for non-adherence and sub-optimal trough levels is important. (2,5)
1) Augmentation of immunosuppression is important, with triple drug immunosuppression (CNI, MMF, steroids). Add steroids, if on a steroid-free regimen.
2) Treatment of Pure Antibody mediated rejection:
5 sessions of Plasma exchange followed by IVIG (100-200mg/kg).
Injection Rituximab 375 mg/m2 following last treatment.
3) Treatment of mixed rejection (both acute cellular rejection and AMR): A combination of therapy to cover both aspects of the rejection. Treatment of cellular rejection component is based on the histological picture:
For Acute T cell mediated rejection:
Banff Ia: IV methylprednisolone 500 mg/d x 3-5 days
Banff Ib: If mild graft dysfunction: IV methylprednisolone 500 mg/d x 3-5 days
Banff Ib: If severe graft dysfunction: rATG 1.5mg/kg/day x 5-7 days or until recovery
Banff IIa, IIb or III: rATG 1.5mg/kg/day x 5-7 days or until recovery
4) Prophylaxis for infection prevention: Pneumocystis prophylaxis, CMV prophylaxis needs to be given.
References:
1) Sijpkens YW, Doxiadis IIN, Mallat MJK, et al. Early versus late acute rejection episodes in renal transplantation. Transplantation 2003;75:204-208.
2) Schinstock CA, Mannon RB, Budde K, et al. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantation Society Working Group. Transplantation 2020;104:911-922.
4) Tait BD, Susal C, Gebel HM, et al. Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation. Transplantation 2013;95:19-47.
4) Crespo M, Zarraga S, Alonso A, et al. Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper. Transplantation 2020;104:S1-S12.
5) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol 2020;15: 430–438.
good, this is a non-inferiority trial.
How do you define late AMR?
This is the antibody-mediated rejection that occurs. 6 months after transplantation.
summary:
Its goal was to see how the proteasome inhibitor bortezomib affected the course of late ABMR. Bortezomib may lower DSA levels and slow the course of allograft damage by reducing alloantibody-producing plasma cells.
Overall, 1076 recipients met the criteria for participation (age>.18, 180 days posttransplant, eGFR>20 ml/min per 1.73 m2), and 741 patients were prescreened for anti-HLA antibodies until patient enrollment in the intervention experiment (part B) was completed.
Three hundred ninety-eight patients (53.7%) demonstrated detectable HLA class I and/or II antibody reactivity. One hundred eleven (15%) patients had DSA, and 86 had a protocol biopsy. Twenty-five patients were not biopsied due to non-consent or other exclusion criteria. Included in part B were HLA class I and II DSA and an index biopsy with at least one of the following morphologic characteristics indicative of ABMR: glomerulitis, peritubular capillaritis, transplant glomerulopathy, C4d staining along peritubular capillaries, or MLPTC. The exclusion criteria were: An active viral, bacterial, or fungal infection; an active malignant disease; pregnancy or breastfeeding; any serious medical or psychiatric illness precluding study inclusion; and participation in another clinical trial.
The result:
In the 24-month follow-up biopsy specimens, there were no variations in urine protein concentration, DSA levels, or the morphologic or molecular rejection phenotypes between the bortezomib-treated and placebo-treated groups (33 vs 42 ml/min per 1.73 m2; P=0.31). But Bortezomib has gastrointestinal and hematologic toxicity. Despite severe toxicity, our study failed to establish that bortezomib improves histologic or molecular disease characteristics or lowers DSA.
a- avoid minimization of immunosuppressive medication, especially in high-risk patients.
b- adherence to immunosuppressive medications.
c- follow up DSA post-transplant in patients with DSA positive pretransplant.
d-protocol biopsy in high immunological risk patients.
TTT: optimise the immunosuppressive medications, treatments are glucocorticoids, intravenous IVIG, and, rituximab if there is evidence of active microvascular inflammation on kidney biopsy.
Bortezomib as rescue therapy.
What is late AMR, how is it different from chronic AMR?
How do you define late AMR?
Late antibody mediated rejection is the rejection happened after the first 6 months post transplantation. According to revised Banff classification 2017 of ABMR:
The main features based on detection of donor specific antibodies (DSAs) and distinct morphologic lesions which includes microcirculation inflammation/injury and the optional finding of capillary C4d deposits. ABMR is associated with characteristic patterns of gene expression.
The aim of the randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection Trial), to investigate the effect of bortezomib on the course of late DSA-positive ABMR in terms of effect on GFR change (serial eGFR measurements at 0, 6, 12, 18, and 24 months) and on DSA levels.
