Metabolomic Profiling to Identify Early Urinary Biomarkers and Metabolic Pathway Alterations in Autosomal Dominant Polycystic Kidney Disease.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous fluid-filled cysts that lead to progressive loss of functional nephrons. Currently, there is an unmet need for diagnostic and prognostic indicators of early-stage ADPKD. Metabolites were extracted from the urine of early-stage ADPKD patients (n=48) and age- and sex-matched normal controls (n=47) and analyzed by liquid chromatography-mass spectrometry. Orthogonal partial least squares-discriminant analysis was employed to generate a global metabolomic profile of early ADPKD for the identification of metabolic pathway alterations and discriminatory metabolites as candidate diagnostic and prognostic biomarkers. The global metabolomic profile exhibited alterations in metabolism of steroids, fatty acids, pyruvate, amino acids, and the urea cycle. A panel of 46 metabolite features were identified as candidate diagnostic biomarkers. Notable putative identities of candidate diagnostic biomarkers for early detection include creatinine, cAMP, dCMP, various androgens, betaine aldehyde, phosphoric acid, choline, 18-hydroxycorticosterone, and cortisol. Metabolic pathways associated with variable rates of disease progression included metabolism of steroids, vitamin D3, fatty acids, amino acids, sialic acid, the pentose phosphate pathway, the tricarboxylic acid cycle, and chondroitin sulfate and heparin sulfate degradation. A panel of 41 metabolite features were identified as candidate prognostic biomarkers. Notable putative identities of candidate prognostic biomarkers include ethanolamine, C20:4 anandamide phosphate, progesterone, various androgens, betaine aldehyde, inflammatory lipids, and choline. Our exploratory data support metabolic reprogramming in early ADPKD and demonstrate the ability of mass spectrometry-based global metabolomic profiling to detect metabolic pathway alterations as new therapeutic targets and biomarkers of ADPKD.