Role of Potassium Supplementation in Potassium Losing Nephropathy

An Overview of Physiological Potassium Excretion

The human body in a steady state maintains the potassium equilibrium. While the standard serum levels of potassium lie within the range of 3.5 to 5.0 mmol/L, equivalence is achieved by balancing its intake (60-80 mmol/day) and excretion (renal and stool excretion: 50-65 mmol/day and 10-15 mmol/day, respectively). The kidneys play a central role in the regulation of potassium. It can increase or diminish the renal excretion depending upon the potassium intake, from 5-10 mmol/day to 450 mmol/day, respectively in a healthy individual. The physiological mechanism includes filtration of 180 L of plasma per day, as a result of which 720 mmol potassium reaches the lumen of the nephron. Upon further filtration, the majority of this potassium (nearly 500 mmol) is reabsorbed in the proximal tubule. Besides, the principal cells of the cortical collecting duct (CCD) are chief in controlling the potassium secretion, which is also modulated by the activity of aldosterone and delivery of sodium and water to the CCD. Aldosterone reinstates the electrical neutrality by compensating the increase in sodium reabsorption from the lumen with secretion of potassium into the lumen (figure 1).¹Hughes J, Jefferson JA. Clinical Chemistry Made Easy. Elsevier Health Sciences;2008. Chapter 2, Disorders of potassium balance; 21-37.  Therefore, long-term (hours to days) potassium homeostasis is determined by the renal potassium excretion.²Kjeldsen K. Hypokalemia and sudden cardiac death.

Exp Clin Cardiol.2010;15(4):e96-e99.  Maintenance of the ratio between extracellular and intracellular concentrations to a normal value is essential for preserving resting membrane potential (RMP) and neuromuscular functioning. Other than these, intracellular potassium is vital for several functions, which comprise cell growth, maintenance of cell volume, deoxyribo nucleic acid (DNA) and protein synthesis, enzymatic function and acid-base balance. Disturbance in the physiological process results in development of disorders of potassium balance, contributing to significant numbers of ambulatory and in-hospital deaths.³Hoskote SS, Joshi SR, Ghosh AK. Disorders of potassium homeostasis:pathophysiology and management. J Assoc Physicians India. 2008 Sep;56:685-93.  

An Introduction to Hypokalemia

Hypokalemia is a term ascribed to concentration of plasma potassium below 3.5 mEq/L. Although its prevalence is seen in nearly 21% patients admitted to hospital, it remains undertreated in about onefourth of all cases. A number of disease processes may underline hypokalemia such as renal and extra-renal loses, distribution errors or reduced dietary intake, however, use of diuretics account for majority of cases of hypokalemia (box 1). Other common medications that cause hypokalemia are stated in box 2. Consequently, RMP and the acid-base status of the body are deranged, resulting in hyperpolarized myocyte, which becomes even more refractory to excitation.³Hoskote SS, Joshi SR, Ghosh AK. Disorders of potassium homeostasis:pathophysiology and management. J Assoc Physicians India. 2008 Sep;56:685-93.  Depending upon the potassium level, hypokalemia may manifest as mild, moderate, or severe. Mild hypokalemia (3-3.5 mmol/L)

often remains symptoms free. Moderate hypokalemia (2.5-3.0 mmol/L) may affect the smooth muscle of the gastrointestinal tract and precipitate muscle weakness, fatigue, paresthesia as well as ileus and constipation. Occasionally, severe form of hypokalemia may even cause rhabdomyolysis (table 1). Furthermore, hypokalemia may also lead to impaired ability of the kidney to concentrate the urine, thereby inducing nephrogenic diabetes insipidus, characterized by polyuria and polydipsia.¹Hughes J, Jefferson JA. Clinical Chemistry Made Easy. Elsevier Health Sciences;2008. Chapter 2, Disorders of potassium balance; 21-37.  

