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Hypokalemia-induced kidney dysfunction

Hypokalemia-induced kidney dysfunction
Literature review current through: Sep 2023.
This topic last updated: Aug 31, 2023.

INTRODUCTION — Hypokalemia, especially if persistent, can induce a variety of changes in kidney function, impairing tubular transport and possibly inducing chronic tubulointerstitial disease and cyst formation [1-7]. One function that is not impaired is the ability to appropriately conserve potassium, which can be important in distinguishing between extrarenal and renal sources of potassium loss when the cause of hypokalemia is not clear [4]. (See 'Renal potassium conservation' below and "Evaluation of the adult patient with hypokalemia", section on 'Assessment of urinary potassium excretion'.)

KIDNEY DYSFUNCTION — The following kidney abnormalities, most of which are reversible with potassium repletion, can be induced by hypokalemia [3]:

Impaired urinary concentrating ability

Intracellular acidosis

Increased ammonia production

Increased bicarbonate reabsorption

Altered sodium reabsorption

Hypokalemic nephropathy

Impaired urinary concentrating ability — Chronic hypokalemia (plasma potassium concentration usually ≤3 mEq/L) can lead to a modest reduction in urinary concentrating ability. The magnitude of the concentrating defect was evaluated in a study in which hypokalemia was induced by a low-potassium diet (0.1 mEq/kg per day) in nine men [8]. The maximum urine osmolality fell from a mean of 1140 mosmol/kg at baseline to 328 mosmol/kg at four weeks despite the administration of exogenous vasopressin. Most of the reduction in concentrating ability occurred in the first two weeks. The ability to excrete a dilute urine was not impaired.

The concentrating defect induced by hypokalemia is associated with decreased collecting tubule responsiveness to antidiuretic hormone (ie, arginine vasopressin resistance, formerly called nephrogenic diabetes insipidus). Two factors that play at least a contributory role are decreased expression of aquaporin-2, the water channel that fuses with the luminal membrane under the influence of antidiuretic hormone [9], and decreased activity of Na-K-2Cl cotransporter in the thick ascending limb, which plays a central role in generating the countercurrent gradient [10,11]. The reduction in aquaporin-2 is an early event that is likely caused by autophagic degradation of the channel [12]. Because of sexual dimorphism in kidney potassium handling, females are more prone to develop hypokalemia-induced vasopressin resistance [13]. (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Clinical manifestations and causes", section on 'Hypokalemia'.)

Patients with hypokalemia may complain of polyuria and polydipsia. However, as illustrated by the above observations, the concentrating defect is not usually severe enough to account for these symptoms. Studies in animals suggest that potassium depletion also stimulates thirst [14].

Intracellular acidosis — The development of hypokalemia and potassium depletion causes potassium to exit from cells and this net outward movement of cations is generally counterbalanced by a movement of protons into cells. The net effect is intracellular acidosis and some degree of extracellular alkalosis. The development of intracellular acidosis within renal tubular cells has several effects described below.

Increased ammonia production — Hypokalemia increases renal tubular production of ammonia, which then enters both the tubular lumen and the peritubular capillary [15]. This effect is partially related to intracellular acidosis within renal tubular cells (described above), which increases the production of ammonia from glutamine [16], a process that is appropriate when the intracellular acidosis occurs in the setting of metabolic acidosis [15,17]. The hypokalemia-induced increase in ammonia entry into the renal vein may be clinically important in patients with advanced cirrhosis, possibly precipitating hepatic encephalopathy [3,18,19]. (See "Hepatic encephalopathy in adults: Treatment", section on 'Commonly used treatments'.)

Increased bicarbonate reabsorption — The intracellular acidosis induced by hypokalemia promotes increased secretion of hydrogen ions, which can react with luminal bicarbonate, leading to bicarbonate reclamation or to urinary buffers such as ammonia to produce ammonium. This increase in hydrogen ion secretion increases net bicarbonate reabsorption and can contribute to the maintenance of a metabolic alkalosis since it prevents the excretion of the excess bicarbonate in the urine [20]. (See "Pathogenesis of metabolic alkalosis", section on 'Hypokalemia'.)

Increased sodium reabsorption — Mild to moderate hypokalemia can impair the ability to excrete a sodium load by increasing sodium reabsorption in the proximal and distal tubules [1,10]. In the proximal tubule, hypokalemia-induced intracellular acidosis (described above) may stimulate the Na-H exchanger in the luminal membrane [1,10]. This will act to restore a normal intracellular pH and simultaneously enhance sodium reabsorption. In the distal convoluted tubule, a low plasma potassium is sensed by the basolateral Kir4.1/Kir5.1 potassium channels, which in turn reduces the intracellular chloride concentration and activates with-no-lysine (WNK) kinases and the sodium-chloride cotransporter [21,22]. The resulting sodium retention produces volume expansion and can modestly elevate the blood pressure (up to 5 mmHg), an effect that may be important in patients with hypertension [23]. (See "Potassium and hypertension".)

