Medullary sponge kidney (MSK) disease is a benign congenital disorder but sometimes leads to significant complications, particularly hematuria, urinary tract infection, and calcium nephrolithiasis. Three pathogenic factors including urinary stasis in the outpouchings (or cysts) of inner medullary collecting duct (IMCD), increased promoters (e.g., hypercalciuria, hyperuricosuria and hyperoxaluria) and decreased inhibitors (e.g., hypocitraturia) contribute to calcium nidus formation and eventually lithogenesis in MSK patients. Evidence of molecular stone pathogenesis in MSK is scant.