The trial composed of two parts:
1-Screening part where HLA antibody screening of 741 kidney transplant recipients from total transplant number of 1165 and identified 45 patients eligible for randomization in the interventional part of the trial.
2- Interventional part: From 44 recipients 21 patients received bortezomib and 23 received placebo.
In conclusion:
As per results of the randomized trial there was no significant effect on GFR change, donor specific antibody levels, rejection phenotypes, or graft survival. Bortezomib as a single agent may not stop the progression of late rejection.
In a recent nonhuman primate model of desensitization, a short course of bortezomib failed to decrease DSA in serum, despite a considerable reduction of plasma cells. That was explained by a process of “humoral compensation” due to B cell proliferation within secondary lymphoid organs and generation of new antibody-producing cells shortly after treatment.
How would you prevent and treat late AMR?
This can be done by careful selection of suitable donor with better HLA matching. Pre transplant Screening for anti HLA antibodies and DSA and monitor for de novo DSA after transplantation. Protocol biopsies that can discover histological evidence of sub clinical rejection and management accordingly. Monitor other markers to follow graft function as change in GFR, appearance of proteinuria. induction for high immunological risk for rejection. Emphasis on patient compliance on immunosuppressions.
Treatment of documented late AMR with tissue diagnosis by optimization of immunosuppression therapy, Pulse steroids, PP,IV IG and Rituximab (the aim of treatment to clear or decrease the level of DSA and trial to prevent the new formation)
Would you like to reconsider your definition of late AMR
BROTOJECT STUDY
1. How do you define late AMR?
late mean after 1st 6m post transplantation
ABMR its pathological diagnosis based of finding of 2 or more of the following
1. microvascular inflammation (glomerulitis and peritubular capillarities)
2. TMA without other possible explanation
3. c4d deposition in peritubular capillaries
4. gene expression and molecular data
5. with circulation DSA in the serum
ABMR usually present clinically with rapid deterioration of kidney function within days or weeks with or without proteinuria.
2. Summarise the methodology and the conclusion of this study in your own words.
1165 patients had the inclusion criteria which includec6m post transplant and eGFR more than 20ml/min
DSA screening (only 741 done >398 positive with only 111 have DSA) then kidney biopsy done (86 accepted)>>>45 patients only had late ABMR
divided into 2 parallel groups study and control (19 patients was preformed DSA were divided between the 2 groups
the control group here received placebo and the other group received bortizomab only followed by valgancylovir prophlaxix
1ry end point was eGFR at the end of 24m(2y)
2 year graft survival ,DSA level ,urinary protein creatinine ratio and biopsy finding after 1year also evaluated
conclusion
according efficacy:no significant difference regarding eGFR,patient and graft survival,DSA titre(intra and inter individual difference) and biopsy scoring after 1y.
regarding safety: hospitalization ,sever adverse effect,GIT toxicity,hematological and adverse effect was more in the bortizomib armbut infection and peripheral neuropathy and malignancy was similar to control group
so bortozomib seems to be not agood option for treatment late ABMR
3. How would you prevent and treat late AMR?
prevention
· donor selection and better matching
· keep patient under good immune suppression (induction if needed ,types and doses should be tailored to each patient)
· promote adherence to treatment
· early detection by DSA screening and regular monitoring of kidney function
treatment
· 1st year post transplant :role of plasmapheresis is important + small dose IVIG(0.5gm/kg) OR high dose IVIG (2gm/kg) with or without rutiximab 500mg once after one week
· after 1st year post transplant: same plane but role of plasma exchange is lower and risks against benefits should be dicussed with the patient
reference
–uptodate-
Would you like to reconsider your definition of Late AMR. ?? ”
https://journals.lww.com/transplantjournal/fulltext/2020/05000/recommended_treatment_for_antibody_mediated.11.aspx“
How do you define late AMR?
Late refers to after 6 months in the post transplant period
AMR refers to the followings:
Methodology of the Trial.
Study Type: Randomized, Placebo Controlled Trial to assess the outcome of bortezomib on the course of late ABMR.
(Prospective, randomized, double-blind, placebo-controlled, parallel group, single-center phase 2 trial).
Data Collection:
1.Cross-sectional Screening (part A)
+ Age > 18 y/o.
+ 6 months post transplant completed.
+ eGFR > 20 ml/min/1.73 m2
2.Interventional Trial (part B)
+ Presence of HLA class I and/or II DSA.
+ Index biopsy with at least one of the following features suggestive of ABMR: glomerulitis, peritubular capillaritis,transplant
glomerulopathy, C4d staining along peritubular capillaries, or MLPTC on electron microscopy.
