Metabolic Insights into Cystic Fluid Composition and Pathogenesis in Polycystic Kidney Disease

Polycystic kidney disease (PKD) is a genetic disorder caused by mutations in the PKD1 or PKD2 genes, leading to autosomal dominant PKD (ADPKD), the most common inherited kidney disease. The disease is characterized by the formation of large, fluid-filled cysts in the kidneys, which often progresses to renal failure. Analyzing the composition of the cystic fluids (CF) could provide valuable insights into mechanisms underlying cyst development and disease progression. In this study, we utilized samples from the MUSC Kidney Translational Research Center (KTRC) and the Weill Cornell Medicine serum and CF library. The samples were obtained from male and female patients diagnosed with ADPKD, and benign cystic fluids were obtained from healthy discarded transplant kidneys (CF vs. benign; n ≥ 6 patients per sex for ADPKD, and n = 4 patients for benign groups). Metabolomic profiling revealed 72 significantly altered metabolites in CF compared to benign fluid: 47 metabolites were upregulated and 14 were downregulated, including purine cycle metabolites inosine, hypoxanthine, and histamine. Serum metabolomics of ADPKD patients highlighted an increase in amino acid (AA) profiles compared to benign cyst patients, with marked upregulation of taurine, glutamine, cysteine, ornithine, and citrulline. Additionally, the purine salvage pathway was strongly activated in ADPKD, as evidenced by elevated inosine, adenosine monophosphate, and xanthosine levels. While no significant differences in plasma metabolites were observed between male and female ADPKD patients, CF metabolomic profiles were influenced by biological sex. In a separate cohort of CF samples from ADPKD patients (n = 6 per sex), we measured taurine concentrations, osmolality, and Na + , K + , and phosphate (Pi) levels. Following classical ADPKD studies, cysts were classified as proximal (non-gradient, high Na + /low K + ) or distal (gradient, low Na + /high K + ). We had 9 proximal (5F, 4M) and 3 distal cysts (1F, 2M). Distal cysts K + concentrations were 24.1, 26.8, and 34 mM, Na + concentrations were 5.9, 11.9, and 2.5 mM, and Pi concentrations were 21.4, 8.2, and 9.27 mM). The average proximal cysts concentrations were 2.7±0.3 mM K + , 165±3.9 mM Na + , and 1.56±0.05 mM Pi. No sex-specific differences were observed in ion concentrations or osmolality (average: 310 ± 2.8 mOsms). Taurine concentrations averaged 3.3 ± 0.6 ng/mL in proximal cysts and ranged from 3.15 to 7.61 ng/mL in distal cysts. These findings provide a foundational characterization of CF metabolism in PKD, highlighting dysregulated pathways associated with disease pathogenesis. This work may inform dietary recommendations and identify therapeutic targets, particularly within purinergic and amino acid signaling pathways. R00HL153686, R01DK126720, U24DK126110 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.