However, an opposite effect may occur with severe hypokalemia (plasma potassium concentration usually below 2 mEq/L). In this setting, maximum sodium chloride reabsorption is impaired, resulting in an inability to lower the urine chloride concentration below 15 mEq/L in the presence of volume depletion [24]. The mechanism by which this occurs is unclear, but diminished reabsorption in the loop of Henle and collecting tubules appear to play at least a contributory role [11]. As noted above, reduced loop of Henle reabsorption also contributes to the concentrating defect induced by hypokalemia. (See 'Impaired urinary concentrating ability' above.)

Hypokalemic nephropathy — Chronic potassium depletion in humans produces characteristic although nonspecific vacuolar lesions in the epithelial cells in the proximal tubule and occasionally the distal tubule [2,4,7]. Another phenomenon is the presence of so-called "WNK bodies" in the distal convoluted tubule, which are punctate, membraneless structures in the cytoplasm [25].

The pathogenesis of these changes is not well understood. One hypothesis that has been documented in experimental animals is that the hypokalemia-induced increase in renal ammonium production described above results in ammonia accumulation in the interstitium [26]. This ammonia can activate complement, which may then damage the tubular cells. The associated intracellular acidosis is a stimulus for cell growth that could account for the cellular proliferation required for cyst formation [27].

Another possible explanation for kidney injury is alterations in growth factors and cytokines in response to hypokalemia. These include vascular endothelial growth factor, insulin growth factor-I, insulin growth factor binding protein-1, angiotensin II, monocyte chemoattractant protein-1, and/or transforming growth factor-beta [28-30].

Hypokalemic nephropathy generally requires at least one month to develop and is readily reversible with potassium repletion. However, prolonged hypokalemia (as with surreptitious diuretic use, eating disorders, laxative abuse, or primary aldosteronism) can lead to more severe changes, including interstitial nephritis and fibrosis, tubular atrophy, and cyst formation that is most prominent in the renal medulla [5-7,31-33]. Correction of the hypokalemia can lead to a decrease in the number and size of cysts although the tubulointerstitial lesions and associated kidney function impairment may be irreversible [5,6]. Acute kidney injury at least in part induced by hypokalemia has also been described [34,35]. Observational studies have shown that low urinary potassium excretion (as proxy for dietary intake) is associated with progression of chronic kidney disease [36,37]. This suggests that kidney injury secondary to a low-potassium diet or hypokalemia may contribute more generally to the pathogenesis and progression of chronic kidney disease [38].

RENAL POTASSIUM CONSERVATION — One kidney function that is not impaired in hypokalemia is the ability to appropriately conserve potassium by reducing distal sodium delivery, decreasing distal potassium secretion and increasing active distal potassium reabsorption [4,39]. (See "Evaluation of the adult patient with hypokalemia", section on 'Regulation of potassium excretion'.)

This response is important clinically since it allows measurement of urinary potassium excretion to distinguish between extrarenal and renal losses as the cause of otherwise unexplained hypokalemia. Potassium excretion should be less than 25 mEq/day with extrarenal losses (or with diuretic therapy after the effect of the drug has worn off) [39]; when using spot urine, a potassium-to-creatinine ratio ≤22 mEq/g (2.5 mEq/mmol) is used as threshold [40]. In comparison, a higher value usually indicates at least some component of renal potassium wasting as might be seen with diuretic therapy, tubulopathy, one of the forms of primary aldosteronism, or during the bicarbonaturic phase in a patient with vomiting. (See "Evaluation of the adult patient with hypokalemia", section on 'Assessment of urinary potassium excretion'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

Chronic hypokalemia (plasma potassium concentration usually ≤3 mEq/L) can lead to a modest reduction in urinary concentrating ability and stimulation of thirst. (See 'Impaired urinary concentrating ability' above.)

Hypokalemia increases the tubular production of ammonia, which then enters both the tubular lumen and the peritubular capillary.

The associated increase in ammonia entry into the renal vein may be clinically important in patients with advanced cirrhosis, possibly precipitating hepatic encephalopathy. (See 'Increased ammonia production' above.)

An increase in acid secretion, both as free hydrogen ions and as ammonium, in response to the intracellular acidosis induced by hypokalemia promotes net bicarbonate reabsorption. This effect can contribute to the maintenance of a concurrent metabolic alkalosis. (See 'Increased bicarbonate reabsorption' above.)

Mild to moderate hypokalemia can impair the ability to excrete a sodium load by increasing proximal and distal sodium reabsorption. This sodium retention and subsequent volume expansion can produce a modest elevation in blood pressure (up to 5 mmHg), an effect that may be important in patients with hypertension. However, severe hypokalemia may have the opposite effect and increase NaCl excretion. (See 'Increased sodium reabsorption' above.)

Chronic potassium depletion produces characteristic, although nonspecific vacuolar lesions in the epithelial cells in the proximal tubule and occasionally the distal tubule. This abnormality generally requires at least one month to develop and is readily reversible with potassium repletion. However, prolonged hypokalemia can lead to more severe changes, including interstitial nephritis and fibrosis, tubular atrophy, and cyst formation that is most prominent in the renal medulla. Correction of the hypokalemia can lead to a decrease in the number and size of cysts, although the tubulointerstitial lesions and associated kidney function impairment may be irreversible. (See 'Hypokalemic nephropathy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Sterns, MD, who contributed to earlier versions of this topic review.

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