A practical approach to genetic hypokalemia

Abstract

Mutations in genes encoding ion channels, transporters, exchangers, and pumps in human tissues have been increasingly reported to cause hypokalemia. Assessment of history and blood pressure as well as the K(+) excretion rate and blood acid-base status can help differentiate between acquired and inherited causes of hypokalemia. Familial periodic paralysis, Andersen's syndrome, congenital chloride-losing diarrhea, and cystic fibrosis are genetic causes of hypokalemia with low urine K(+) excretion. With respect to a high rate of K(+) excretion associated with faster Na(+) disorders (mineralocorticoid excess states), glucoricoid-remediable aldosteronism and congenital adrenal hyperplasia due to either 11β-hydroxylase and 17α-hydroxylase deficiencies in the adrenal gland, and Liddle's syndrome and apparent mineralocorticoid excess in the kidney form the genetic causes. Among slow Cl(-) disorders (normal blood pressure, low extracellular fluid volume), Bartter's and Gitelman's syndrome are most common with hypochloremic metabolic alkalosis. Renal tubular acidosis caused by mutations in the basolateral Na(+)/HCO(3) (-) cotransporter (NBC1) in the proximal tubules, apical H(+)-ATPase pump, and basolateral Cl(-)/HCO(3) (-) exchanger (anion exchanger 1, AE1) in the distal tubules and carbonic anhydroase II in both are genetic causes with hyperchloremic metabolic acidosis. Further work on genetic causes of hypokalemia will not only provide a much better understanding of the underlying mechanisms, but also set the stage for development of novel therapies in the future.

Keywords: acid-base equilibrium; aldosterone; blood pressure; genes; hypokalemia; mutation; renin; urine electrolyte.

Fig. 1

Regulation of K⁺ redistribution in cells and K⁺ secretion in the cortical collecting duct (CCD). The circle depicts the cell membrane (upper panel). Na⁺,K⁺-ATPase, Na⁺/H⁺ exchanger (NHE), and K⁺ channels are three major elements controlling K⁺ shift. Na⁺,K⁺-ATPase is activated by β₂-adrenergics, insulin and thyroid hormone. NHE, which causes the electroneutral entry of Na⁺ into cells and thus the net exit of positive voltage via the Na⁺,K⁺-ATPase, is also activated by insulin. K⁺ channels which permit K⁺ exit is responsible for generating the majority of the resting membrane potential and blocked by barium. The barrel shaped structures represent the terminal CCD (lower panel). The reabsorption of Na⁺ faster than Cl^- (right) or Cl^- slower than Na⁺ (left) in the CCD creates the lumen negative voltage that drives the net secretion of K⁺. Fast Na⁺ disorders cause extracellular fluid (ECF) volume expansion and high blood pressure, whereas, slow Cl^- disorders lead to diminished ECF volume and low to normal blood pressure. ENaC, epithelial Na⁺ channels.

Fig. 2

Algorithm for the approach to hypokalemia with a high urine [K⁺]_CCD (TTKG). CCD, cortical collecting duct; TTKG, transtubular K⁺ gradient; ECF, extracellular fluid; BP, blood pressure; RVH, right ventricular hypertrophy; AME, Apparent mineralocorticoid excess; DOC, 11-deoxycorticosterone; ACTH, adrenocorticotrophic hormone; RTA, renal tubular acidosis; GS, Gitelman's syndrome; BS, Bartter's syndrome

Fig. 3

Transport proteins in the thick ascending limb (TAL) of loop of Henle (LOH) (left panel) and distal convoluted tubule (DCT) (right panel) affected by gene mutations. Mutations that inactivate Na⁺/K⁺/2Cl^- cotransporter (NKCC2) or renal outer medullary K⁺ channel (ROMK) lead to antenatal Bartter syndrome/hyperprostaglandin E syndrome (aBS/HPS) (BS type I and II) and mutations inactivating ClCKb cause classic Bartter syndrome (cBS) (BS type III). Mutations in barttin (chloride channel βsubunit) cause antenatal BS with sensorineural deafness (BSND) (BS type IV). Mutations that activate the calcium-sensing receptors (CaSR) occur in patients with autosomal dominant hypoparathyroidism (ADH) (BS type V). Mutations inactivating Na⁺/Cl^- cotransporter (NCC) or basolateral Cl^- channel (ClC-Kb) can cause Gitelman's syndrome (GS). Mutations in Kir4.1 channel cause seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME) syndrome. ADH, anti-diuretic hormone

Fig. 4

Mechanisms for persistent hypokalemia in Gitelman's syndrome (GS). Enhanced epithelial Na⁺ channels (ENaC), renal outer medullary K⁺ channel (ROMK)1 and Maxi-K expression leads to hypokalemia (middle). High K⁺ supplement stimulates more accentuated maxi-K expression, accounting for persistent hypokalemia (left). DCT, distal convoluted tubule; CNT, cortical connecting tubules; CCD, cortical colleting duct.