Long-term graft survival in patients with chronic antibody-mediated rejection with persistent peritubular capillaritis treated with intravenous immunoglobulin and rituximab

Abstract Background and Aims Antibody Mediated Rejection (ABMR) is a severe complication that frequently occurs after kidney transplantation. The present RCT designed to evaluate the role of adding Bortezomib to standard regimen with plasma exchange, intravenous immunoglobulin and Rituximab in treatment of AMR after kidney transplantation. Method 26 kidney transplant recipients (KTRs) with a biopsy proven diagnosis of AMR and positive DSA in a randomized clinical trial were compared: Thirteen KTRs treated with plasmapheresis, intravenous immunoglobulin and rituximab (PE-IVIG- RTX ) plus bortezomib versus 13 patients treated with standard of care regimen without bortezomib. We evaluated graft survival and DSA titer with MFI during a year after biopsy proven diagnosis. Results Statistical difference in graft survival between the two groups was noted: three out of 13 patients in the PE-IVIG-RTX group (23%) and 1/13 in the bortezomib group (7.5%) experienced loss of allograft function at a median time after diagnosis of 6 month and 12 month, respectively. DSA MFI titers 12 month after AMR diagnosis showed significant reducing slope in Bortezomib group. Regarding pathological changes micro vascular inflammation (glomerulitis + peritubular capillaritis score) reduced after PE-IVIG- RTX plus bortezomib in 7 out of 13 patients whom underwent protocol biopsies after treatment (53%) (Median score 3 in pre- treatment biopsy vs. 1 in post-treatment biopsy; P = 0.036). Conclusion Although DSA titer may not differ at 6 months after treatment of AMR between those who received standard regimen and those treated with adding Bortezomib, but at the end of one year patients treated with standard regimen plus Bortezomib reached lower MFI DSA titer. Adding Bortezomib to PE-IVIG- RTX for the treatment of AMR after kidney transplantation may enable clinicians to fight the DSA better and change the future of next generation of highly sensitized kidney transplant candidates.

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Inhibition of Terminal Complement Components in Presensitized Transplant Recipients Prevents Antibody-Mediated Rejection Leading to Long-Term Graft Survival and Accommodation

The Journal of Immunology ◽

10.4049/jimmunol.179.7.4451 ◽

2007 ◽

Vol 179 (7) ◽

pp. 4451-4463 ◽

Cited By ~ 78

Author(s):

Hao Wang ◽

Jacqueline Arp ◽

Weihua Liu ◽

Susan J. Faas ◽

Jifu Jiang ◽

...

Keyword(s):

Graft Survival ◽

Transplant Recipients ◽

Complement Components ◽

Antibody Mediated Rejection ◽

Terminal Complement

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Long-term survival of the transplanted kidney and the clinical relevance of donor-specific antibodies

Molecular and experimental biology in medicine ◽

10.33602/mebm.3.1.3 ◽

2020 ◽

Vol 3 (1) ◽

pp. 17-22

Author(s):

Eva Svobodova ◽

Sarka Valhova ◽

Ondrej Viklicky ◽

Ilja Striz ◽

Jelena Skibova ◽

...

Keyword(s):

Graft Survival ◽

Solid Phase ◽

Kidney Graft ◽

Term Survival ◽

Specific Antibodies ◽

Antibody Mediated Rejection ◽

Number Of Patients ◽

Single Antigen ◽

Donor Specific Antibodies

The aim of our study was to evaluate the relevance of donor-specific antibodies (DSA) as defined by solid-phase single-antigen (SA) assays for predicting long-term graft survival after kidney transplantation. Sera from 132 kidney transplant recipients were retrospectively tested before, 3, 6 and 12 months after transplantation. The incidence of rejection and graft survival was followed up for 7 years. We found 29 episodes of acute cellular rejection (CR), 21 cases of antibody-mediated rejection (AMR) and 18 graft failures due to immunological reasons. Pre-transplant DSA and DSA three months after transplantation correlated with an increased rate of AMR and impaired graft function. After the fourth year, recipients with persistent DSA were at a higher risk of graft failure (p = 0.0317). Antibody specificity was prevailingly to HLA class I antigens (66.6% DSA, 75% non-DSA). During the first year after transplantation, the number of patients with non-DSA decreased (30.3% to 10.7%), while, due to de novo production of antibodies, the number of DSA positive patients remained constant. Conclusion: Detection of antibodies to HLA antigens using solid-phase assays, especially single-antigen bead technology before and three months after transplantation is predictive for increased incidence of antibody-mediated rejection and impaired long-term kidney graft survival.

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Long-Term Immunosuppression Management

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.15040920 ◽

2021 ◽

pp. CJN.15040920

Author(s):

David Wojciechowski ◽

Alexander Wiseman

Keyword(s):

Graft Survival ◽

Kidney Function ◽

Calcineurin Inhibitor ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Kidney Transplant Recipients ◽

Major Barrier ◽

Antibody Mediated Rejection ◽

Maintenance Immunosuppression

The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5–8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor–based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.

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Preformed Donor-Specific HLA Antibodies in Living and Deceased Donor Transplantation

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.13401118 ◽

2019 ◽

Vol 14 (7) ◽

pp. 1056-1066 ◽

Cited By ~ 8

Author(s):

Malte Ziemann ◽

Wolfgang Altermann ◽

Katharina Angert ◽

Wolfgang Arns ◽

Anette Bachmann ◽

...

