Urinary HSP90 as a non-invasive biomarker of active tubular injury in kidney transplant recipients: A multicenter prospective study

We previously demonstrated that serum heat shock protein 90 (HSP90) is a promising biomarker for severe acute allograft rejection involving vascular endothelial injury; however, the clinical significance of urinary HSP90 (uHSP90) remains unclear. We hypothesized that uHSP90 reflects acute T cell-mediated rejection (ATCMR), a common form of allograft rejection characterized by tubulitis. This multicenter prospective study included 262 paired urine and serum samples from 112 kidney transplant recipients, along with corresponding renal allograft biopsy specimens. uHSP90 levels were measured and normalized to urinary creatinine (uHSP90/Cr). Histopathological findings were evaluated according to the Banff (2022) classification, and HSP90 expression was assessed by immunohistochemistry. uHSP90/Cr levels were significantly elevated in conditions associated with active tubular injury, including ATCMR, calcineurin inhibitor nephropathy, and BK virus nephropathy, although they were not specific to ATCMR. uHSP90/Cr levels were significantly associated with Banff scores for interstitial inflammation, tubulitis, interstitial fibrosis, and tubular atrophy. In contrast, renal tissue HSP90 expression was significantly decreased and negatively correlated with uHSP90/Cr levels (ρ = -0.29, P < .001). uHSP90/Cr demonstrated moderate diagnostic performance for active tubular injury, with an area under the receiver operating characteristic curve of 0.713, comparable to that of β2-microglobulin and superior to that of N-acetyl-β-D-glucosaminidase. Multivariable analysis demonstrated that detectable uHSP90 was independently associated with active tubular injury (odds ratio, 4.93; 95% confidence interval, 2.21-11.00; P < .001). These findings suggest that uHSP90 may serve as a biomarker of renal allograft tubular injury, although it is not specific for allograft rejection.