+ acute rejection within 1 month before screening.
+ acute deterioration of graft function suspicious of acute rejection
+ intolerance of bortezomib.
+ active infection.
+ active malignancy.
+ pregnancy or breastfeeding.
+ serious medical or psychiatric illness precluding study inclusion.
+ T cell–mediated rejection classified Banff grade .1
+ de novo or recurrent severe thrombotic microangiopathy, polyoma virus nephropathy,
de novo or recurrent GN.
+ a thrombocytopenia ,30 g/L, neutrophil count ,1 g/L,.
+ peripheral neuropathy greater than or equal to grade 2.
Data Analysis:
It was quantitative analysis, including gene expression analysis to compute molecular classifiers.
Conclusion of the Article
How would you prevent and treat late AMR?
Prevention:
Suitable pairing and matching in kidney donation.
Desensitization regimens to be used in high risk KTRs.
Good adherence to Immunosuppression medications.
Treatment:
Although difficult to treat the followings can be attempted :
MethylPred pulses, Plasmapheresis, IVIG,rATG or monoclonal antibodies.
Maintenance Immunosuppression : TAC based Immunosuppression ,MMF and Prednisolone.
https://journals.lww.com/transplantjournal/fulltext/2020/05000/recommended_treatment_for_antibody_mediated.11.aspx.
2. Would you like to reconsider your definition of late AMR after seeing this paper.
▪︎How do you define late AMR?
Late AMR is rejection that occurs 6 months post transplantation . But may occurs at any time up to years after transplantation.It
can cause graft failure.
The salient features of active AMR based on the Banff 2017 classification are
(1) histological evidence of graft injury via microvascular inflammation (MVI), intimal or transmural arteritis (v > 0), acute thrombotic microangiopathy in the absence of any other cause, or acute tubular injury in the absence of any other apparent cause;
(2) histological evidence of antibody-endothelial interactions either by C4d deposition or at least moderate MVI.
(3) the presence of circulating DSA, predominantly anti-HLA antibody .
characteristic patterns of gene expression and molecular data relevant to this type of rejection were included in the Banff classification.
▪︎Summarise the methodology and the conclusion of this study in your own words.
It is randomized, placebo-controlled trial
Aim of the study to investigate whether bortezomib can prevent GFR decline by halting the progression of late DSA positive ABMR.
44 DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years,
preformed DSA was found in 19 of them
, were randomly assigned to receive bortezomib or placebo.
The study was designed to detect a difference in the slope of eGFR measured every 6 month ( at 0,6,12,18 and 24months), a surrogate end point of long-term graft survival.
Secondary outcome parameters included the course of DSA, rejection phenotypes by protocol biopsy , and measured GFR after 2 years follow-up.
Also included gene expression analysis to compute molecular classifiers reflecting rejection and chronic transplant injury.
▪︎Conclusion
trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, with significant gastrointestinal and hematologic
toxicity.
▪︎Treatment and prevention of Late AMR
Prevention;
by proper matching of recipient and donor whenever possible;
pretransplant detection of DSA and post-transplant check for de novo DSAs in the first 3 month after that monitoring DSA has no standard protocol some studies suggested at 3 ,6 and 12 months other studies recommended screening in the early 3 months then yearly for 3 years
Induction for high risk patients
Protocol biopsy for high risk patients
Ensure adherence of recipient to IS
Treatment :
there is very little high-level evidence to support the use of any therapy
optimizing immunosuppression and supportive care, with reintroduction of steroids (if on a steroid-free regimen),
maintaining trough tacrolimus levels >5 ng/mL,
Use of MMF
optimizing medical management with focus on blood pressure, blood glucose, and lipid control are the main broad lines of treatment
Active ABMR within first year may be treated with pulse
methyleprednisolone,plasmapheresis, and IVIG with or without rituximab .
Active ABMR after one year is treated by glucocorticoids ,but plasmapheresis showed no clear effect .
Prophylaxis against viral infections especially CMV to avoid lowering IS doses
Schinstock, Carrie A. MD1; Mannon, Roslyn B.et al .Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group.
Transplantation: May 2020 – Volume 104 – Issue 5 – p 911-922
see this paper and try again to answer.
https://journals.lww.com/transplantjournal/fulltext/2020/05000/recommended_treatment_for_antibody_mediated.11.aspx
Late AMR
Can occur after the first 6 months post transplantation though it can occur any time
It indicates morphological changes of the allograft caused by antibody-mediated injury manifested by C4d deposition in the capillary basement membrane, the presence of DSA , and evidence of chronic tissue injury such as glomerular double contours compatible with transplant glomerulopathy, peritubular capillary basement membrane multilayering, interstitial fibrosis/tubular atrophy, with characteristic patterns of gene expression, and molecular data specific to this rejection were included in the Banff classification.