Hypokalemia Associated Nephropathy

Long-term hypokalemia has an established association with renal hypertrophy and tubulointerstitial disease. This can be attributed to the hypokalemic effects in the form of renal vasoconstriction, reduced medullary blood flow, and intrarenal ischemia (with intrarenal angiotensin II and endothelin-1 generation). Activation of intrarenal complement system may further aggravate the renal disease. Moreover, expression of growth factors such as insulin-like growth factor-1 and transforming growth factor-β plausibly generate renal hypertrophic response precipitating nephropathy. Hypokalemic nephropathy is therefore a tubulointerstitial disease, clinically characterized by prolonged hypokalemia, polyuria, metabolic alkalosis, proteinuria, and progressive loss of renal function. The renal lesion in particular presents as renal hypertrophy and renal tubular cell hyperplasia (comprising medullary collecting ducts and to a lesser extent, the thick ascending limb) along with tubular atrophy, interstitial macrophage infiltration, and interstitial fibrosis.4 The most common associated conditions comprise of metabolic alkalosis, adrenocortical hormone excess, intrinsic renal disease such as renal tubular acidosis or hyperplasia of juxtaglomerular cells.⁵Dorland’s Illustrated Medical Dictionary. 32 edition. United States of America: Elsevier Health Sciences; 2011. Nephropexy; pg 1242.  As the condition advances, the loss of capillaries increases, which closely correlates with progressive development of fibrosis.⁴Reungjui S, Roncal CA, Sato W, Glushakova OY, Croker BP, Suga S, Ouyang X, Tungsanga K, Nakagawa T, Johnson RJ, Mu W. Hypokalemic nephropathy is associated with impaired angiogenesis. J Am Soc Nephrol. 2008 Jan;19(1):125-34.  The chronic hypoxia in the kidney may eventually lead to end-stage renal failure.⁶Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006 Jan;17(1):17-25.  Therefore, careful clinical and laboratory assessment of this pathology is of utmost importance.⁷Bagga A, Bajpai A, Menon S. Approach to Renal Tubular Disorders. Indian J Pediatr. 2005;72(9):771-776.  

Evaluation begins with a proper history of upper gastrointestinal loss (vomiting and nasogastric drainage), use of diuretics, and recording blood pressure. Chloride levels in urine differentiate the non-renal causes (< 10 mEq/L) of hypokalemic alkalosis from the renal ones (> 20 mEq/L). Similarly, high blood pressure may be suggestive of true (hyperaldosteronism, glucocorticoid remediable aldosteronism, congenital adrenal hyperplasia) or apparent mineralocorticoid excess (Liddle syndrome, syndrome of apparent mineralocorticoid excess). Therefore, appropriate diagnosis is essential for specific management of these conditions other than primary potassium supplementation therapy.⁷Bagga A, Bajpai A, Menon S. Approach to Renal Tubular Disorders. Indian J Pediatr. 2005;72(9):771-776.  

Potassium Supplementation Among Individuals with Hypokalemic Nephropathy

Persistent hypokalemia is usually displayed by totalbody potassium depletion or increased renal potassium clearance. In those individuals presenting with simple potassium depletion, potassium replacement therapy improves the serum potassium concentration. The urgency of the treatment is guided by the severity of symptoms, however, the extent and rate of potassium replacement is directed by the results of serum potassium levels obtained on reassessment. Nonetheless, the objective of the therapy remains correction of the potassium deficit, without inducing hyperkalemia. Oral replacement of potassium is the choice of method in the cases with no electrocardiogram changes, neurologic symptoms, cardiac ischemia, or digitalis therapy.⁸Asmar A, Mohandas R, Wingo CS. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012 Sep;60(3):492-7.  An overview of the management approach is depicted in figure 2.

