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.