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Diuretic-induced hyponatremia

Diuretic-induced hyponatremia
Literature review current through: Sep 2023.
This topic last updated: Oct 13, 2022.

INTRODUCTION — Hyponatremia is an occasional but potentially fatal complication of diuretic therapy. Virtually all cases of severe diuretic-induced hyponatremia have been due to a thiazide-type diuretic [1-7]. A loop diuretic is much less likely to induce this problem unless the diuretic has induced volume depletion or water intake is very high (since loop diuretics partially impair urinary diluting capacity) [8].

PATHOGENESIS

Loop versus thiazide diuretics — The difference in hyponatremic risk between thiazide and loop diuretics may be related to differences in their tubular site of action (see "Mechanism of action of diuretics"):

Loop diuretics inhibit sodium chloride (NaCl) reabsorption in the thick ascending limb of the loop of Henle. The reabsorption of sodium chloride without water in the medullary aspect of this segment is normally the first step in the generation of the hyperosmotic gradient in the medullary interstitium. In the presence of antidiuretic hormone (ADH), the highly concentrated interstitium allows water to be reabsorbed in the medullary collecting tubule down the favorable osmotic gradient between the tubular lumen and the interstitium, resulting in the excretion of a concentrated urine.

Administration of a loop diuretic interferes with this process by impairing the accumulation of sodium chloride in the medulla. Thus, although the loop diuretic can increase ADH levels by inducing volume depletion, responsiveness to ADH is reduced because of the impairment in the medullary gradient [9]. As a result, water retention and the development of hyponatremia will be limited, unless distal delivery is very low or water intake is very high.

The thiazides, in comparison, act in the cortex in the distal tubule; as a result, they do not interfere with medullary function or with ADH-induced water retention. In addition, in vitro data indicate that thiazides increase water permeability and water reabsorption in the inner medullary collecting duct, an effect that is independent of ADH [10]. In addition to water retention, the combination of increased sodium and potassium excretion (due to the diuretic) and enhanced water reabsorption (due to ADH) can result in the excretion of urine with a sodium plus potassium concentration higher than that of the plasma [3]. Loss of this fluid can directly promote the development of hyponatremia independent of the degree of water intake. (See "Causes of hypotonic hyponatremia in adults".)

Mechanisms of thiazide-induced hyponatremia — Although hypovolemia can contribute to thiazide-induced hyponatremia, most patients appear clinically euvolemic, and several other factors appear to play a role in the development of hyponatremia [11]:

An underlying tendency to increased water intake (see 'Increased water intake' below)

A reduction in diluting ability and therefore impaired water excretion, which is a direct effect of reduced sodium chloride reabsorption without water in the distal tubule

Increased water intake — Many patients with thiazide-induced hyponatremia appear to have an underlying tendency to increased water intake (polydipsia). As examples:

A study of 15 older adults with a history of thiazide-induced hyponatremia and 15 age- and sex-matched hypertensive controls found that, after washout of thiazide diuretics, water intake was higher (2543 versus 1828 mL/day) and urine osmolality was lower (630 versus 804 mosmol/kg) in those with a history of hyponatremia [12].

A similar study of 11 older adult patients with thiazide-induced hyponatremia and 10 healthy controls found that both the prethiazide serum sodium concentration (mean 138 versus 141 mEq/L) and the urine osmolality (306 versus 513 mosmol/kg) were lower in those who developed hyponatremia [2].

Impaired water excretion — In most patients, increased water intake will not lead to hyponatremia unless there is an impairment in water excretion. (See "Causes of hypotonic hyponatremia in adults".)

A variety of mechanisms may contribute to impaired water excretion in such patients [11]:

Volume depletion can stimulate the release of ADH, leading to the production of a concentrated urine [1,3,8].

Enhanced ADH release may be a secondary event induced by nausea and other neurologic symptoms.

Thiazide diuretics may be associated with water retention that is independent of ADH [10].

Approximately 50 percent of patients who develop thiazide-induced hyponatremia carry a single-nucleotide polymorphism in the gene encoding the prostaglandin transporter, expressed in the renal collecting duct. The variant transporter allows higher levels of luminal prostaglandin E2, which activate the luminal prostaglandin E2 receptor 4, thereby activating water reabsorption in the collecting duct, despite suppression of ADH [13].

Patients treated with diuretics may have a reduced glomerular filtration rate, which is a common contributor to hyponatremia in older adults. In addition, patients who have thiazide-induced hyponatremia may have lower prethiazide estimated glomerular filtration as compared with those who do not have thiazide-induced hyponatremia (72 versus 94 mL/min in one study) [12].