Methodology of this study
The study was designed as a prospective, randomized, double-blind, placebo-controlled, parallel group, single-center study to evaluate the effect of the proteasome inhibitor bortezomib on the course of late ABMR.
It was approved by the institutional ethics committee including 1165 kidney transplant recipients registered in the nephrology outpatient clinic during the screening period from October of 2013 to February of 2015
Involving in two steps (parts A and B). Part A consisted of a systematic cross-sectional rejection screening in a prevalent transplant cohort.
1076 of these recipients fulfilled the inclusion criteria and 741 patients underwent anti-HLA antibody pre screening, 398 patients had detectable HLA class I and/or II antibody reactivity and were subjected to single-antigen flow bead testing. 111 recipients were DSA positive, and 86 of them were subjected to a protocol biopsy , 25 patients did not undergo biopsy .
44 recipients fulfilled the criteria and entered the intervention trial part B in an online randomised way ,in a double blind fashion to receive two cycles of either bortezomib or placebo at 3-month intervals.
For all study participants, the protocol included predefined adjustments of baseline immunosuppression.
The patients were followed for 24 months where the primary outcome was eGFR measurements at 0, 6, 12, 18, and 24 months, calculated using the Mayo equation ,and secondary outcomes were course of anti-HLA ,DSA MFI levels , measured GFR at 0 and 24 months; urinary protein excretion at 0, 3, 6, 12, 18, and 24 months; 2-year patient and graft survival; acute rejection requiring treatment; and the results of 24-month follow-up protocol biopsies
Conclusion of this study
Bortezomib did not delay the decrease in eGFR, donor-specific antibody levels, rejection phenotypes, and did not affect long-term graft survival, despite significant toxicity
Opposing previous observational studies conclusions.
Emphasising the requirement of trials to test new therapeutic strategies for late AMR.
Treatment and Prevention of late AMR
Plasmapheresis and high-dose intravenous immunoglobulin have proved to be effective in preventing and treating AMR,
Treatment also includes tacrolimus/mycophenolic acid , intravenous Ig plus rituximab, terminal complement blockade,and interference with IL-6/IL-6 receptor signaling.
*Late ABMR is rejection that occurs commonly 6 months after transplantation .However, it occurs at any time. It is a leading cause of graft failure.
Summary of methodology :
A randomized controlled trial from October 2013 to Feb 2015.The study aimed at exploring effect of Bortizomib on ABMR with late DSA. Persons included are more than 18 years old, with eGFR more than 20 ml/min and 180 plus days after transplantation. The study fulfilled the ethical aspect Secondary outcome .Primary outcome considered change in eGFR slope as a surrogate of graft survival. Secondary outcome considered follow up of DSA ,rejection phenotypes and follow up measurement of GFR after two years.
Conclusion:
The study found that bortizomib could not prevent GFR decline ,could not improve rejection histological and molecular features, and reduce DSA .Additionally, its use was associated with gastrointestinal and hematologic side effects.
Prevention of ABMR:
includes detection of preformed DSA and de novo DSA .In case of preformed DSA ,with availability of potential living donor ,used of paired kidney donation (pkd) is better than desensitization. Some use desensitization and pkd; applied in case of positive CDC XM, strong positive FCXM. In case of positive virtual XM, or mild or moderate positive FCXM, desensitization including plasmapheresis, r ATG-thymoglobulin and Rituximab is used.In case of unavailability of potential living donor ,HLA desensitization is implemented .All patients must have induction and maintenance protocols as high risk patients
.Detection of de novo DSA targets non adherence and under immunosuppression with adjusting safety and efficacy of long term immunosuppression.
Treatment of ABMR:
aims at removing of DSA to eradicate B cells or plasma cells and detection and treatment of subclinical ABMR by surveillance biopsy .Active ABMR within first year is treated by glucocorticoids, plasmapheresis, and IVIG with or without rituximab .Active ABMR after one year is treated by glucocorticoids ,without plasmapheresis .All patients will need antimicrobial and antiviral prophylaxis .In patients responding by decrease in creatinine, use of increased TAC to achieve trough value of 20-25percent higher than the level at rejection plus monitoring of kidney function .Extended release TAC could be used in case of intolerance. All patients will need oral prednisolone .Re biopsy is needed in case of no response. Chronic ABMR is treated by glucocorticoids and IVIGwith rituximab in case of active microvascular affection .No place for either bortizomib or ecluzomib .
