Figure 115

Bartter syndrome. Bartter syndrome is a hereditary renal functional disorder characterized by hypokalemic metabolic alkalosis, renal salt wasting with normal or low blood pressure, polyuria, and hypercalciuria. Other features include juxtaglomerular hyperplasia, secondary hyperreninemia and hyperaldosteronism, and excessive urinary excretion of prostaglandin E. It often has been noted that patients with Bartter syndrome appear as if they were chronically exposed to loop diuretics; in fact, the major differential diagnosis is with diuretic abuse. Bartter syndrome often presents with growth retardation in children, and nephrocalcinosis is common. Bartter syndrome is inherited as an autosomal recessive trait.

The speculation that this syndrome could be explained by impaired reabsorption in the loop of Henle has now been confirmed by molecular studies. R.P. Lifton's group [6-8] identified loss-of-function mutations in three genes encoding different proteins, each involved in the coordinated transport of salt in the thick ascending limb of the loop of Henle. In this nephron segment, sodium chloride is transported into the cell together with potassium by the bumet-amide-inhibitible sodium-potassium-2 chloride cotransporter (NKCC2). Recycling of potassium back to the lumen through an apical potassium channel (ROMK) allows an adequate supply of potassium for optimal activity of the NKCC2. Chloride exits the basolateral side of the cell through a voltage-gated chloride channel (ClC-Kb), and sodium is expelled separately by the sodium-potassium adenosine triphosphatase cotransporter. Inactivating mutations in NKCC2, ROMK, and ClC-Kb have been identified in patients with Bartter syndrome [6-8].

Approximately 20% of filtered calcium is reabsorbed in the thick ascending limb, and inactivation of any of these three transport proteins can lead to hypercalciuria. Nephrocalcinosis occurs in almost all patients with mutations in NKCC2 or ROMK, but it is less common in patients with a mutation in the basolateral chloride channel ClC-Kb, even though patients with chloride-channel mutations currently make up the largest reported group [8]. This interesting observation is unexplained at present. In addition, a significant number of patients with Bartter syndrome have been found to have normal coding sequences for all three of these genes, indicating that mutations in other gene(s) may explain Bartter syndrome in some patients.

In contrast, the Gitelman variant of Bartter syndrome is associated with hypocalciuria. In this respect these patients resemble people treated with thiazide diuretics. In fact, mutations have been found in the thiazide-sensitive sodium chloride cotransporter of the distal tubule [9]. Hypomagnesemia is common and often severe, and patients with Gitelman syndrome do not develop nephrocalcinosis. ATP—adenosine triphosphate. (From Simon and coworkers [8]; with permission.)

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