Efficacy of Potassium Chloride in Improving Hypokalemic States

Individuals presenting with more protracted illnesses or mild hypokalemia, placed on diuretics, are the suitable candidates to receive potassium supplementation via oral route. Oral preparations for replenishing the potassium stores are principally of three types; potassium bicarbonate, potassium chloride, and potassium phosphate, of which potassium chloride is the most preferred. Administration of 40-60 mEq of potassium chloride, every 4-6 hours is beneficial and well tolerated.⁹Pepin J, Shields C. Advances in diagnosis and management of hypokalemic and hyperkalemic emergencies. Emerg Med Pract. 2012 Feb;14(2):1-17;quiz 17-8.  Evidences have suggested that its liquid preparations demonstrate rapid absorption (probably from the stomach), stating a good rationale supporting its use.¹⁰Levene DL. Potassium chloride: absorption and excretion. Can Med Assoc J.1973 Apr 7;108(7):853-855.   An open, randomized study¹¹Meyer-Lehnert H, Evers WM, Krück F. Potassium substitution via the oral route:does its efficacy depend on the anion of the potassium salt? Klin Wochenschr.1991 Oct 31;69(17):797-801.   was performed to evaluate the efficacy oral potassium chloride in individuals with hypokalemia (below or equal to 3.5 mmol/L). The subjects received 80 mmol of potassium chloride daily and were examined on days 0, 2, 4, and 6, based on parameters such as serum potassium concentration, acid-base status, and urinary electrolyte excretion. The potassium concentration increased from 3.2 +/- 0.2 (mean +/- SD) on day 0 to 3.8 +/- 0.4 mmol/L on day 2, to 4.0 +/- 0.5 mmol/L on day 4. On day 6, the levels were similar to those observed on day 4 (4.0 +/- 0.4 mmol/L), depicted in figure 3. Blood pH did not reflect any significant changes during the study, however a dip in carbon dioxide partial pressure was observed from 38.7 +/- 4.9 on day 0 to 36.4 +/- 3.6 on day 2. The results of this study can be corroborated with the outcomes of another trial,¹²Wuermser LA, Reilly C, Poindexter JR, Sakhaee K, Pak CY. Potassium-magnesium citrate versus potassium chloride in thiazide-induced hypokalemia. Kidney Int. 2000 Feb;57(2):607-12.   which revealed the effectiveness of potassium chloride therapy in correcting thiazide-induced hypokalemia. After 3-weeks of 50 mg/day hydrochlorothiazide therapy (subsequent to which participants developed hypokalemia), subjects were administered 42 mEq/day of potassium chloride for next three weeks along with of hydrochlorothiazide. An increase in the serum potassium concentration was observed from 3.45 +/- 0.44 mEq/L to about 3.8 mEq/L. Moreover, potassium chloride therapy was also shown to improve hydrochlorothiazide-induced hypochloridemia and hyperbicarbonatemia. Thus, it may be stated that patients who present with mild hypokalemia or other hypokalemia-associated conditions, may benefit from the use of potassium chloride.

To Conclude…

Hypokalemia manifests when the concentration of plasma potassium reaches below 3.5 mEq/L. Long-term hypokalemia is highly correlated with renal hypertrophy and tubulointerstitial disease, precipitating nephropathy. With further progress of the condition, there may be significant capillary loss, with continuous interstitial fibrosis, which may eventually lead to end-stage renal failure. To prevent the onset of such grave complications, potassium chloride, which is the most common method of oral supplementation, is highly effective and well tolerated.

References

1. Hughes J, Jefferson JA. Clinical Chemistry Made Easy. Elsevier Health Sciences;2008. Chapter 2, Disorders of potassium balance; 21-37.
2. Kjeldsen K. Hypokalemia and sudden cardiac death. Exp Clin Cardiol.2010;15(4):e96-e99.
3. Hoskote SS, Joshi SR, Ghosh AK. Disorders of potassium homeostasis:pathophysiology and management. J Assoc Physicians India. 2008 Sep;56:685-93.
4. Reungjui S, Roncal CA, Sato W, Glushakova OY, Croker BP, Suga S, Ouyang X, Tungsanga K, Nakagawa T, Johnson RJ, Mu W. Hypokalemic nephropathy is associated with impaired angiogenesis. J Am Soc Nephrol. 2008 Jan;19(1):125-34.
5. Dorland’s Illustrated Medical Dictionary. 32 edition. United States of America: Elsevier Health Sciences; 2011. Nephropexy; pg 1242.
6. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006 Jan;17(1):17-25.
7. Bagga A, Bajpai A, Menon S. Approach to Renal Tubular Disorders. Indian J Pediatr. 2005;72(9):771-776.
8. Asmar A, Mohandas R, Wingo CS. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012 Sep;60(3):492-7.
9. Pepin J, Shields C. Advances in diagnosis and management of hypokalemic and hyperkalemic emergencies. Emerg Med Pract. 2012 Feb;14(2):1-17;quiz 17-8.
10. Levene DL. Potassium chloride: absorption and excretion. Can Med Assoc J.1973 Apr 7;108(7):853-855.
11. Meyer-Lehnert H, Evers WM, Krück F. Potassium substitution via the oral route:does its efficacy depend on the anion of the potassium salt? Klin Wochenschr.1991 Oct 31;69(17):797-801.
12. Wuermser LA, Reilly C, Poindexter JR, Sakhaee K, Pak CY. Potassium-magnesium citrate versus potassium chloride in thiazide-induced hypokalemia. Kidney Int. 2000 Feb;57(2):607-12.