How do you define late AMR?
Occurring more than 6 months following transplantation .
Summarise the methodology and the conclusion of this study in your own words.
The objective of this of this study was to evaluate the effect of the proteasome inhibitor bortezomib on the course of late ABMR.
Study design was, randomized, double-blind, placebo-controlled, parallel group, single-center phase 2 trial .
Study approval was obtained from the institutional ethics committee (Medical University of Vienna) and the Austrian regulatory authority (Federal Office for Safety in Health Care, Austrian Agency for Health and Food Safety).
The study was conducted in two steps (parts A and B).
Part A ;
Part A consisted of a systematic cross-sectional rejection screening in a prevalent transplant cohort.
Study area; nephrology outpatient clinic (Medical University of Vienna).
Sample size ; 1076 recipients who fulfilled the key inclusion criteria .
The key inclusion criteria for part A; (age .18 years old, $180 days post transplantation, eGFR.20 ml/min per 1.73 m2) .
741 patients underwent anti-HLA antibody prescreening .Three hundred ninety-eight (53.7%) patients had detectable HLA class I and/or II antibody reactivity. One hundred eleven (15%) recipients were DSA positive, and 86 of them were subjected to a protocol biopsy.
Part B ; (interventional part)
Key inclusion criteria for part B were the ;
detection of HLA classI and/or II DSA
index biopsy showing at least one of the following morphologic features suggestive of ABMR: glomerulitis, peritubular capillaritis, transplant glomerulopathy, C4d staining along peritubular capillaries, or MLPTC on electron microscopy.
Exclusion criteria for part B were as follows:
biopsy-proven acute rejection within 1 month before screening;, acute deterioration of graft function , suspicious of acute rejection ,documented intolerance of bortezomib ,active viral, bacterial, or fungal infection ,active malignant disease ,pregnancy or breastfeeding ,any serious medical or psychiatric illness precluding study inclusion , participation in another clinical trial. ,T cell–mediated rejection classified Banff grade more than 1 , de novo or recurrent severe thrombotic microangiopathy ,polyoma virus nephropathy , de novo or recurrent GN , thrombocytopenia less than 30 g/L ,neutrophil countless than1 g/L ,peripheral neuropathy greater than or equal to grade 2.
Sample size of part B;
45 recipients met the eligibility criteria defined for part B and were randomized. One recipient withdrew her consent after randomization (placebo group), shortly before trial medication, and was not included in the final analysis. The remaining 44 recipients entered the intervention trial .
Randomization and Interventions
Patients eligible for part B of the study were randomized in a 1:1 ratio by computer assignment using an online randomization tool . The trial was carried out in a double-blind fashion. Therefore, study participants, care providers, and those assessing outcomes were unaware of the randomization sequence.
Patients were randomly assigned to receive two cycles of either bortezomib or placebo at 3-month intervals in double-blinded fashion. Each treatment cycle consisted of bortezomib at 1.3 mg/m2 administered intravenously twice weekly on days 1, 4, 8, and 11. For antiviral prophylaxis, bortezomib-treated patients received oral valacyclovir at 500 mg/d (eGFR,30 ml/min per 1.73 m2: 250 mg/d) for 3 weeks after initiation of each cycle.
Patients in the control group received placebo instead of bortezomib (0.9% sodium chloride solution) and instead of valacyclovir (hard gelatin capsules filled with maltodextrin).
Outcomes of the study :
The primary outcome (intention to treat analysis) was the slope of eGFR (milliliter per minute per 1.73 m2 per year) computed from eGFR measurements at 0, 6, 12, 18, and 24 months.
The Secondary outcome measures were as follows:
1-course of anti-HLADSA MFI levels measurements at 0, 3, 6, 12, 18, and 24 months.
2- measured GFR (clearance of chromium-51 ethylenediaminetetraacetic acid on the basis of the slope-intercept method49) at 0 and 24 months .
3-urinary protein excretion (protein-to-creatinine ratio; milligrams per gram; measured in spot urine) at 0, 3, 6, 12, 18, and 24 months.
4- 2-year patient and graft survival; occurrence of acute clinically overt rejection necessitating treatment.
5-the results of 24-month follow-up protocol biopsies.
Statistical Analyses;
For statistical analysis, IBM SPSS Statistics 24 (IBM Corporation, Armonk, NY), SAS for Windows (The SAS Institute Inc., Cary, NC), and the R package (www.r-project.org) were used .
Conclusion ;
The trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. The results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.
