Autosomal Dominant Polycystic Kidney Disease: Genetic Insights, Phenotypic Spectrum, and Advances in Prognosis and...

Autosomal dominant polycystic kidney disease is a leading cause of inherited kidney failure, primarily due to pathogenic variants in PKD1 (80%) and PKD2 (15%), with rare contributions from genes like GANAB and DNAJB11. This review summarizes the understanding of autosomal dominant polycystic kidney disease's genetic and phenotypic diversity, emphasizing genotype-phenotype correlations that influence disease severity and progression. Truncating PKD1 variants are linked to earlier kidney failure (median onset in the fifth to sixth decade) and a faster estimated glomerular filtration rate decline (-4.7 to -1.44 mL/min/1.73 m²/year) than nontruncating variants or PKD2 variants. Atypical presentations, such as nonenlarged kidneys and absent family history, often relate to phenocopy genes or cases with no mutation detected, exhibiting milder phenotypes. Prognostic tools, such as the Mayo Imaging Classification and the Predicting Renal Outcomes in autosomal dominant polycystic kidney disease score, use height-adjusted total kidney volume in conjunction with clinical and genetic data to assess progression risk. Tolvaptan, the only disease-modifying therapy, slows total kidney volume growth and estimated glomerular filtration rate decline in rapidly progressing cases, although it may have adverse effects. Emerging therapies, like metformin and sodium-glucose co-transporter 2 inhibitors, are under investigation. This review highlights the importance of integrating genetic, imaging, and clinical data for personalized management of autosomal dominant polycystic kidney disease.