ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Hypokalemia-induced kidney dysfunction

Hypokalemia-induced kidney dysfunction
Literature review current through: Jan 2024.
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.

  1. Mount DB, Zandi-Nejad K. Disorders of potassium balance. In: Brenner and Rector's The Kidney, Brenner BM (Ed), W.B Saunders, Philadelphia 2008. p.547.
  2. Mujais SK, Katz AL. Potassium deficiency. In: The Kidney: Physiology and Pathophysiology, Seldin DW, Giebisch G (Eds), Lippincott Williams & Wilkins, 2000. p.1615.
  3. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.860.
  4. Schwartz WB, Relman AS. Effects of electrolyte disorders on renal structure and function. N Engl J Med 1967; 276:383.
  5. Riemenschneider T, Bohle A. Morphologic aspects of low-potassium and low-sodium nephropathy. Clin Nephrol 1983; 19:271.
  6. Torres VE, Young WF Jr, Offord KP, Hattery RR. Association of hypokalemia, aldosteronism, and renal cysts. N Engl J Med 1990; 322:345.
  7. Yalamanchili HB, Calp-Inal S, Zhou XJ, Choudhury D. Hypokalemic Nephropathy. Kidney Int Rep 2018; 3:1482.
  8. RUBINI ME. Water excrtion in potassium-deficient man. J Clin Invest 1961; 40:2215.
  9. Marples D, Frøkiaer J, Dørup J, et al. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Clin Invest 1996; 97:1960.
  10. Elkjaer ML, Kwon TH, Wang W, et al. Altered expression of renal NHE3, TSC, BSC-1, and ENaC subunits in potassium-depleted rats. Am J Physiol Renal Physiol 2002; 283:F1376.
  11. Luke RG, Booker BB, Galla JH. Effect of potassium depletion on chloride transport in the loop of Henle in the rat. Am J Physiol 1985; 248:F682.
  12. Khositseth S, Uawithya P, Somparn P, et al. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus. Sci Rep 2015; 5:18311.
  13. Al-Qusairi L, Grimm PR, Zapf AM, Welling PA. Rapid development of vasopressin resistance in dietary K+ deficiency. Am J Physiol Renal Physiol 2021; 320:F748.
  14. Berl T, Linas SL, Aisenbrey GA, Anderson RJ. On the mechanism of polyuria in potassium depletion. The role of polydipsia. J Clin Invest 1977; 60:620.
  15. Tizianello A, Garibotto G, Robaudo C, et al. Renal ammoniagenesis in humans with chronic potassium depletion. Kidney Int 1991; 40:772.
  16. COOKE RE, SEGAR WE, CHEEK DB, et al. The extrarenal correction of alkalosis associated with potassium deficiency. J Clin Invest 1952; 31:798.
  17. Jaeger P, Karlmark B, Giebisch G. Ammonium transport in rat cortical tubule: relationship to potassium metabolism. Am J Physiol 1983; 245:F593.
  18. Gabduzda GJ, Hall PW 3rd. Relation of potassium depletion to renal ammonium metabolism and hepatic coma. Medicine (Baltimore) 1966; 45:481.
  19. Artz SA, Paes IC, Faloon WW. Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy. Gastroenterology 1966; 51:1046.
  20. Sabatini S, Kurtzman NA. The maintenance of metabolic alkalosis: factors which decrease bicarbonate excretion. Kidney Int 1984; 25:357.
  21. Terker AS, Zhang C, McCormick JA, et al. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 2015; 21:39.
  22. Hoorn EJ, Gritter M, Cuevas CA, Fenton RA. Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis. Physiol Rev 2020; 100:321.
  23. Ellison DH, Welling P. Insights into Salt Handling and Blood Pressure. N Engl J Med 2021; 385:1981.
  24. Garella S, Chazan JA, Cohen JJ. Saline-resistant metabolic alkalosis or "chloride-wasting nephropathy". Report of four patients with severe potassium depletion. Ann Intern Med 1970; 73:31.
  25. Thomson MN, Schneider W, Mutig K, et al. Patients with hypokalemia develop WNK bodies in the distal convoluted tubule of the kidney. Am J Physiol Renal Physiol 2019; 316:F292.
  26. Tolins JP, Hostetter MK, Hostetter TH. Hypokalemic nephropathy in the rat. Role of ammonia in chronic tubular injury. J Clin Invest 1987; 79:1447.
  27. Alpern RJ, Toto RD. Hypokalemic nephropathy--a clue to cystogenesis? N Engl J Med 1990; 322:398.
  28. Tsao T, Fawcett J, Fervenza FC, et al. Expression of insulin-like growth factor-I and transforming growth factor-beta in hypokalemic nephropathy in the rat. Kidney Int 2001; 59:96.
  29. Suga S, Mazzali M, Ray PE, et al. Angiotensin II type 1 receptor blockade ameliorates tubulointerstitial injury induced by chronic potassium deficiency. Kidney Int 2002; 61:951.
  30. Reungjui S, Roncal CA, Sato W, et al. Hypokalemic nephropathy is associated with impaired angiogenesis. J Am Soc Nephrol 2008; 19:125.
  31. Cremer W, Bock KD. Symptoms and course of chronic hypokalemic nephropathy in man. Clin Nephrol 1977; 7:112.
  32. Elitok S, Bieringer M, Schneider W, Luft FC. Kaliopenic nephropathy revisited. Clin Kidney J 2016; 9:543.
  33. Kudose S, Dounis H, D'Agati VD. Multicellular vacuoles in hypokalemic nephropathy. Kidney Int 2020; 97:618.
  34. Menahem SA, Perry GJ, Dowling J, Thomson NM. Hypokalaemia-induced acute renal failure. Nephrol Dial Transplant 1999; 14:2216.
  35. Lee EY, Yoon H, Yi JH, et al. Does hypokalemia contribute to acute kidney injury in chronic laxative abuse? Kidney Res Clin Pract 2015; 34:109.
  36. Ogata S, Akashi Y, Sakusabe T, et al. A multiple 24-hour urine collection study indicates that kidney function decline is related to urinary sodium and potassium excretion in patients with chronic kidney disease. Kidney Int 2022; 101:164.
  37. Gritter M, Rotmans JI, Hoorn EJ. Role of Dietary K+ in Natriuresis, Blood Pressure Reduction, Cardiovascular Protection, and Renoprotection. Hypertension 2019; 73:15.
  38. Wieërs MLAJ, Mulder J, Rotmans JI, Hoorn EJ. Potassium and the kidney: a reciprocal relationship with clinical relevance. Pediatr Nephrol 2022; 37:2245.
  39. SQUIRES RD, HUTH EJ. Experimental potassium depletion in normal human subjects. I. Relation of ionic intakes to the renal conservation of potassium. J Clin Invest 1959; 38:1134.
  40. Grams ME, Hoenig MP, Hoorn EJ. Evaluation of Hypokalemia. JAMA 2021; 325:1216.
Topic 2295 Version 19.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