|Year : 2019 | Volume
| Issue : 3 | Page : 69-74
Diuretic-induced dyselectrolytemia and its clinical implications
Vijoy Kumar Jha1, KV Padmaprakash2, Rajesh Pandey3
1 Department of Nephrology, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Departments of Medicine and GE Medicine, INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
3 Departments of Cardiology, INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
|Date of Submission||02-Jun-2018|
|Date of Acceptance||25-Aug-2019|
|Date of Web Publication||26-Sep-2019|
Dr. Vijoy Kumar Jha
Physician and Nephrologist, Department of Nephrology, Command Hospital Air Force, Old Airport Road, Bengaluru - 560 007, Karnataka
Source of Support: None, Conflict of Interest: None
Diuretics are the most important and commonly used therapeutic agent in daily clinical practice, particularly in edematous states and hypertension. They increase urinary sodium and water losses by diminishing sodium reabsorption at different sites of a nephron. These drugs can influence the renal handling of electrolyte-free water, sodium, potassium, calcium, etc., depending on the sites of action leading to electrolyte disturbances which sometimes can be life-threatening if not carefully monitored and managed. This review focuses on the electrolyte imbalances in the setting of diuretic use and its clinical implications.
Keywords: Aldosterone, antidiuretic hormone, loop diuretics, renin–angiotensin–aldosterone system, syndrome of inappropriate antidiuretic hormone
|How to cite this article:|
Jha VK, Padmaprakash K V, Pandey R. Diuretic-induced dyselectrolytemia and its clinical implications. Curr Med Issues 2019;17:69-74
| Introduction|| |
Diuretics are the most commonly used therapeutic agents in our clinical practice. They act by diminishing sodium reabsorption at different sites of action of nephron leading to a variety of fluid and electrolyte complications. This review focuses on the electrolyte disturbances associated with the use of diuretics and its clinical implications.
| Diuretic-Induced Hyponatremia|| |
Hyponatremia is not so uncommon, and sometimes, it occurs as a life-threatening condition of diuretic therapy. Severe hyponatremia is always more common with thiazide-type diuretics. A loop diuretic is unlikely to cause this condition unless water intake is very high or there is severe volume depletion. There is reabsorption of sodium chloride (NaCl) without water resulting in the generation of a hyperosmotic gradient in the medullary interstitium. In the presence of the antidiuretic hormone (ADH), water gets reabsorbed in medullary collecting tubule resulting in concentrated urine excretion. Loop diuretics impair the accumulation of NaCl in the medulla and so ADH responsiveness in the form of water retention is reduced. Loop diuretics, therefore, cause less development of hyponatremia unless distal delivery is very low or water intake is very high.
Thiazides act on distal tubule in the cortex and do not have any role in medullary function or in ADH-induced water retention. They increase water permeability and water reabsorption in the inner medullary collecting duct independent of ADH. The combination of increased sodium and potassium excretions in the urine along with enhanced water reabsorption due to ADH results in the development of hyponatremia. In susceptible patients, there may be excess water retention, cation depletion, or sodium shift or sequestration or some combination of these. Thiazide diuretics increase in diuresis and total solute excretion without appreciable increased free water excretion in the setting of established water diuresis. The antidiuretic effect on free water excretion can be persistent in patients whose sodium intake is too low. All those diuretics which act distally to the loop of Henle do not abolish the medullary concentrating mechanism and finally limit renal diluting capacity if vasopressin is present and kidney responds to these hormones.
In the setting of the syndrome of inappropriate ADH (SIADH), thiazide intake may increase susceptibility to hyponatremia. The thiazide-sensitive (NaCl) cotransporter of the distal convoluted tubule and the epithelial sodium channel of the late distal tubule through the collecting duct play an important role in sodium homeostasis during vasopressin escape. Thiazide action on the NaCl cotransporter in SIADH significantly impairs the sodium reabsorptive capacity of the distal tubule worsening the hyponatremia of SIADH. Ware et al. recently demonstrated that thiazide-related hyponatremia may be associated with a genetic variant in distal nephron prostaglandin receptor and reduced prostaglandin reabsorption through this transporter facilitates activation of the prostaglandin EP4 receptor to increase water reabsorption.
Possible risk factors for thiazide-induced hyponatremia are shown in [Table 1].