Decreased dietary protein intake, due to dietary preferences or acute illness, may limit electrolyte-free water excretion and predispose to hyponatremia in patients treated to thiazides. In the previously mentioned study of patients with a history of thiazide-induced hyponatremia, urea excretion was lower among cases after washout of diuretics than among controls (251 versus 346 mmol/24 hours), although this was not explained by significant differences in dietary history [12].

Older adult patients generally have a reduced ability to excrete a water load, an effect that is most prominent in those who have previously developed thiazide-induced hyponatremia [14]. In the study mentioned above, for example, both plasma ADH and electrolyte-free water clearance were lower before and after hydrochlorothiazide administration in 15 patients with a history of thiazide-induced hyponatremia as compared with 15 hypertensive controls with no history of hyponatremia [12].

Retention of water as a primary event can explain why many patients with thiazide-induced hyponatremia behave as if they are volume expanded: The body weight may initially increase [2], the blood urea nitrogen and plasma creatinine concentration are generally low-normal [4,15], and hypouricemia due to enhanced urinary uric acid excretion may be present [8,15]. All of these findings are similar to those in the syndrome of inappropriate ADH secretion (SIADH), which is also associated with initial volume expansion. (See "Diagnostic evaluation of adults with hyponatremia" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Pathogenesis of hyponatremia'.)

In the aggregate, these observations suggest that there are two different forms of diuretic-induced hyponatremia: one in which volume depletion stimulates the release of ADH and another in which the patient may be slightly volume expanded [15].

In most patients, the combination of sodium plus potassium loss and water retention accounts for essentially all of the fall in the plasma sodium concentration [2,4]. However, there are patients in whom this does not appear to be the case, raising the possibility that the hyponatremia is due in part to osmotic inactivation of sodium in the cells or perhaps bone [16]. How or if this actually occurs is not clear. A similar hypothesis was proposed in SIADH and then seemingly excluded by careful balance studies [17,18].

INCIDENCE AND PATIENTS AT RISK — Thiazides are one of the most common causes of hyponatremia requiring hospitalization. As an example, in a case-control study among Swedish adults, thiazide diuretics were identified as a precipitating cause in more than 25 percent of hospitalizations for hyponatremia [19]. During the first week of thiazide treatment, the risk of hospitalization for hyponatremia increased by almost 50-fold and then gradually declined; individuals taking thiazides chronically had a threefold higher risk of hospitalization for hyponatremia. However, thiazide use was highly prevalent, and therefore the absolute risk of severe hyponatremia secondary to thiazide treatment in this study was low (0.12 percent).

The incidence of milder thiazide-induced hyponatremia is uncertain [20-22]. The best data come from a retrospective cohort study of 2613 newly treated hypertensive patients followed for 10 years [20]. Hyponatremia, defined as a serum sodium of 130 mEq/L or less, developed in 66 of 220 patients initiated on a thiazide (30 percent) compared with 422 of 2393 patients started on alternate therapy (18 percent). Most cases of hyponatremia in patients taking thiazides occurred in the first three months of treatment. However, the risk of hyponatremia continued to be higher in the group exposed to thiazides throughout the 10 years of observation. Among those that developed hyponatremia, the median time to diagnosis was 1.75 years, emphasizing the importance of continued follow-up of patients started on thiazide diuretics. The incidence of hyponatremia associated with thiazide therapy was slightly, but not significantly, more common with advancing age (ie, 37 versus 24 percent comparing those above and below 60 years of age). After taking into account other risk factors for hyponatremia, thiazide therapy was associated with one excess case of hyponatremia for every 15 patients treated.

The association of thiazide-induced hyponatremia with older age, particularly those with low body weight, has been noted in several studies [1-5,11,19,23-25]. As an example, a case-controlled study in hospitalized patients found that patient age and body mass were independent risk factors for thiazide-induced hyponatremia [5]. Each 10-year increment of age was associated with a twofold increase in risk, and every 5 kg increment in body mass decreased the odds ratio by 27 percent. Individuals with alcohol use disorder, particularly beer drinkers, and patients with psychogenic polydipsia who depend on the excretion of maximally dilute urine to maintain water balance are also at risk. In addition, genetic factors may increase the risk of thiazide-induced hyponatremia. A study of Chinese patients, for example, found that two polymorphisms of the KCNJ1 gene encoding the ROMK potassium channel (rs1231254 and rs2509585) were significantly more common among 48 thiazide-treated patients with serum sodium concentrations of <125 mmol/L than among 211 normonatremic thiazide-treated controls [25].

