Figure 328

Approach to hyperkalemia: low aldosterone with normal to increased plasma renin. Heparin impairs aldosterone synthesis by inhibiting the enzyme 18-hydroxylase. Despite its frequent use, heparin is rarely associated with overt hyperkalemia; this suggests that other mechanisms (eg, reduced renal potassium secretion) must be present simultaneously for hyperkalemia to manifest itself. Both angiotensin-converting enzyme inhibitors and the angiotensin type 1 receptor blockers (ATi) receptor blockers interfere with adrenal aldosterone synthesis. Generalized impairment of adrenal cortical function manifested by combined glucocor-ticoid and mineralocorticoid deficiencies are seen in Addison's disease and in defects of aldosterone biosynthesis.

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Approach to hyperkalemia: pseudohypoaldosteronism. The mechanism of decreased potassium excretion is caused either by failure to secrete potassium in the cortical collecting tubule or enhanced reabsorption of potassium in the medullary or papillary collecting tubules. Decreased secretion of potassium in the cortical and medullary collecting duct results from decreases in either apical sodium or potassium channel function or diminished basolateral Na+-K+-ATPase activity. Alternatively, potassium may be secreted normally but hyperkalemia can develop because potassium reabsorption is enhanced in the intercalated cells of the medullary collecting duct (see Fig. 3-4). The transtubule potassium gradient (TTKG) in both situations is inappropriately low and fails to normalize in response to mineralocorticoid replacement.

Mechanism of hyperkalemia in pseudohypoaldosteronism type I (PHA I). This rare autosomally transmitted disease is characterized by neonatal dehydration, failure to thrive, hyponatremia, hyperkalemia, and metabolic acidosis. Kidney and adrenal function are normal, and patients do not respond to exogenous mineralocorti-coids. Genetic mutations responsible for PHA I occur in the a and ß subunits of the amiloride-sensitive sodium channel of the collecting tubule. Frameshift or premature stop codon mutations in the cyto-plasmic amino terminal or extracellular loop of either subunit disrupt the integrity of the sodium channel and result in loss of channel activity. Failure to reabsorb sodium results in volume depletion and activation of the renin-aldosterone axis. Furthermore, since sodium reabsorption is indirectly coupled to potassium and hydrogen ion secretion, hyperkalemia and metabolic acidosis ensue. Interestingly, when mutations are introduced into the cytoplasmic carboxyl terminal, sodium channel activity is increased and Liddle's syndrome is observed [4].

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