LAUSR

In the early era of kidney transplantation, acute T cell– mediated rejection (TCMR) was the main clinical concern, significantly mitigated by potent immunosuppression since then. Today TCMR episodes are considered rare and clinically reversible but remain a key endpoint in drug trials. Although a higher risk of chronic graft damage and graft loss has been recently associated with recurring/persisting TCMR,1 our focus has shifted toward antibodymediated rejection (ABMR) as a major cause for graft loss, with TCMR becoming less of a concern.2 In this issue of the AJT, Rampersad et al. report important observations from a large cohort of patients with TCMR and serial biopsies.3 Among 775 patients, of whom 631 had biopsies performed, 30% had a first TCMR event seen in either protocol or indication biopsy, and up to 64% of these patients had either persistent or subsequent TCMR seen in later biopsies. Persistent TCMR was defined by the authors as any borderline or TCMR present on first followup biopsy within 6 months of an initial event, and subsequent TCMR as a second TCMR after an intervening normal biopsy, or any TCMR detected >6 months from the first event. Of the first TCMRs, 62% were borderline. Importantly, although already the first TCMR correlated with a higher risk of de novo DSA and deathcensored graft loss, patients with a persistent or subsequent TCMR event were at even higher risk. These findings highlight the importance of preventing and adequately treating acute TCMR to further optimize graft outcome. In addition, the authors show that alloimmune risk categories based on HLADR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events and Banff TCMR grade. Although data on the treatment of TCMR were not available in this study, common practice is that TCMR events are treated with highdose steroids,4 despite little evidence from the current era. Surprisingly little is known about the histological response of TCMR to treatment, as only a few studies have included followup biopsies after treatment. Furthermore, no consensus exists on if or when to perform a followup biopsy to evaluate any treatment responses. The data from the current study show that the treatment response is often inadequate and TCMR either persists or recurs in many patients, highlighting the need to revisit our current concepts of treating TCMR. While clinical trials primarily aim to avoid TCMR, this study defines the need for finding the optimal treatment for TCMR, including the need for appropriate followup schemes to confirm adequate treatment responses. Despite highlighting important gaps in the understanding of TCMR, there are some caveats to note. More than 40% of the first TCMR events were diagnosed in protocol biopsies and therefore subclinical, but the cohort also included 144 patients (19%) with no biopsies taken at any time point due to low immunological risk, which may have resulted in some of the milder rejection phenotypes being missed. In addition, as the decision to take a followup biopsy after TCMR was not systematic, although higher than in most centers with up to 78% of the patients with TCMR, the true prevalence of resolved TCMR is difficult to estimate as not all patients had followup biopsies. The timing of the followup biopsy was decided by clinical judgment with wide variation from a few weeks up to several months, potentially confounding the definition of persistent TCMRs. Lastly, data on treatment of the TCMR episode were not available and therefore not included in the models, potentially confounding the conclusions, as subclinical borderline TCMR may follow a different course after treatment compared to clinical TCMR in indication biopsy. Nevertheless, the study confirms that in the modern era of immunosuppression not only prevention but also timely diagnosis and treatment of acute TCMR remain important to improve longterm outcome. While the diagnosis of TCMR has long been defined by Banff consensus, no international consensus exist for standards in the treatment of TCMR and the definition of response to treatment, that is, remission of TCMR. The latter is a valid clinical trial endpoint in the oncology field, while in transplantation still the mere presence of TCMR is the endpoint. This seems counterintuitive and potentially detrimental to the clinical value of new, nextgeneration immunemodulating drugs. For example, the last regulatory approved drug in the field of transplantation, belatacept, demonstrated an increased rate of TCMR, while reducing de novo donorspecific antibodies, being associated with better allograft function, and improved overall graft survival.5 With timely diagnosis and effective treatment of TCMR, this former adverse trial endpoint may become a treatable and thus tolerable side effect, for example, of novel drugs associated with improved overall graft survival. This study of Rampersad et al. sustains that early TCMR is still harmful under modern immunosuppression protocols, especially if persistent or repeated in the context of increased eplet mismatch and consecutive de novo DSA. This finding triggers a call to action by the international transplant community to develop consensus for the effective treatment of TCMR so regulatory agencies can refine