CLINICAL MANIFESTATIONS — The clinical manifestations of diuretic-induced hyponatremia are similar to those of other causes of hyponatremia. Most patients do not exhibit signs of volume depletion [2,6]. (See "Manifestations of hyponatremia and hypernatremia in adults".)

As with other diuretic-induced fluid and electrolyte complications, hyponatremia often develops within the first one to two weeks of therapy if diuretic dose and dietary intake remain relatively constant (figure 1) [1,3,26]. After this period, the patient is in a new steady state in which further sodium and water losses do not occur. However, in many patients with diuretic-induced hyponatremia, the disorder first appears after many months of uncomplicated thiazide therapy [5,23]. In these patients, perturbation of the steady state, such as an acute gastrointestinal or respiratory illness; an increase in diuretic dose; or the development of heart failure, may explain the hyponatremia. (See "Time course of loop and thiazide diuretic-induced electrolyte complications".)

The hyponatremia typically corrects over a period of days to two weeks after the cessation of therapy [2,3].

Diuretic-induced hyponatremia is rarely, if ever, associated with cerebral edema severe enough to cause herniation of the brain. This was illustrated in a series of 223 patients hospitalized for symptomatic hyponatremia due to thiazide diuretics; the mean plasma sodium was 115 mEq/L [6]. The major symptoms were malaise, lethargy, dizzy spells, and vomiting, all of which are well described manifestations of severe hyponatremia. There was only a 1 percent incidence of seizures and no cases of herniation [6].

The older literature includes reports of brain damage in outpatients with thiazide-induced hyponatremia [3,7]. However, at the time of the study, the consequences of overly rapid correction were unknown. The reported patients were all treated with hypertonic saline, increasing the plasma sodium concentration by more than 25 mEq/L in 48 hours, a rate of correction now known to be associated with osmotic demyelination in the brain. (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia".)

The reproducibility of thiazide-induced hyponatremia was evaluated in a study of 11 older adult patients with a history of thiazide-induced hyponatremia to below 130 mEq/L [2]. Rechallenge with a single 50 mg dose of hydrochlorothiazide lowered the plasma sodium concentration by 5 to 6 mEq/L in the first six hours [2]. A more pronounced effect was noted in another study of two older adult patients who had recovered from episodes of severe thiazide-induced hyponatremia (serum sodiums of 109 and 116 mEq/L) [3]. Rechallenge with either metolazone (10 mg/day) or hydrochlorothiazide (100 mg/day) resulted in a decrease in serum sodium from 142 to 124 mEq/L in 36 hours in one patient and from 133 to 120 mEq/L in 37 hours in the other patient [3].

TREATMENT — Treatment of diuretic-induced hyponatremia consists of discontinuing the diuretic and administering either isotonic saline or, if the hyponatremia is severe or symptomatic, hypertonic saline [11]. There is a potential risk of overly rapid correction of the hyponatremia with either regimen. Once the diuretic has been cleared and the patient becomes euvolemic, antidiuretic hormone (ADH) release will be appropriately suppressed, resulting in the excretion of a dilute urine, which can lead to rapid excretion of the excess water. Thus, patients with moderate to severe hyponatremia must be monitored carefully during treatment to minimize the risk of osmotic demyelination [1]. Preemptive administration of desmopressin has been used to prevent the excretion of dilute urine. (See "Overview of the treatment of hyponatremia in adults" and "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia".)

Prevention — There is no proven way to identify patients at risk of developing hyponatremia after diuretic therapy, making prevention difficult. Nevertheless, it may be prudent to avoid thiazide diuretics in beer drinkers and patients with psychogenic polydipsia and to measure the plasma sodium concentration within a few days after therapy has begun in older adult patients, especially those with a low body mass [5,21]. Patients should be told to temporarily stop the diuretic during intercurrent illnesses that result in decreased dietary intake or increased gastrointestinal fluid losses. A thiazide diuretic should generally not be used in patients who have had a previous episode of hyponatremia.

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: Hyponatremia" and "Society guideline links: Fluid and electrolyte disorders in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Hyponatremia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pathogenesis – Thiazide diuretics are more likely to cause hyponatremia than loop diuretics because they impair sodium chloride (NaCl) reabsorption in the distal convoluted tubule. As a result, there is an intact medullary concentration gradient, which is dependent on sodium chloride reabsorption in the loop, and patients treated with thiazide diuretics can excrete a concentrated urine if antidiuretic hormone (ADH) is present. (See 'Pathogenesis' above.)

