Pathogenesis of primary hypercalciuria

Hypercalciuria may be classified into absorptive, renal and resorptive forms, depending on whether the primary defect is intestinal hyperabsorption of calcium, renal leak of calcium, or excessive bone resorption. In absorptive hypercalciuria, the pathogenetic role of vitamin D is uncertain, and mutations in the chloride channel may occur mainly in association with Dent’s disease. Early studies suggest that a new soluble adenylyl cyclase (A H R A C) may be etiologically important in this condition, since base changes in this gene occur much more frequently and are directly correlated with intestinal calcium absorption. The distal nephron is the site of reabsorption of the final 20% of filtered calcium. The transcellular reabsorption of calcium begins with a passive entry of Ca2 + through apical calcium channels, followed by diffusion through cytosol and active extrusion across the basolateral membrane. Calcium transport in the nephron is regulated by luminal pH, calcitriol, estrogen, parathyroid hormone, prostaglandin E2, and sodium load. A biochemical picture of renal hypercalciuria may be produced by acid load from dietary animal proteins, prostaglandin E2 excess, sodium load, hypoparathyroidism, and estrogen deficiency. So far, mutations in apical calcium channel have not been found. The hallmark of resorptive hypercalciuria is primary hyperparathyroidism. Bone loss often accompanies absorptive hypercalciuria. A H R A C may be implicated, since base changes in this gene are inversely correlated with spinal bone density. Dietary acid load from high animal protein diet may cause hypercalciuria, in part by stimulating bone loss.