Early Acute T Cell-Mediated Rejection and Kidney Transplant Outcomes

Background: Kidney transplant rejection can either be T cell-mediated (TCMR) or antibody-mediated. With routine use of T-cell targeted therapies for both prevention and treatment, TCMR is broadly considered clinically benign. We hypothesized that irrespective of its severity, TCMR diagnosed in the first-year post-transplantation still poses a major clinical challenge with suboptimal therapeutic response that portends premature allograft loss. Methods: We conducted an observational cohort study of all adult patients who underwent kidney transplantation between January 2013 and December 2019 at six centers in the US and Europe. We examined the prevalence of TCMR in the first-year post-transplantation, assessed clinical and histological response to treatment, and whether treatment-response influenced allograft survival. Patients routinely underwent at least 2 surveillance biopsies plus for-cause biopsy, unless there was a medical contraindication. Results: We analyzed 5828 patients with 9780 biopsies in the first-year post-transplantation, of whom 824 (14.3%) had TCMR (clinical TCMR, 55%; subclinical TCVMR, 45%). Despite treatment, 37% of patients still demonstrated clinical deterioration (seCr failed to return to within 80% of baseline) and 33% had persistent ≥1A TCMR on follow-up biopsies. This lack of therapeutic response was noted across all TCMR-grades and seen in both subclinical and clinical TCMR. While only 51% of patients with clinical improvement had complete histological resolution of rejection, 44% with clinical deterioration had persistent rejection, indicating a clinical-histological mismatch in treatment-response and highlighting the limitation of using seCr to monitor treatment response. TCMR was associated with increased seven-year graft loss (HR, 2.3; 95% CI, 1.95-2.7; p<0.001). Importantly, histological persistence was associated with increased seven-year graft loss (HR, 2.6; 95% CI, 1.8-3.8; p<0.001) compared to resolution, irrespective of TCMR-severity and independent of potential confounders and across key patient sub-groups. Conclusion: TCMR in the first-year post-kidney transplantation persists despite treatment and negatively impacts long-term allograft survival, prompting the need for closer monitoring and newer therapeutics. Funding: Other NIH Support - NIAID