Early acute T cell-mediated rejection and kidney allograft outcomes

Despite the prevalent notion that early acute T cell-mediated rejection (TCMR) in kidney transplant patients is clinically benign, how it responds to treatment and whether treatment responses impact long-term graft survival remain unclear and poorly characterized.

To comprehensively address this issue, we conducted an observational cohort study of all adult patients who underwent kidney transplantation between January 2013 and December 2019 across six centers in the United States and Europe. We evaluated the incidence of TCMR in the first post-transplant year, assessed clinical and histological responses to treatment, and examined their association with long-term graft outcomes.

Among 5,762 patients undergoing 9,780 biopsies, 790 (13.6%) developed TCMR. Despite treatment, 36% of patients demonstrated clinical deterioration and 32% had persistent TCMR on follow-up biopsy, indicating frequent treatment resistance. Clinical and histologic responses were frequently discordant. While only 51% of patients with clinical improvement had no rejection, 37% with clinical deterioration also showed no rejection. TCMR was significantly associated with worse graft survival (death-censored graft loss hazard ratio 2.84, 95% confidence interval 2.38-3.3). Importantly, persistent TCMR conferred a substantially higher risk of graft loss compared with responsive TCMR (3.21, 2.19-4.71) independent of clinical response and other confounders. This association was consistent across subgroups and supported by time-dependent and landmark analyses. Increasing tubulointerstitial inflammation (Banff Δ 't+i' scores) demonstrated a graded association with adverse outcomes, and trajectory analyses showed a stepwise increase in graft loss with persistent or recurrent inflammation.

TCMR is common, frequently treatment-resistant, and persistent TCMR is strongly associated with inferior long-term graft survival. Clinical improvement often failed to reflect histologic response. These findings challenge the notion that TCMR is clinically benign and identify persistent inflammation as a key driver of graft loss, underscoring the need for response guided monitoring and more effective targeted therapies.