How would you prevent and treat late AMR?
Prevention ;
Improved medication adherence.
Implementation of MMF treatment is associated with reduced alloantibodies levels .
Monitoring DSA post transplantation .
Treatment ;
Late antibody –mediated rejection (ABMR) is a major cause of graft failure , for which there is no proven effective treatment .
Current therapeutic approaches are primarily on the basis of the results obtained in retrospective studies and pilot trials and include the use of tacrolimus/mycophenolic acid (MPA), intravenous Ig plus CD20 antibody rituximab, terminal complement blockade,8 and interference with IL-6/IL-6 receptor signaling. The true benefit of such therapies remains unproven, and related toxicities or high treatment costs strongly reinforce the need of systematic trials .
How do you define late AMR?
Summarise the methodology and the conclusion of this study in your own words.
How would you prevent and treat late AMR?
Risk factors for developing denovo DSA
Prevention of late ABMR
1- Use of HLA matched kidney whenever possible especially in HLA DR locus
2- Therapeutic drug monitoring monthly in the first 3 years and then every 3 months
3- Limit the of CNI minimization and mTOR based immunosuppression protocols
4- Use of CMV prophylaxis in patients who are using ATG or aggressive immunosuppressive regimens for treatment of rejection this is because activation of CMV, later on, will require under immunosuppression
5- Limit the use of ATG induction to high-risk patients to decrease the risk of infections and malignancies which will require reduction of immunosuppression with subsequent increase in the possibility of development of DSA
6- Monitoring of DSA
DSA should be monitored once in the early post-transplant period (first 3 months) in all patients
After the first 3 months, some recommend no further testing is required except in the following situations :
Some recommend assessment of DSA annually (most convenient for me to prevent late ABMR)
Some recommend measurement of DSA / 3months for first 3 years
All patients with detectable DSA should undergo renal biopsy
Treatment of late ABMR
Late AMR defined as progressive & slow graft dysfunction usually caused by non- compliance, reducing or stopping IS agents. Till now there is no consensus on the best treatment strategy of late AMR but treatment with plasmapheresis & IVIG with rituximab show little response , therefore late AMR is associated with poor graft outcome. So the prevention is better than treatment. Prevention achieved by monitoring of de novo DSA & encourage drug adherence.
Summary :
Randomized, double-blind, placebo-controlled, single center phase 2 study.
Aim: assessment the effect of bortezomib on the progression of late ABMR.
The study consist of 2 part (A & B). Part A is systemic cross sectional study aimed for rejection screening. 1165 renal transplant recipient who attend nephrology out patients clinic through 2 years are enrolled in this part & only 1076 recipients are meet inclusion criteria which include:
only 741 recipients were screened for anti-HLA Ab class I or/& class II, & 15 % had +ve DSA. The primary outcome ( for part A) was slop of GFR( eGFR at 0,6,12,18 &24 months interval)
Only 45 recipients were eligible for part B study, one patient declined participation in randomization. Patient who included in part B were had anti-HLA I&/or II DSA & confirmed rejection based on Banff criteria, while patient who excluded the following:
23patient randomized to receive bortezomib for 2 cycle with 3 months interval & valacyclovir for 3 weeks in each cycle, 21 patients randomized to receive placebo for 2 cycle with 3 months interval. The secondary outcome ( part B) include:
Conclusion of the study:
late AMR occur 3-6 or 6-12 months post transplantation ( no consensus about exact time)
How do you define late AMR?
There is no consensus on the definition of late antibody mediated rejection in terms of timing. Some articles define late rejection as more than one month after transplantation. Other studies define late AMR as months after transplantation and some more than 6 months or even one year. There is no cutoff.
Summarise the methodology and the conclusion of this study in your own words
This is a randomized controlled trial that aimed to evaluate the effect bortezomib in late ABMR in comparison to placebo control.
Study evaluated 1165 kidney transplant recipients who were registered at the nephrology outpatient clinic in Medical University Vienna from October 2013 to February 2015.
Primary outcome: the difference in the slope of eGFR as surrogate end point of graft survival.
Secondary outcome: Course of DSA, rejection phenotypes, and measured GFR after 2 years follow up.
Results
Bortezomib failed t show benefit on eGFR on followup
Treatment was associated with substantial toxicity.
No significant differences in measured GFR, urinary protein levels, DSA, or the morphologic and molecular features of disease activity in follow-up biopsies.
In conclusion there was no beneficial effect of bortezomib as a treatment for late ABMR.
How would you prevent and treat late AMR?
