The mechanism of hypocalciuria with NaCl cotransporter inhibition

Nat Rev Nephrol. 2011 Sep 27;7(11):669-74. doi: 10.1038/nrneph.2011.138.


Thiazide diuretics are used to prevent the recurrence of calcium-containing kidney stones. The ability of these drugs to reduce urinary calcium excretion has a key role in this process. Although studies have shown a reduction in the recurrence rate of calcium-containing stones in patients treated with thiazides, whether hypocalciuria results from increased calcium reabsorption in the proximal or distal nephron is still unclear. When extracellular fluid volume is considerably reduced, the proximal tubule is likely to have a major role in thiazide-induced hypocalciuria. This process frequently occurs when high doses of thiazides and sodium restriction are prescribed for the treatment of kidney stone disease. The distal tubule is predominantly involved in NaCl cotransporter inhibition-induced hypocalciuria when the extracellular fluid volume is not reduced, a clinical scenario observed in patients with Gitelman syndrome. In this Perspectives article, we discuss the evidence supporting the hypocalciuric effects of NaCl cotransporter inhibition in the proximal and distal nephron.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / urine
  • Calcium Metabolism Disorders / chemically induced*
  • Calcium Metabolism Disorders / urine
  • Diet, Sodium-Restricted
  • Disease Models, Animal
  • Gitelman Syndrome / metabolism
  • Humans
  • Kidney Calculi / drug therapy*
  • Kidney Calculi / prevention & control*
  • Kidney Tubules, Distal / drug effects
  • Kidney Tubules, Distal / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Mice
  • Mice, Knockout
  • Sodium Chloride Symporter Inhibitors / administration & dosage
  • Sodium Chloride Symporter Inhibitors / adverse effects*
  • Sodium-Potassium-Chloride Symporters / metabolism


  • Sodium Chloride Symporter Inhibitors
  • Sodium-Potassium-Chloride Symporters
  • Calcium