The kidney has several defense mechanisms to avert nephrocalcinosis by preventing intratubular crystal formation and adherence. Little is known about the fate of luminally adhered crystals. In order to study post-crystal adhesion defense mechanisms we quantified the number and morphology of crystal-containing tubules in rats at various time points following ethylene glycol administration as well as in renal biopsies of patients diagnosed with nephrocalcinosis of different etiology. In rats, nephrocalcinosis was completely cleared by epithelial overgrowth of adherent crystals, which were then translocated to the interstitium and subsequently disintegrated. These processes correlated with a low to moderate infiltration of inflammatory cells. Patients with nephrocalcinosis due either to acute phosphate nephropathy, primary hyperoxaluria, preterm birth, or transplantation also showed epithelial crystal overgrowth independent of the underlying disorder or the nature of the crystals. Our study found a quantitative association between changes in tubular and crystalline morphology and crystal clearance, demonstrating the presence of an important and active nephrocalcinosis-clearing mechanism in both rat and man.