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T cell–mediated rejection in kidney transplant recipients: The end(point) is also the beginning

Advances in immunosuppression have reduced the rates and severity of clinically manifested acute T cell– mediated rejection (TCMR) in kidney transplant recipients to 5%– 15% in the first year. Lest we forget, acute TCMR remains associated with late graft dysfunction and graft loss, and elements of TCMR pathology such as the Banff iand tscores form part of emerging surrogate endpoints such as the iBOX prognostication system1 in clinical trials of novel immunosuppressive regimens.2 Treatment of acute TCMR, largely unchanged since the 1970s, consists of highdose corticosteroids and antilymphocyte globulins. Response to treatment has not been a traditional research endpoint and primarily is assessed clinically by the return of serum creatinine to baseline.3 This has led to a community thinking that acute TCMR is “a thing of the past” and not a priority in terms of novel therapeutics or management. However, analyses of surveillance biopsies in kidney transplant recipients during periods of stable allograft function have revealed an iceberg of histopathology below the tip of apparent clinical stability. Subclinical TCMR, seen in 11%– 30% of biopsies within the first year, and associated with the development of donorspecific antibodies, graft fibrosis, and graft loss,2 has a particularly devastating impact in children.4 Moreover, inflammation in areas of scarring (fibrosis), an important prognosticator of future graft loss,5 has itself emerged as a probable consequence of previous acute TCMR6 and was incorporated into the Banff classification as the entity “chronic active TCMR” in 2017.7 How, then, do we break the chain of events from acute TCMR to chronic active TCMR to eventual fibrosis and allograft loss? The first link in this chain is the detection and effective treatment of acute TCMR. Persistent inflammation, although noted on followup biopsies after TCMR,8 has not been consistently addressed as a correlate of treatment effect. In this issue, Ho et al. attempt to rectify the gap in our knowledge of the effectiveness of TCMR therapy in the modern era of tacrolimus and mycophenolic acidbased maintenance immunosuppression.9 They systematically identified and performed a metaanalysis of 12 moderatetohighquality studies (involving 1255 participants from 2004– 2019) with information on treatment interventions and posttreatment biopsies. Pulse steroids and augmented maintenance immunosuppression were the mainstays of therapy. The key finding of this analysis is that 39% of patients overall (and 54% of pediatric patients) had persistent histology of rejection (≥borderline TCMR) at 2– 9 months after treatment of ≥Banff 1A rejection. The frequency of persistent rejection histology after treatment remained stable overall even after adjustments for the severity of rejection, subclinical or clinical rejection, and varied definitions of borderline change (Banff 1997 vs. Banff 2005). We commend the authors for their painstaking work of extracting outcomes that were often a secondary focus of the included studies and, in some cases, required additional communications with the original investigators. The search strategy was peerreviewed prior to general implementation and adhered to standard guidelines for systematic reviews. Importantly, their analysis demonstrates that commonly used treatments of acute TCMR are only partially successful in resolving graft inflammation. This finding jolts us out of the complacency of using merely clinical criteria to assess resolution of acute TCMR and argues strongly for the need to define histologic criteria for remission. In finding that untreated subclinical borderline changes persisted in 61% of followup biopsies, this study strengthens the rationale for surveillance biopsies (especially in children and adolescents) as a tool for clinical management, in addition to their known utility for research into the pathogenesis and mechanisms of acute and chronic graft injury. Finally, by providing the boundaries of response to TCMR treatment in the current era of immunosuppression, the authors have created a reference for the planning of clinical trials of new therapeutic agents. Heterogeneity in TCMR therapies across studies, while limiting the specificity of the conclusions, serves as a call to action for the transplant community to establish thresholds for treatment and identify the optimal agent, dose, and duration of treatment. Additional limitations include the lack of subjects on nonCNIbased regimens, incomplete data on concomitant antibodymediated rejection and DSA, the inclusion of both indication and protocol biopsies as followup biopsies (which can introduce a bias toward detecting a higher rate of nonresolution), and variable intervals between the index and followup biopsies. The work by Ho et al. illustrates the critical need for prospective studies to evaluate treatment regimens for acute TCMR, standardize assessments of treatment adequacy, identify histological and clinical predictors of response, and analyze the quality of the response as well as any longterm sequelae. Moving acute TCMR from the end to the beginning will not only improve our understanding of how best to treat this pathology, but also allow us to redefine the role of TCMR and its response to treatment as endpoints in transplant trials.