Potassium (K(+)) ions are the predominant intracellular cations. K(+) homeostasis depends on external balance (dietary intake [typically 100 mmol per day] versus excretion [95% via the kidney; 5% via the colon]) and internal balance (the distribution of K(+) between intracellular and extracellular fluid compartments). The uneven distribution of K(+) across cell membranes means that a mere 1% shift in its distribution can cause a 50% change in plasma K(+) concentration. Hormonal mechanisms (involving insulin, β-adrenergic agonists and aldosterone) modulate K(+) distribution by promoting rapid transfer of K(+) across the plasma membrane. Extrarenal K(+) losses from the body are usually small, but can be marked in individuals with chronic diarrhea, severe burns or prolonged sweating. Under normal circumstances, the kidney's distal nephron secretes K(+) and determines final urinary excretion. In patients with hypokalemia (plasma K(+) concentration <3.5 mmol/l), after the exclusion of extrarenal causes, alterations in sodium ion delivery to the distal nephron, mineralocorticoid status, or a specific inherited or acquired defect in distal nephron function (each of which affects distal nephron K(+) secretion), should be considered. Clinical management of hypokalemia should establish the underlying cause and alleviate the primary disorder. This Review aims to inform clinicians about the pathophysiology and appropriate treatment for hypokalemia.

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The epithelial sodium channel (ENaC) plays a major role in the regulation of sodium balance and BP by controlling Na ϩ reabsorption along the renal distal tubule and collecting duct (CD). ENaC activity is affected by extracellular nucleotides acting on P2 receptors (P2R); however, there remain uncertainties over the P2R subtype(s) involved, the molecular mechanism(s) responsible, and their physiologic role. This study investigated the relationship between apical P2R and ENaC activity by assessing the effects of P2R agonists on amiloride-sensitive current in the rat CD. Using whole-cell patch clamp of principal cells of split-open CD from Na ϩ -restricted rats, in combination with immunohistochemistry and real-time PCR, we found that activation of metabotropic P2R (most likely the P2Y 2 and/or 4 subtype), via phospholipase C, inhibited ENaC activity. In addition, activation of ionotropic P2R (most likely the P2X 4 and/or 4/6 subtype), via phosphatidylinositol-3 kinase, either inhibited or potentiated ENaC activity, depending on the extracellular Na ϩ concentration; therefore, it is proposed that P2X 4 and/or 4/6 receptors might function as apical Na ϩ sensors responsible for local regulation of ENaC activity in the CD and could thereby help to regulate Na ϩ balance and systemic BP.

Distal renal tubular acidosis (RTA) can lead to rickets in children or osteomalacia in adults if undetected. This disorder is normally diagnosed by means of an oral ammonium chloride-loading test; however, the procedure often leads to vomiting and abandonment of the test. In this study, we assess an alternative, more palatable approach to test urinary acidification. This was achieved by the simultaneous oral administration of the diuretic furosemide and the mineralocorticoid fludrocortisone to increase distal tubular sodium delivery, principal cell sodium reabsorption, and alpha-intercalated cell proton secretion. We evaluated 11 control subjects and 10 patients with known distal RTA by giving oral ammonium chloride or furosemide/fludrocortisone in random order on separate days. One control and two patients were unable to complete the study owing to vomiting after NH4Cl; however, there were no adverse effects with the furosemide/fludrocortisone treatment. The urine pH decreased to less than 5.3 in the controls with both tests, whereas none of the patients was able to lower the urine pH below 5.3 with either test. We conclude that the simultaneous administration of furosemide and fludrocortisone provides an easy, effective, and well-tolerated alternative to the standard ammonium chloride urinary acidification test for the diagnosis of distal RTA.