Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Abstract

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Adequate tacrolimus exposure modulates the impact of HLA class II molecular mismatch: a validation study in an American cohort

“…We did not have sufficient histologic data to fully evaluate T cell–mediated rejection in this cohort. However, Wiebe et al found the same molecular mismatch categories used in this study significantly correlated with Banff borderline, Banff ≥IA, and Banff ≥IB T cell–mediated rejection free survival, providing further evidence for their alloimmune basis 15 . Additionally, the number of recurrent T cell–mediated rejections increased significantly with each grade of risk category.…”

Early surveillance biopsy utilization and management of pediatric renal allograft acute T cell–mediated rejection in Canadian centers: Observations from the PROBE multicenter cohort study

“…One exception is a recent evaluation of isolated tubulitis, which did not support the utility of treatment and similar survival to those without tubulitis, 34 and in this study, we explicitly considered this separately as well. A recent report by Wiebe et al, affirms that borderline‐grade rejection is associated with a more than 2‐fold increased hazard for graft failure, and established that HLA DR/DQ mismatch with the donor kidney is important in its pathogenesis 35 . Treatment of Banff borderline changes may be considered as similar to Banff 1A, but are not typically reported in any detail.…”

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation

“…Moreover, the appearance of Human Leukocyte Antigen (HLA) DR/DQ DSA, which associates with worse graft survival, 26,34 frequently accompanied Borderline TCMR 22 . Together with evidence that Borderline TCMR correlates with the degree of HLA DR/DQ molecular mismatch, is linked to subsequent Banff ≥IA TCMR and/or DSA development, and is associated with allograft loss, 34,35 the aggregate evidence supports including Borderline TCMR in a conservative definition of BPAR.…”

“…In the CNI withdrawal RCTs, Borderline TCMR was included in the DSMB’s decision to halt the trials—the DSMB conservatively considered Borderline TCMR after an immune quiescent biopsy to represent loss of control of the primary alloimmune response 22,23 . Moreover, the appearance of Human Leukocyte Antigen (HLA) DR/DQ DSA, which associates with worse graft survival, 26,34 frequently accompanied Borderline TCMR 22 . Together with evidence that Borderline TCMR correlates with the degree of HLA DR/DQ molecular mismatch, is linked to subsequent Banff ≥IA TCMR and/or DSA development, and is associated with allograft loss, 34,35 the aggregate evidence supports including Borderline TCMR in a conservative definition of BPAR.…”