Keyword(s):

Kidney Transplantation ◽

Graft Survival ◽

Graft Loss ◽

Hazard Ratio ◽

Living Donation ◽

Hla Antibodies ◽

Transplant Survival ◽

Antibody Mediated Rejection ◽

Increased Risk

Background and objectivesThe prognostic value of preformed donor-specific HLA antibodies (DSA), which are only detectable by sensitive methods, remains controversial for kidney transplantation.Design, setting, participants, & measurementsThe outcome of 4233 consecutive kidney transplants performed between 2012 and 2015 in 18 German transplant centers was evaluated. Most centers used a stepwise pretransplant antibody screening with bead array tests and differentiation of positive samples by single antigen assays. Using these screening results, DSA against HLA-A, -B, -C, -DRB1 and -DQB1 were determined. Data on clinical outcome and possible covariates were collected retrospectively.ResultsPretransplant DSA were associated with lower overall graft survival, with a hazard ratio of 2.53 for living donation (95% confidence interval [95% CI], 1.49 to 4.29; P<0.001) and 1.59 for deceased donation (95% CI, 1.21 to 2.11; P=0.001). ABO-incompatible transplantation was associated with worse graft survival (hazard ratio, 2.09; 95% CI, 1.33 to 3.27; P=0.001) independent from DSA. There was no difference between DSA against class 1, class 2, or both. Stratification into DSA <3000 medium fluorescence intensity (MFI) and DSA ≥3000 MFI resulted in overlapping survival curves. Therefore, separate analyses were performed for 3-month and long-term graft survival. Although DSA <3000 MFI tended to be associated with both lower 3-month and long-term transplant survival in deceased donation, DSA ≥3000 MFI were only associated with worse long-term transplant survival in deceased donation. In living donation, only strong DSA were associated with reduced graft survival in the first 3 months, but both weak and strong DSA were associated with reduced long-term graft survival. A higher incidence of antibody-mediated rejection within 6 months was only associated with DSA ≥3000 MFI.ConclusionsPreformed DSA were associated with an increased risk for graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA <3000 MFI were associated with worse graft survival. This association was stronger in living than deceased donation.

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Antibody-Mediated Rejection in Kidney Transplantation: A Review

Journal of Transplantation ◽

10.1155/2012/193724 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 58

Author(s):

Chethan Puttarajappa ◽

Ron Shapiro ◽

Henkie P. Tan

Keyword(s):

Kidney Transplantation ◽

Graft Survival ◽

Management Strategies ◽

Clinical Manifestations ◽

Allograft Survival ◽

Current Management ◽

Antibody Mediated Rejection ◽

Emerging Issues

Antibody mediated rejection (AMR) poses a significant and continued challenge for long term graft survival in kidney transplantation. However, in the recent years, there has emerged an increased understanding of the varied manifestations of the antibody mediated processes in kidney transplantation. In this article, we briefly discuss the various histopathological and clinical manifestations of AMRs, along with describing the techniques and methods which have made it easier to define and diagnose these rejections. We also review the emerging issues of C4d negative AMR, its significance in long term allograft survival and provide a brief summary of the current management strategies for managing AMRs in kidney transplantation.

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Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival

Clinical and Developmental Immunology ◽

10.1155/2013/859761 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Qiquan Sun ◽

Yang Yang

Keyword(s):

Graft Survival ◽

Graft Loss ◽

Limited Effect ◽

Hla Antibodies ◽

Specific Antibodies ◽

Antibody Mediated Rejection ◽

Donor Specific Antibodies ◽

Main Barrier ◽

Lines Of Evidence

Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor-specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited effect on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival.

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Safety and effectiveness of kidney transplantation using a donation after brain death donor with acute kidney injury: a retrospective cohort study

Scientific Reports ◽

10.1038/s41598-021-84977-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kyeong Deok Kim ◽

Kyo Won Lee ◽

Sang Jin Kim ◽

Okjoo Lee ◽

Manuel Lim ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Transplantation ◽

Brain Death ◽

Graft Survival ◽

Low Dose ◽

Kidney Injury ◽

Induction Agent ◽

Donor Pool ◽

Donation After Brain Death

AbstractThe use of kidneys from donation after brain death (DBD) donors with acute kidney injury (AKI) is a strategy to expand the donor pool. The aim of this study was to evaluate how kidney transplantation (KT) from a donor with AKI affects long-term graft survival in various situations. All patients who underwent KT from DBD donors between June 2003 and April 2016 were retrospectively reviewed. The KDIGO (Kidney Disease: Improving Global Outcomes) criteria were used to classify donor AKI. The cohort included 376 donors (no AKI group, n = 117 [31.1%]; AKI group n = 259 [68.9%]). Death-censored graft survival was similar according to the presence of AKI, AKI severity, and the AKI trend (p = 0.929, p = 0.077, and p = 0.658, respectively). Patients whose donors had AKI who received using low dose (1.5 mg/kg for three days) rabbit anti-thymocyte globulin (r-ATG) as the induction agent had significantly superior death-censored graft survival compared with patients in that group who received basiliximab (p = 0.039). AKI in DBD donors did not affect long-term death-censored graft survival. Low-dose r-ATG may be considered as an induction immunosuppression in recipients receiving kidneys with AKI because it showed better graft survival than basiliximab.

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