Figure 640

Clinical features and molecular basis of tubular defects of Bartter's and Gitelman's syndromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiating features, Bartter's syndrome presents early in life, frequently in association with growth and mental retardation. In this syndrome, urinary concentrating ability is usually decreased, polyuria and polydipsia are present, the serum magnesium level is normal, and hypercalciuria and nephrocalcinosis are present. In contrast, Gitelman's syndrome is a milder disease presenting later in life. Patients often are asymptomatic, or they might have intermittent muscle spasms, cramps, or tetany. Urinary concentrating ability is maintained; hypocal-ciuria, renal magnesium wasting, and hypomagnesemia are almost constant features. On the basis of certain of these clinical features, it had been hypothesized that the primary tubular defects in Bartter's and Gitelman's syndromes reflect impairment in sodium reabsorption in the thick ascending limb (TAL) of the loop of Henle and the distal tubule, respectively. This hypothesis has been validated by recent genetic studies [28-31]. As illustrated here, Bartter's syndrome now has been shown to be caused by loss-of-function mutations in the loop diuretic-sensitive sodium-potassium-2chloride cotransporter (NKCC2) of the TAL (type 1 Bartter's syndrome) [28] or the apical potassium channel ROMK of the TAL (where it recycles reabsorbed potassium into the lumen for continued operation of the NKCC2 cotransporter) and the cortical collecting duct (where it mediates secretion of potassium by the principal cell) (type 2 Bartter's syndrome) [29,30]. On the other hand, Gitelman's syndrome is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal tubule [31]. Note that the distal tubule is the major site of active calcium reabsorption. Stimulation of calcium reabsorption at this site is responsible for the hypocalci-uric effect of thiazide diuretics.

For alkali gain

Eliminate source of excess alkali

Discontinue administrationof bicarbonate or its precursors.

via gastric route

For H+ loss via renal route

For H+ shift

For decreased GFR

Interrupt perpetuating mechanisms

Administer antiemetics; discontinue gastric suction; administer H blockers or H+-K+ ATPase inhibitors.

• Discontinue or decrease loop and distal diuretics; substitute with amiloride, triamterene, or spironolactone; discontinue or limit drugs with mineralo-corticoid activity.

For Cl responsive acidification defect

Potassium repletion

ECF volume repletion; renal replacement therapy

Administer NaCl and KCl

For Cl resistant acidification defect

• Adrenalectomy or other surgery, potassiuim repletion, administration of amiloride, triamterene, or spironolactone.

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