Because of the poor outcomes of acute rejection, regardless if clinical or subclinical, early or late, rejection should be treated to avoid long term deleterious effects on graft survival.
In patients with biopsy proven late active ABMR, treatment is combination of glucocorticoids, intravenous IVIG, and, in some patients, rituximab if there is evidence of active microvascular inflammation on kidney biopsy.
-IV methylprednisolone 300 500 mg daily for 3-5 days, followed by oral prednisone taper.
-IVIG at a dose of 100 mg/kg after each session of plasmapheresis. Followed by 500 mg/kg per day for one to two days after the final session of plasmapheresis, with a total cumulative target dose of at least 1000 mg/kg of IVIG.
– Rituximab as a single dose of 200 to 375 mg/m2 after completion of IVIG
– plasmapheresis is not performed because of the lack of evidence.
Second-line agents in patients who have failed initial therapy
Bortezomib and Eculizumab can be considered as rescue therapy, but treatment is usually individualized based on the etiology and ABMR and histological findings.
How do you define late AMR?
Late ABMR is the rejection that happen 6 months post transplantation. Mainly caused by non adherence to immunosuppressive medications and under immunosuppression leading to the formation of de novo DSA.
Summarise the methodology and the conclusion of this study in your own words.
Methodology:
Aim of the study: to evaluate the effect bortezomib on the course of late DSA positive ABMR.
Settings: nephrology outpatient clinic in Medical University Vienna from October 2013 to February 2015.
Design: randomized, placebo-controlled trial.
Inclusion criteria:
Exclusion criteria:
Ethical approval: institutional ethics committee, Austrian regulatory authority.
Patients:
1165 patients were registered during the study period.
1076 patients fulfilled the inclusion criteria
741 patients underwent HLA antibody prescreening
389 had HLA class I and/or class II reactivity
111 had DSA in the serum
86 underwent graft biopsy
45 were randomised to either either placebo or bortezomib
21 received bortezomib
23 received placebo
primary outcome: the difference in the slopE of eGFR ( surrogate end point of graft survival).
secondary outcome: course of DSA, rejection phenotypes, and measured GFR after 2 years of follow up.
Conclusion:
Bortezomib fails to prevent GFR loss, improve histological or molecular features of the disease, or reduce DSA and it was associated with GI and hematological toxicity.
How would you prevent and treat late AMR?
Prevention:
Treatment:
Treatment of late ABMR is decided according to the time period post transplantation and the level of chronicity in the biopsy and there is no treatment proven to be effective in the management of late ABMR. the studied options are:
Definition of late antibody mediated rejection:
It is the major cause of late graft loss, can be acute or chronic and characterized by presence of de novo DSA and diagnostic tissue biopsy in the form of glomerular basement membrane double contour, c4d deposition, tubulitis , or may be tubular atrophy and interstitial fibrosis.
No exact treatment for it but can be prevented by strict follow up and regular monitoring of DSA and take the issue of compliance of our mind because it is the main cause of development of late AMR.
SUMMARY:
Randomized control study was done to show the effect of Bortezomib on the course of late AMR , and its effects on DSA level, rejection, and renal function decline.
Bortezomib is first generation proteasome inhibitor FDA approved for treatment of multiple myeloma, It is anti plasma cells , it affects alloantibody response, and decrease DSA level so has a role against antibody mediated rejection.
No significant effect of bortezomib on renal function eGFR as compared to placebo, also no significant differences as regard effect on graft and patient survival.
Hospitalization rate and side effects occurrence like gastrointestinal side effects, peripheral neuropathy, and infections and malignancy are more likely with bortezomib.
More studies needed to evaluate the effect of bortezomib on DSA and graft survival.
Methods:
1- Study design and participants prospective, randomized, double-blind, placebo-controlled, parallel group, single-center phase 2 trial , aimed to evaluate the effect of the proteasome inhibitor bortezomib on the course of late ABMR.
2- Randomization and Interventions Patients eligible for the study were randomized in a 1:1 ratio by computer assignment using an online randomization tool (https://www. meduniwien.ac.at/randomizer).
3- Outcomes Patients were followed for 24 months. The primary outcome (intention to treat analysis) was the slope of eGFR (milliliter per minute per 1.73 m2 per year) computed from eGFR measurements at 0, 6, 12, 18, and 24 months. eGFR was calculated using the Mayo equation. the Secondary outcome measures were as follows: course of anti-HLA DSA MFI levels (measurements at 0, 3, 6, 12, 18, and 24 months); measured GFR (clearance of chromium-51 ethylenediaminetetraacetic acid on the basis of the slope-intercept method49) at 0 and 24 months; urinary protein excretion (protein-to-creatinine ratio; milligrams per gram; measured in spot urine) at 0, 3, 6, 12, 18, and 24 months; 2-year patient and graft survival; occurrence of acute clinically overt rejection necessitating treatment; and the results of 24-month follow-up protocol biopsies.
