Genetic causes of hypercalciuric nephrolithiasis

Abstract

Renal stone disease (nephrolithiasis) affects 3-5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. 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 disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). 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 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (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 hypercalciuria and nephrolithiasis.

Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis

“…Several of the above biochemical parameters have been implicated as predictors of renal calcifications 31 and metabolic bone disease. 32 To identify predictors in our HHRH kindreds, we first performed a univariate logistic regression analysis in individuals with all genotypes (n=133) ( Table 2).…”

“…Several genes that cause rare monogenic disorders have been associated with hypercalciuric nephrolithiasis (i.e., CLCN5, CASR, CLDN16, CLDN19, ADCY10, SLC34A1, SLC9A3R1, GLUT2, HSPG2, and FN1), 31,33 whereas variants of uromodulin and fetuin seem to be protective. 34 Some of these genes affect tubular handling of calcium and phosphate in a way that is similar to what is observed in our patients with SLC34A3/NPT2c mutations.…”

Investigação de nefrolitíase no Oeste do Paraná

“…Idiopathic hypercalciuria is a heterogeneous disorder that includes absorptive, renal and resorptive forms [29][30][31] . A hypersodic diet must be taken into account for the pathogenesis of hypercalciuria 32 .…”

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

“…Loss-of-function mutations in the human Npt2c gene have been identified as the cause of hereditary hypophosphatemic rickets with hypercalciuria and accompanying nephrolithiasis renal phosphate wasting 6,38 . In contrast, human Npt2a mutations were found to be associated with a considerably milder phenotype of osteoporosis and nephrolithiasis 39,40 .…”