Detection of subclinical tubular injury after renal transplantation:: Comparison of urine protein analysis with allograft histopathology

Background. Tubulointerstitial injury due to rejection leads to tubular atrophy (TA)/interstitial fibrosis (IF) followed by deterioration of allograft function. This study investigated whether urinary tubular injury biomarkers can detect subclinical tubulitis found in protocol biopsies allowing for a noninvasive screening procedure. Methods. Four rigidly defined groups (stable transplants with normal tubular histology [n = 24], stable transplants with subclinical tubulitis [n = 38], patients with clinical tubulitis Ia/Ib [n = 18), and patients with other clinical tubular pathologies [n = 20]) were compared for differences in urinary intact/cleaved beta 2-microglobulin (i/c beta 2m), retinol-binding protein (RBP), neutrophil-gelatinase-associated lipocalin (NGAL), and alpha 1-microglobulin (alpha 1m). Results. Tubular proteinuria was present in 38% (RBP) to 79% (alpha 1m) of patients in the stable transplant with normal tubular histology group. The stable transplant with subclinical tubulitis group had slightly higher levels of i/c beta 2m (P=0.11), RBP (P=0.17), alpha 1m (P=0.09), and NGAL (P=0.06) than the stable transplant with normal tubular histology group with a substantial overlap. The clinical tubulitis Ia/Ib and the other clinical tubular pathology groups had significantly higher levels of RBP, NGAL, and alm than stable transplants with normal tubular histology or stable transplants with subclinical tubulitis (P<0.002). Conclusions. None of the investigated biomarkers allow for clear differentiation between stable transplants with normal tubular histology and stable transplants with subdinical tubulitis. Therefore, the protocol allograft biopsy currently remains the preferred tool to screen for subclinical tubulitis. Further longitudinal studies should determine whether tubular proteinuria in stable transplants with normal tubular histology indicates a clear risk for early development of TA/IF.