Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation

Abstract

The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability—and ambiguity—in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.

Randomized Trial to Assess the Clinical Utility of Renal Allograft Monitoring by Urine CXCL10 Chemokine

“…The clinical relevance of borderline changes is still debated and thus might be a problematic trial end point. 50 Advantages of this study are the broad inclusion criteria reflecting a real-life population and the high compliance with the study protocol including 1-year surveillance biopsies. However, there are also some limitations such as the singlecenter design and the reduced biomarker assessment density (i.e., months 1, 3, and 6).…”

Urine CXCL10 as a biomarker in kidney transplantation

“…classification. The clinical relevance of borderline changes is still debated and thus might be a problematic trial endpoint [42]. Thus, further studies including multicenter studies are warranted to characterize the clinical utility of urine CXCL10 monitoring in kidney transplantation.…”

Rationale for Surrogate Endpoints and Conditional Marketing Authorization of New Therapies for Kidney Transplantation

“…The incidence of acute cellular (i.e., T cell-mediated [TCMR]) rejection in the early months after transplantation is ∼10% and rarely leads to immediate graft loss if treated appropriately, but TCMR is also an important, relevant, risk factor for long-term graft loss ( 10 ). Chronic TCMR has been described as a pathological entity and seems associated with impaired outcome, but its true prevalence and importance remain poorly defined ( 4 , 44 ). By contrast, AMR diagnosis—and individual parameters of AMR—clearly show detrimental long-term effects on the graft ( 3 , 10 ).…”

“…ESOT sees different options for this conversion of CMA to full marketing authorization. For example, applicants could consider requests for full marketing authorization based on long-term registration studies with accepted primary endpoints relating to graft rejection ( 2 – 4 ) function ( 5 ) and/or graft failure. Applicants could also consider requesting full marketing authorization based on comprehensive high-quality evidence from open-label study data, comparing findings to appropriate historic controls.…”

“…CMA applications based on clinical trials using surrogate endpoints should not replace full marketing authorization applications based on studies using accepted primary endpoints. As discussed elsewhere in this Special Issue, graft rejection is acceptable as a primary endpoint for obtaining full marketing authorization by the EMA, because graft rejection is considered directly clinically meaningful, requiring therapies for rejection ( 2 – 4 ). Kidney function (incidence of end-stage renal disease, proportional decrease in eGFR, and annual decrease in eGFR—slope) is also well accepted by the EMA/CHMP as a primary endpoint to assess efficacy of medicinal products to slow progression of chronic renal insufficiency in chronic kidney disease.…”