Genetics of Hypercalciuric Nephrolithiasis

Abstract

Renal stone disease (nephrolithiasis) affects 5% of adults and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in more than 35% of patients, and may occur as a monogenic disorder, or as a polygenic trait involving 3 to 5 susceptibility loci in man and rat, respectively. Studies of monogenic forms of hypercalciuric nephrolithiasis in man, for example, Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels, and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal recessive disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) cotransporter, the renal outer-medullary potassium channel (ROMK), the voltage-gated chloride channel, CLC-Kb, or in its beta subunit, Barttin. Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis, is due to mutations of the chloride/proton antiporter, CLC-5; ADHH is associated with activating mutations of the calcium-sensing receptor, which is a G protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate cotransporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to kidney stones and bone disease.

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria

“…Patients with idiopathic hypercalciuria (IH), defined as excessive urinary calcium without a demonstrable metabolic cause, generally have normal serum calcium, normal or elevated serum 1,25-dihydroxyvitamin D3, normal or elevated serum parathyroid hormone (PTH), normal or low serum phosphate, and low bone mass. 1,4,5 IH exhibits a polygenic mode of inheritance. [4][5][6] The annual incidence of kidney stones in industrialized nations exceeds 1 per 1000 persons, with a lifetime risk of about 7% in women and about 11% in men.…”

“…1,4,5 IH exhibits a polygenic mode of inheritance. [4][5][6] The annual incidence of kidney stones in industrialized nations exceeds 1 per 1000 persons, with a lifetime risk of about 7% in women and about 11% in men. 7 After an initial episode of nephrolithiasis, approximately 60%-80% of patients form at least one recurrent stone.…”

“…39,47 Hypercalciuria is a polygenic trait in GHS rats, 44 as it is in humans. [4][5][6] When fed a standard, ample calcium diet, all GHS rats develop kidney stones, 27,28,31,32 which are composed of CaP. 27,31,33,34 Addition of hydroxyproline to the diet of GHS rats results in CaOx stone formation.…”

The Effect of Aflatoxins on Male Reproduction

“…Hypercalcemia with hypercalciuria cause the occurrence of calcium nephrolithiasis, by increasing the urinary saturation of calcium salts and by binding negatively charged inhibitors of stone formation (13,14). Between 35% and 65% of hypercalciuric stome formers and up to 70% of subjects with hypercalciuria have relatives with nephrolithiasis (15,16). Calcium stones are also associated with several monogenic mendelian traits, many of which affect ion channels and membrane transporters (16).…”

“…Between 35% and 65% of hypercalciuric stome formers and up to 70% of subjects with hypercalciuria have relatives with nephrolithiasis (15,16). Calcium stones are also associated with several monogenic mendelian traits, many of which affect ion channels and membrane transporters (16). Goodman et all concluded that stone formers have a relative risk of having abnormal calciemia and calciuria 9,18 times more than do nonstone formers (17).…”