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Polycystic kidney disease (PKD) is a monogenic disease affecting nearly 1:400 individuals, characterized by the accumulation of large, fluid-filled cysts that slowly replace healthy tissue until organ failure. These cystic cells also exhibit altered cellular metabolism favoring primarily glucose. The slow-onset of PKD implies environmental factors as causative agents for cyst growth with diet appearing to strongly effect PKD outcome as PKD patients suffer more frequently from metabolic disease and nephrolithiasis. By using an evolutionary perspective, we identified potential dietary causes of cyst growth and interventions for the treatment of PKD. Previously our lab found that caloric restriction effectively reduced disease progression in a rodent model of PKD and recently, we found that both a ketogenic diet and time restricted feeding reduce disease severity. Additionally, we discovered an evolutionarily conserved mechanism for the normal clearance of kidney microcrystals which appears to be aberrantly activated in PKD leading to cyst growth.