Association of Baseline Urinary Metabolic Biomarkers with ADPKD Severity in TAME-PKD Clinical Trial Participants

Background: Recent work suggests that dysregulated cellular metabolism may play a key role in autosomal dominant polycystic kidney disease (ADPKD) pathogenesis. The TAME-PKD clinical trial is testing the safety, tolerability and efficacy of metformin, a regulator of cell metabolism, in ADPKD patients. This study investigates the cross-sectional association of urinary metabolic biomarkers with ADPKD severity among TAME-PKD trial participants at baseline. Methods: Concentrations of total protein, targeted metabolites (lactate, pyruvate, succinate, and cAMP), and key glycolytic enzymes (pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1)) were measured by ELISA, enzymatic assays and immunoblotting in baseline urine specimens of 95 TAME-PKD participants. These analytes, normalized by urinary creatinine or osmolality to estimate excretion, were correlated with patients9 baseline height-adjusted total kidney volumes (htTKV) by MRI and estimated GFR (eGFR). Additional analyses were performed adjusting for participants9 age and sex using multivariable linear regression. Results: Greater htTKV correlated with lower eGFR (r=-0.385; P=0.0001). Urinary protein excretion modestly correlated with eGFR (negatively) and htTKV (positively). Urinary cAMP normalized to creatinine positively correlated with eGFR. Among glycolytic enzymes, PKM2 and LDHA excretion positively correlated with htTKV, while PKM2 excretion negatively correlated with eGFR. These associations remained significant after adjustments for age and sex. Moreover, in adjusted models succinate excretion was positively associated with eGFR, and protein excretion more strongly associated with both eGFR and htTKV in patients