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.