4- Safety Safety evaluation included a monitoring of all adverse effects and serious adverse effects that occurred throughout the 24- month study period as defined by the International Conference on Harmonization guidelines and the World Health Organization Good Clinical Practice guidelines. For grading of hematologic toxicities, we used the National Cancer Institute Common Terminology Criteria for Adverse Events as also described for an earlier cohort of patients with transplants treated with bortezomib.
5- Sample Size Calculation
6- HLA Antibody Detection LAB Screen Mixed assays
7- Transplant Biopsies Renal allograft biopsies were performed using ultrasound-guided percutaneous technique (two cores per biopsy; 16-gauge needle). Histomorphology was evaluated on formalin-fixed paraffin-embedded sections applying standard methodology.
8- Statistical Analyses.
How do you define late AMR?
Acute AMR occurring after 6 months of transplantation.
Summarise the methodology and the conclusion of this study in your own words.
Methodology-
It is a investigator-initiated, prospective, randomized, double-blind, placebo-controlled, parallel group, single-center phase 2 trial.
Aim – evaluate the effect of the proteasome inhibitor bortezomib on the course of late ABMR.
inclusion criteria for part A-
age 18 years old
> 180 days post transplantation
eGFR>20 ml/min per 1.73 m2
741 patients underwent anti-HLA antibody prescreening until patient recruitment in the intervention trial (part B) was completed.
Three hundred ninety-eight (53.7%) patients had detectable HLA class I and/or II antibody reactivity and were subjected to single-antigen flow bead testing.
One hundred eleven (15%) recipients were DSA positive, and 86 of them were subjected to a protocol biopsy.
inclusion criteria for part B –
the detection of HLA class I and/or II DSA
index biopsy showing at least one of the following morphologic features suggestive of ABMR: glomerulitis,
peritubular capillaritis,
transplant glomerulopathy,
C4d staining along peritubular capillaries, or
MLPTC on electron microscopy.
Exclusion criteria were-
biopsy-proven acute rejection within 1 month before screening;
acute deterioration of graft function suspicious of acute rejection;
documented intolerance of bortezomib, boron, or mannitol;
an active viral, bacterial, or fungal infection;
an active malignant disease;
pregnancy or breastfeeding;
any serious medical or psychiatric illness
T cell–mediated rejection classified Banff grade >1,
de novo or recurrent severe thrombotic microangiopathy,
polyoma virus nephropathy,
de novo or recurrent GN,
thrombocytopenia <30 g/L,
neutrophil count <1 g/L,
peripheral neuropathy greater than or equal to grade 2.
Intervention-
Patients eligible for part B of the study were randomized in a 1:1 ratio.
Patients were randomly assigned to receive two cycles of either bortezomib or placebo at 3-month intervals in double-blinded fashion. Each treatment cycle consisted of bortezomib at 1.3 mg/m2 administered intravenously twice weekly on days 1, 4, 8, and 11. For antiviral prophylaxis, bortezomib-treated patients received oral valacyclovir at 500 mg/d for 3 weeks after initiation of each cycle.
Patients were followed for 24 months.
primary outcome –
the slope of eGFR computed from eGFR measurements at 0, 6, 12, 18, and 24 months.
Secondary outcome-
course of anti-HLA DSA MFI levels (measurements at 0, 3, 6, 12, 18, and 24 months);
measured GFR at 0 and 24 months;
urinary protein excretion at 0, 3, 6, 12, 18, and 24 months;
2-year patient and graft survival;
occurrence of acute clinically overt rejection necessitating treatment;
results of 24-month follow-up protocol biopsies.
Conclusion –
The randomized trial was not able to show that bortezomib prevents the progression of graft dysfunction or reduces features of disease activity in late DSA-positive ABMR.
Observed increase in the number of AEs do not support the use of bortezomib in the treatment
of late ABMR.
How would you prevent and treat late AMR?
Prevention –
DSA evaluation pre transplant by Luminex SAB if DSA detected by screening beads and ATG only or ATG plus desensitisation protocols according to DSA MFI.
Maintaining CNI in the target range.
Prevent non adherence to medication by patient.
DSA monitoring post transplant.
Treatment –
Plasmapheresis
Intravenous Immunoglobulin
Rituximab
Proteasome Inhibitor
Complement Inhibition