Most of the hyponatremia develops during the first 2–3 weeks of diuretic therapy if they are going to occur. This is because a new steady state is reached in which solute and water intake and its excretion are roughly equal due to compensatory changes that limit further losses. Sodium and water losses initially induced by diuretic therapy lead to increases in a variety of sodium-retaining factors, such as angiotensin II, aldosterone, norepinephrine, and structural adaptations in a distal part which contributes to the compensatory sodium retention. The pattern of daily sodium excretion is also altered with diuretic therapy: sodium will be lost during the period when the diuretic is acting, and for the remaining day due to increased activity of the sodium-retaining mechanism, it will be very low. Maximal natriuretic response to an intravenous (IV) diuretic is seen within the first few hours, even with continuous IV infusion of a loop diuretic. The natriuresis usually begins to decrease within the first 12 h except in patients who are markedly volume expanded due to renal sodium retention in which the renin–angiotensin system is suppressed. Hence, in a hypervolemic state, the second and subsequent doses of diuretics may produce as large natriuresis as the original dose until most of the excess fluid has been removed; however, the first dose still represents the maximum response.
Most of the patients with hyponatremia are relatively asymptomatic. They may have nonspecific symptoms such as confusion, nausea, lethargy, and mental confusion. A typical patient will be relatively thin, older women on thiazide diuretics with vague symptoms. Severe symptoms such as coma, agitation, stupor, or encephalopathy can be seen. The clinical symptoms depend on the rate and magnitude of decrease in sodium level as well as comorbid conditions. Most of the patients lack any of the clinical or laboratory evidence of overt hypovolemia.,
Laboratory evaluation of biochemical and urine analyses/indices is quite variable and is not diagnostic. In the setting of diuretic-induced hyponatremia, there are hypokalemia and increased fractional excretion of potassium. Patients with SIADH, regardless of whether they were on diuretics or not, had lower serum uric acid and higher uric acid excretion than patients with diuretic-induced hyponatremia. Low uric acid levels and increased fractional excretion of uric acid may be seen in a subset of patients whose response to thiazides is similar to that of patients with SIADH and are characterized by a quick onset of severe hyponatremia.
While correcting hyponatremia, it is very important to correct hypokalemia as it is very common in the setting of thiazide-induced hyponatremia. Any athlete with hyponatremia and neurological symptoms should be treated immediately with a bolus infusion of 100 mL of 3% NaCl to acutely reduce brain edema, with up to 2 additional 100 mL of 3% NaCl bolus infusions at 10-min intervals if there is no clinical improvement. It is usually suggested a goal of 6–8 mmol/L in 24 h, 12–14 mmol/L in 48 h, and 14–16 mmol/L in 72 h as baseline rates of correction for hyponatremic patients with few comorbidities, with consideration for even slower correction in various comorbid conditions. Various studies suggest that the presence of hypokalemia seems to be associated with an increased risk of central pontine myelinolysis, and one report attributes neurological abnormality in a patient with hyponatremia solely due to the correction of the hypokalemia. The causative diuretics must be stopped to remove the stimulus for hyponatremia. The administered fluid in the setting of emergency not only corrects any subclinical fluid depletion but also makes cations available for distal delivery, and a water diuresis may ensue further metabolizing thiazides and help in hyponatremia correction.
| Diuretic-Induced Hypokalemia|| |
Diuretics can induce hypokalemia either through the direct effect or most importantly through secondary effects. The direct effect of diuretics is shown in [Table 2].
Majority of kaliureses are due to secondary effects induced by these diuretics. Under normal conditions, potassium delivery to the distal nephron remains small and is fairly constant. However, the rate of potassium secretion by the distal nephron is regulated according to physiologic needs and is generally responsible for most of the urinary potassium excretions. Increases or decreases in effective arterial blood volume result in changes in distal Na delivery and circulating aldosterone levels in such a way that renal K excretion is independent of volume changes. The kaliuretic effect of aldosterone is suppressed because there is a simultaneous reduction in distal sodium and fluid delivery as a result of enhanced reabsorption at proximal nephron sites. It is increased K secretion rather than decreased proximal K reabsorption which is more important.
