Metabolomics in renal cystic disease: links to mechanisms and identification of pathways for potential pre-diagnosis

Polycystic kidney disease (PKD) is a common hereditary kidney disorder with an insidious onset and complex mechanisms, making early diagnosis challenging. Current diagnostic methods, including imaging and genetic testing, have limitations. Imaging detects cysts only once formed, and genetic testing is costly, labour-intensive, and unable to guarantee complete diagnostic accuracy or predict onset and progression. Metabolomics may offer an approach to uncover PKD mechanisms by detecting metabolic alterations that precede clinical manifestations, enabling identification of disease-specific biomarkers and providing earlier and more practical detection than imaging or genetic testing. This review synthesizes existing metabolomics studies of human PKD and renal cystic disease with significant metabolites extracted, and pathway enrichment analyses conducted at the levels of overall cystic kidney disease and the ADPKD /Pkd1/non-Pkd1 subsets to identify significant pathways and their associated metabolic features. Overall, the top-ranked pathways were arginine biosynthesis; alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism, and the citrate cycle, with glycine, serine and threonine metabolism only associated with ADPKD /Pkd1 mouse models. These pathways indicate marked activation of amino acid metabolism accompanied by relative suppression of carbohydrate-related energy metabolism, suggesting a shift in metabolic substrate utilization rather than a complete loss of energy supply. This study provides a foundation for applying metabolomics to early diagnosis and mechanistic investigation of cystic kidney disease.