Unlocking the roles of plasma soluble T-cell immunoglobulin and mucin domain-containing protein 3 in kidney diseases: findings from native and allograft biopsy cohorts.

Chronic kidney disease (CKD) and renal allograft failure represent escalating global health burdens characterized by progressive tissue remodeling. Although interstitial fibrosis and tubular atrophy (IF/TA) are the primary determinants of long-term prognosis, their assessment currently relies on invasive kidney biopsies, which are unsuitable for longitudinal monitoring. Here, we identify soluble T-cell immunoglobulin and mucin domain-containing protein 3 (sTIM-3) as a robust, non-invasive indicator of renal histopathology and clinical outcomes. In this multi-cohort study, we enrolled 256 kidney transplant recipients (KTRs) with allograft biopsies, 442 native CKD patients with biopsy-confirmed diagnoses, and 44 KTRs with longitudinal follow-up. Pre-biopsy plasma sTIM-3 levels were quantified by ELISA and analyzed for associations with renal function, histopathological parameters, and adverse outcomes. We found that elevated sTIM-3 levels consistently correlated with impaired renal function across diverse etiologies. Notably, post-transplantation sTIM-3 exhibited slower decline kinetics compared to estimated glomerular filtration rate (eGFR), suggesting that it may reflect active tissue remodeling rather than transient functional shifts. Histopathological analyses revealed that sTIM-3 levels increased progressively with IF/TA severity, demonstrating good discriminative capacity for moderate-to-severe fibrosis. Furthermore, in KTRs, elevated sTIM-3 predicted both allograft failure and rapid eGFR decline, with its prognostic value for the latter persisting after adjustment for eGFR and urine protein. Collectively, these findings establish sTIM-3 as a non-invasive biomarker reflecting tubulointerstitial fibrosis and adverse outcomes across diverse kidney disease settings, offering complementary information to conventional functional markers.