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.

Fig. 1

Suggested algorithm for the investigation of a child with hypercalciuria and nephrolithiasis/nephrocalcinosis, based initially on measurements of plasma calcium and PTH. For the hypocalcemic patient, hypoparathyroidism in this context, i.e. in association with hypercalciuria, is rare and is included here for completeness. One study of 85 patients with hypoparathyroidism and 15 ADHH patients has shown that prior to their treatment with vitamin D to correct the hypocalcemia, the urinary calcium/creatinine ratio in ADHH patients was generally higher than that found in patients with hypoparathyroidism, although there was an overlap [94]. Following treatment with vitamin D, the urinary calcium/creatinine ratios in ADHH and hypoparathyroid patients were similar [94]. Hence, it may be difficult for patients with hypoparathyroidism to be distinguished from those with ADHH on the sole basis of urinary calcium excretion evaluations [94]