Risk factors – Thiazide-induced hyponatremia most commonly occurs in older adult patients, particularly those with a low body mass. (See 'Incidence and patients at risk' above.)

Clinical manifestations – Patients with thiazide-induced hyponatremia often appear clinically euvolemic, sharing many features in common with patients with the syndrome of inappropriate ADH secretion (SIADH). (See 'Clinical manifestations' above.)

Management – Treatment consists of stopping the diuretic and administering either isotonic saline or, if the hyponatremia is severe or symptomatic, hypertonic saline. Patients with thiazide-induced hyponatremia are at risk of overly rapid correction because the ability to dilute the urine is restored once the effect of the diuretic clears and the patient becomes euvolemic. Thus, careful monitoring is needed during therapy to avoid osmotic demyelination. (See 'Treatment' above.)

  1. Sonnenblick M, Friedlander Y, Rosin AJ. Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients. Chest 1993; 103:601.
  2. Friedman E, Shadel M, Halkin H, Farfel Z. Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis. Ann Intern Med 1989; 110:24.
  3. Ashraf N, Locksley R, Arieff AI. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70:1163.
  4. Fichman MP, Vorherr H, Kleeman CR, Telfer N. Diuretic-induced hyponatremia. Ann Intern Med 1971; 75:853.
  5. Chow KM, Szeto CC, Wong TY, et al. Risk factors for thiazide-induced hyponatraemia. QJM 2003; 96:911.
  6. Chow KM, Kwan BC, Szeto CC. Clinical studies of thiazide-induced hyponatremia. J Natl Med Assoc 2004; 96:1305.
  7. Mozes B, Pines A, Werner D, et al. Thiazide-induced hyponatremia: an unusual neurologic course. South Med J 1986; 79:629.
  8. Sonnenblick M, Rosin AJ. Significance of the measurement of uric acid fractional clearance in diuretic induced hyponatraemia. Postgrad Med J 1986; 62:449.
  9. Szatalowicz VL, Miller PD, Lacher JW, et al. Comparative effect of diuretics on renal water excretion in hyponatraemic oedematous disorders. Clin Sci (Lond) 1982; 62:235.
  10. César KR, Magaldi AJ. Thiazide induces water absorption in the inner medullary collecting duct of normal and Brattleboro rats. Am J Physiol 1999; 277:F756.
  11. Filippone EJ, Ruzieh M, Foy A. Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology. Am J Kidney Dis 2020; 75:256.
  12. Frenkel NJ, Vogt L, De Rooij SE, et al. Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2. J Hypertens 2015; 33:627.
  13. Ware JS, Wain LV, Channavajjhala SK, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. J Clin Invest 2017; 127:3367.
  14. Clark BA, Shannon RP, Rosa RM, Epstein FH. Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol 1994; 5:1106.
  15. Decaux G, Schlesser M, Coffernils M, et al. Uric acid, anion gap and urea concentration in the diagnostic approach to hyponatremia. Clin Nephrol 1994; 42:102.
  16. Johnson JE, Wright LF. Thiazide-induced hyponatremia. South Med J 1983; 76:1363.
  17. Cooke CR, Turin MD, Walker WG. The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation. Medicine (Baltimore) 1979; 58:240.
  18. Verbalis JG. Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis. Am J Physiol 1994; 267:R1617.
  19. Mannheimer B, Bergh CF, Falhammar H, et al. Association between newly initiated thiazide diuretics and hospitalization due to hyponatremia. Eur J Clin Pharmacol 2021; 77:1049.
  20. Leung AA, Wright A, Pazo V, et al. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med 2011; 124:1064.
  21. Clayton JA, Rodgers S, Blakey J, et al. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Pharmacol 2006; 61:87.
  22. Rodenburg EM, Hoorn EJ, Ruiter R, et al. Thiazide-associated hyponatremia: a population-based study. Am J Kidney Dis 2013; 62:67.
  23. Sharabi Y, Illan R, Kamari Y, et al. Diuretic induced hyponatraemia in elderly hypertensive women. J Hum Hypertens 2002; 16:631.
  24. Gross P, Palm C. Thiazides: do they kill? Nephrol Dial Transplant 2005; 20:2299.
  25. Huang CC, Chung CM, Hung SI, et al. Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia. Medicine (Baltimore) 2015; 94:e1422.
  26. Maronde RF, Milgrom M, Vlachakis ND, Chan L. Response of thiazide-induced hypokalemia to amiloride. JAMA 1983; 249:237.
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