Diuretics stimulate the renin–angiotensin–aldosterone system (RAAS), increase distal tubule flow and release of arginine vasopressin (AVP), and generate a metabolic alkalosis, all of which enhance K+ secretion in the collecting ducts. Two distinct mechanisms are responsible for K+ secretion in the collecting ducts: one mediated by the renal outer medullary K+ (ROMK) channels and the other by big K+ (BK) channels. Whereas the basal secretion traverses ROMK channels, flow-dependent K+ secretion is mediated by calcium-activated maxi or BK channels. Diuretic combines increased distal tubule flow with maintained or increased AVP release due to nonosmotic stimulation which is common in an edematous patient. The diuretic treatment enhances the secretion of aldosterone and AVP but increases distal flow, thereby accounting for the particular importance of aldosterone and AVP in promoting K+ loss with diuretics.
Serum potassium concentration in patients not receiving KCl supplements decreases by an average of 0.3 mmol/L with furosemide and by 0.6 mmol/L with thiazides. The less hypokalemia in loop diuretics may be due to shorter half-life of loop diuretics and the ability of loop diuretics to inhibit calcium absorption in the loop of Henle. The increase in calcium delivery to the lumen of the distal nephron inhibits Na reabsorption and diminishes K secretion. The ingestion of large amounts of dietary Na (180–200 mEq/L) or extreme dietary restriction renders a patient, particularly vulnerable to the development of hypokalemia. -Moderate sodium intake (70–100 mEq/L) causes only a slight increase in aldosterone levels and less delivery of Na to the distal nephron resulting in an overall decrease in renal K excretion. It will provide the maximal antihypertensive effect and also may limit the degree of K depletion. The decrease in the serum K concentration usually develops within the first 2 weeks of therapy and then stabilizes as a new steady state is achieved. More severe hypokalemia in the setting of chronic diuretic administration suggests some disturbances in K balance such as an intercurrent illness leading to extrarenal K loss like diarrhea, a decrease in K intakes like vomiting, or a change in diuretic dose. A major component of diuretic-induced hypokalemia is mediated by a transcellular shift from the extracellular to the intracellular compartment mediated with increased circulating levels of catecholamines and aldosterone as well as the development of metabolic alkalosis.
Steady state of hypokalemia due to chronic diuretic dose is reached due to increased reabsorption of Na in the proximal nephron as a result of the diuretic-induced decreases in extracellular fluid volume which diminishes Na and fluid delivery to the distal nephron, decrease in mineralocorticoid activity, direct cellular effect of hypokalemia leading to decreased distal nephron K excretion, and increased activity of the H-K adenosine triphosphatase (ATPase) pump in the collecting duct resulting in increased K reabsorption. There is a casual relationship between diuretic-induced hypokalemia and the development of sudden death. Significant decreases in the serum K concentration should be prevented and K replacement should be started when it is present.
Diuretic-induced hypokalemia can be prevented by the measures as given in [Table 3].
Correction of hypokalemia can be done through either oral or IV therapy. Oral doses of 40 mEq are well tolerated and can be given as often as every 4 h. Patients with an immediately life-threatening condition and those who are unable to take anything by the mouth should require IV replacement therapy with KCl. The rate of infusion should not exceed 20 mEq/h unless paralysis or malignant ventricular arrhythmia present, and the maximum concentration of administered K+ should be no >40 mEq/L through a peripheral vein or 100 mEq/L through a central vein.
| Diuretic-Induced Hyperkalemia|| |
The entry of filtered sodium into principal cells of collecting tubules is mediated by selective sodium channels in the apical luminal membrane. The energy for this process is provided by the favorable electrochemical gradient for sodium (cell interior electronegative and low cell sodium concentration). Reabsorbed sodium is pumped out of the cell by the Na-K-ATPase pump in the basolateral (peritubular) membrane. The reabsorption of cationic sodium makes the lumen electronegative, creating a suitable gradient for the secretion of potassium into the lumen through potassium channels in the apical membrane. Aldosterone in combination with the cytosolic mineralocorticoid receptor leads to enhanced sodium reabsorption and potassium secretion by increasing the number of open sodium channels Na-K-ATPase pumps. Spironolactone blocks the binding of aldosterone to its cytoplasmic receptor, and as a result, the mechanisms by which aldosterone normally enhances renal K excretion are inhibited. It also inhibits aldosterone biosynthesis but only at a drug concentration far greater than those required to inhibit mineralocorticoid receptor binding in the kidney. Eplerenone is a selective aldosterone receptor antagonist with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects of spironolactone.
