Myra L. Chiang
Hypokalemic salt-losing tubulopathies comprise a set of clinically and genetically distinct inherited renal disorders previously summarized under the designation Bartter syndrome (BS). Recent identification of mutations in four renal membrane proteins involved in electrolyte reabsorption have made it possible to distinguish various subtypes of BS and the closely related Gitelman syndrome (GS), all of which follow autosomal recessive inheritance and share characteristic clinical features: renal salt wasting, hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure.
TABLE 338.1. CLINICAL MANIFESTATIONS OF BARTTER SYNDROME AND GITELMAN SYNDROME
Active sodium chloride transport in the thick ascending limb of the loop of Henle requires the integrated function of different transporters and ion channels, namely the loop diuretic–sensitive sodium-potassium-chloride cotransporter (NKCC2) that allows sodium chloride entry into the tubular cells; the renal outer medullary potassium channels (ROMK) that permit reabsorbed potassium to leak back into the lumen; and the basolateral chloride channels (ClC-K) that permit the chloride that has entered the cell to exit and return to systemic circulation. Abnormalities in any of the three transporters result in impairment of sodium chloride reabsorption in the thick ascending limb, leading to volume depletion and activation of the renin-angiotensin-aldosterone system. The combination of increased sodium chloride in the distal tubule and hyperaldosteronism enhances secretion of potassium and hydrogen ion at the collecting tubules, leading to hypokalemia and metabolic alkalosis. Hypokalemia and volume contraction, in turn, stimulates the synthesis of vasodilator prostaglandins, which directly stimulates release of renin and synthesis of aldosterone, thereby exacerbating loss of potassium in the urine. The induced hypokalemia, along with the decreased medullary hypertonicity from the decreased reabsorption of sodium chloride in the ascending limb, explains the abnormal concentrating capacity seen in this disorder.