Antibody‐mediated rejection (ABMR) in kidney transplantation is a major cause of late graft loss, and despite all efforts to date the “standard of care” remains plasmapheresis, IVIg, and steroids, ...which itself is based on low quality evidence. This review focuses on the risk factors leading to memory and de novo donor‐specific antibody (DSA)‐associated ABMR, the optimal prevention strategies for ABMR, and advances in adjunctive and emerging therapies for ABMR. Because new agents require regulatory approval via a Phase 3 randomized control trial (RCT), an overview of progress in innovative trial design for ABMR is provided. Finally, based on the insights gained in the biology of ABMR, current knowledge gaps are identified for future research that could significantly affect our understanding of how to optimally treat ABMR.
This review details the lessons learned regarding the standard of care, emerging therapies, and requirements for innovative trial design in the battle against antibody‐mediated rejection, while in the interim strongly advocating for primary prevention strategies.
Chronic active antibody‐mediated rejection (caAMR) in kidney transplantation is a major cause of late graft loss and despite all efforts to date, there is no proven effective therapy. Indeed, the ...Transplant Society (TTS) consensus opinion called for a conservative approach optimizing baseline immunosuppression and supportive care focused on blood pressure, blood glucose, and lipid control. This review provides the rationale and early evidence in kidney transplant recipients with caAMR that supported the design of the IMAGINE study whose goal is to evaluate the potential impact of targeting the IL6/IL6R pathway.
Alloimmunity remains a barrier to long-term graft survival that necessitates lifelong immunosuppressive therapy after renal transplant. Medication nonadherence has been increasingly recognized as a ...major impediment to achieving effective immunosuppression. Electronic medication monitoring further reveals that nonadherence manifests early after transplant, although the effect is delayed. The etiology of nonadherence is multifactorial, with the strongest risk factors including past nonadherence and being an adolescent or young adult. Other risk factors with smaller but consistently important effects include minority race/ethnicity, poor social supports, and poor perceived health. In children, risk factors related to parental and child psychologic and behavioral functioning and parental distress and burden are also important. Qualitative systematic reviews highlight the need to tailor interventions to each transplant recipient's unique needs, motivations, and barriers rather than offer a one size fits all approach. To date, relatively few interventions have been studied, and most studies conducted were underpowered to allow definitive conclusions. If the kidney transplant community's goal of "one transplant for life" is to become a reality, then solutions for medication nonadherence must be found and implemented.
Understanding the events leading to allorecognition and the subsequent effector pathways engaged is key for the development of strategies to prolong graft survival. Optimizing patient outcomes will ...require 2 major advancements: (1) minimizing premature death with a functioning graft in the patients with stable graft function, and (2) maximizing graft survival by avoiding the aforementioned allorecognition. This necessitates personalized immunosuppression to avoid known metabolic side effects, risk for infection, and malignancy, while holding the alloimmune system in check. Since the beginning of transplant a key strategy to achieve this goal is to minimize HLA mismatching between donor and recipient. What has not evolved is any refinement in our evaluation of HLA relatedness between donor and recipient when HLA mismatch exists. Donor-recipient HLA mismatch at the amino acid level can now be determined. These mismatches serve as potential epitopes for de novo donor specific antibody development and correlate with late rejection and graft loss. It is in this context that HLA epitope analysis is considered as a strategy to permit safe immunosuppression minimization to improve patient outcomes through: (1) improved allocation schemes that favor donor-recipient pairs with a low HLA epitope mismatch load (especially at the class II loci) or avoiding specific epitope mismatches known to be highly immunogenic and (2) immunosuppressive minimization in patients with low epitope mismatch loads or without highly immunogenic epitope mismatches.
Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves ...precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA-DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA-DR/DQ whole antigen mismatch, HLA-DR/DQ single molecule eplet mismatch improved the correlation with de novo donor-specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell–mediated rejection (P = .0006), HLA-DR/DQ de novo donor-specific antibody development (P < .0001), antibody-mediated rejection (P < .0001), as well as all-cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA-DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.
Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II
donor-specific antibody (
DSA) ...development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before
DSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of
DSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of
DSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ
DSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before
DSA development were significantly lower than the levels >6 months before
DSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing
DSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of
DSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for
DSA may be advisable in this setting.
To date, traditional pre-transplant risk factors have failed to provide accurate risk stratification in transplantation. As a result, the practice of precision medicine remains elusive, resulting in ...a one-size-fits-all therapeutic approach for most patients. However, recent advancements in the understanding of HLA molecules at the molecular level have revitalized interest in HLA mismatch assessment. This review discusses HLA molecular mismatch as a potential prognostic and predictive biomarker available at the time of transplantation and answers some of the common questions and critiques of this approach. We highlight the retrospective data that supports single molecule risk categorization and explore the next steps required to evaluate its potential in clinical practice.
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