Introduction: In kidney transplant patients (KTPs), renal function evaluation by seCr is the current gold standard for monitoring response to anti-rejection therapy. How changes in seCr reflect histological response, and whether follow-up histological evaluation adds prognostic value to clinical assessment by seCr is unknown.
Methods: To address this question, we conducted an observational cohort study of KTPs transplanted between 2013 and 2019 at six centers in Europe and USA (Basel, Barcelona, Vienna, Lyon, Leuven & Pittsburgh) and assessed the relationship between Δ serum creatinine (from nadir level pre-index biopsy (Bx) to 6mos post-treatment), follow-up allograft histology and 7-yr graft survival in KTPs with TCMR diagnosed in the first post-transplant year. Patients at all the centers underwent two protocol Bxs at 3mos and 12mos in addition to for-cause Bx.
Results: We analyzed 8740 Bxs from 5316 KTPs, of whom 818 (15.4%) had TCMR (47% Banff 1A, 19% 1B, 34% ≥2/mixed TCMR/ABMR) in the 1st post-transplant year. Of these, 73% had at least one follow-up Bx within a year of TCMR diagnosis allowing assessment of histological resolution. Irrespective of TCMR-grade, only 47% of patients exhibited clinical improvement (seCr improvement to ≤15% of nadir) despite anti-rejection therapy. Similarly, only 39% of KTPs had complete histological TCMR-resolution (34% had partial resolution), whereas 27% had persistent TCMR at same/worse grade despite therapy (Fig 1A). Strikingly, TCMR was persistent in 35% of patiets with the mild-1A  TCMR, suggesting that histological persistence was not related to rejection severity on index Bx. Only 24% of patients with clinical improvement demonstrated full histological resolution, while 27% had persistent TCMR despite clinical improvement. In contrast, 63% of patients without clinical improvement demonstrated either complete or partial histological resolution, suggesting a clinical-histological mismatch (Fig 1B). Irrespective of index-histological grade and independent of potential confounders, early histological persistence was associated with significantly worse 7-yr-late AR-free survival and 7-yr-death-censored graft survival. Lack of clinical resolution was associated with significantly worse late AR-free survival or graft survival only when there was early histological persistence of TCMR (Figs C&D).
Conclusions: Histological evaluation by follow-up allograft biopsies  provides valuable prognostic information after TCMR diagnosis and should be considered in routine clinical practice.