Urinary Clusterin is a biomarker of renal epithelial senescence and predicts human kidney disease progression

Abstract

Cellular senescence drives organ fibrosis and ageing, and accumulating evidence supports the ability of senescence-depleting drugs to improve outcomes in experimental models of disease. The lack of non-invasive biomarkers represents a major obstacle to the design of human trials of candidate senolytics. On samples from 51 patients with chronic kidney disease (CKD), we performed liquid chromatography mass spectrometry (LC-MS) analysis of urine samples alongside immunofluorescence staining of paired kidney biopsies for p21, Ki67, and CD10+Pancytokeratin as senescence, proliferation and pan-epithelial cell markers respectively. Only Urinary Clusterin (uClusterin) correlated tightly with p21+ epithelial senescence in vivo (rho >0.5, p<0.001) and was upregulated in the in vitro SASP atlas. This was validated in a second cohort of matched urine and kidney samples from n=53 participants, with uClusterin predicting levels of senescence after adjusting for renal function, age and albuminuria. In spatial transcriptomic data from n=13 CKD patients, Clusterin colocalised with senescence marker CDKN1A. In a larger cohort of n=322 participants, elevated levels of uClusterin predicted CKD progression (defined as reaching ESKD or >40% reduction in renal function) after adjusting for baseline eGFR, albuminuria, age, systolic blood pressure (SBP) and sex. uClusterin levels represents a surrogate for histological quantification of p21+Ki67- senescent renal epithelia and predicts outcomes in human kidney disease independent of existing clinical risk factors.