Amiloride and triamterene inhibit sodium transport in principal cells of the initial collecting duct and the cortical collecting duct. By inhibiting luminal Na entry into the cell, amiloride and triamterene limit potassium secretion by preventing the development of a lumen-negative potential that normally provides a favorable driving force for potassium secretion. Decreased intracellular Na concentration leads to decreased activity of the basolateral Na-K-ATPase and thereby less favorable diffusion gradient for K across the apical membrane. The effects of spironolactone and the sodium channel blockers are additive as they act by distinct mechanisms. Risk of hyperkalemia is dose dependent, and it increases in patients with renal failure or those taking K supplements or any other agents that interfere with the RAAS.
The patient should be managed by stopping the offending agent and in case of hyperkalemic emergencies in the form of muscle paralysis or cardiac conduction abnormalities should be treated with rapidly acting therapies, for example, IV calcium, insulin, and glucose or with therapies that remove potassium from the body, for example, hemodialysis, diuretics, and gastrointestinal cation exchanger.
| Diuretic-Induced Hypomagnesemia|| |
Chronic thiazide use leads to hypomagnesemia, particularly in the elderly. Cellular magnesium depletion occurs in up to 50% of patients receiving thiazide diuretics and can be present even with normal serum magnesium concentration. Hypomagnesemia often coexists with hyponatremia and hypokalemia. Hypokalemia and hypocalcemia found in association with low serum magnesium concentration can be refractory to treatment unless serum magnesium is corrected. In a study by Martin and Milligan, only the group taking thiazide diuretics out of those hospitalized patients taking diuretics had hypomagnesemia. The 24-h urine sampling from representative subgroups demonstrated impaired magnesium-conserving ability in hypomagnesemia patients receiving loop and thiazide diuretic therapy. Those taking potassium-sparing diuretic had no significant evidence of reduced magnesium-conserving ability. The mechanism behind this magnesium wasting with thiazide use is not well understood. Although there is a risk of arrhythmia in the setting of hypomagnesemia, the clinical significance of magnesium disturbances induced by chronic thiazide diuretic is questionable and so routine monitoring is not indicated. The use of a potassium-sparing diuretic will reduce the degree of magnesium wasting associated with thiazide diuretics. Symptomatic patients, such as those with tetany, arrhythmias, or seizures, should receive IV magnesium and should have continuous cardiac monitoring. In the acute setting, hemodynamically unstable patients 1–2 g (8–16 meq [4–8 mmol]) magnesium sulfate can be given initially over 2–15 min. In hemodynamically stable patients with severe symptomatic hypomagnesemia, magnesium sulfate (1–2 g) in 50–100 mL of 5% dextrose in water can be given initially over 5–60 min followed by an infusion.
| Diuretic-Induced Hypocalciuria/hypercalcemia|| |
Thiazides occasionally can give rise to mild hypercalcemia. Severe hypercalcemia is rare as a minor increase in serum calcium will have a suppressive effect on parathyroid hormone release. Thiazide is used for the treatment of idiopathic hypercalciuria. Thiazide-related decreased urinary calcium excretion leads to a positive calcium balance, increased bone density, and reduced risk of hip fracture.
Thiazide induces hypocalciuria through effects that stimulate calcium reabsorption in both the proximal and distal nephrons. In the proximal nephron, calcium reabsorption is increased as a result of extracellular fluid volume contraction and increased proximal salt and water reabsorption. Increases in proximal tubule sodium and volume absorption lead to an increase in luminal calcium concentration and more calcium being passively absorbed through the paracellular pathway. In the distal nephron, thiazides stimulate calcium reabsorption through transcellular flux through increasing the activity of the basolateral sodium/calcium exchanger and apically located epithelial calcium channel TRPV5.
Loop diuretics also have significant effects on renal calcium handling. The reabsorption of calcium in the loop of Henle is primarily passive, being driven by the electrochemical gradient created by NaCl transport through the paracellular pathway. Inhibiting the reabsorption of NaCl by loop diuretics increases calcium excretion, thus reducing serum calcium level. Earlier, saline plus high dose of furosemide was the main treatment of hypercalcemia. Volume expansion is still important, but other drugs, such as bisphosphonates and calcitonin, have largely replaced loop diuretics in the management of hypercalcemia.
| Conclusion|| |
Diuretics are therapeutic agents to inhibit sodium transport system along the renal tubule. They can influence renal handling of electrolytes and so dyselectrolytemia is quite common in the setting of diuretic use. These complications can be life-threatening and can be minimized with careful monitoring, dosage titration, and replacement of electrolyte loss.
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[Table 1], [Table 2], [Table 3]