- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor Emeritus
- University of Rochester School of Medicine and Dentistry
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).
The difference in hyponatremic risk between thiazide-type 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 NaCl 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 NaCl 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 . 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 . 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 . Loss of this fluid can directly promote the development of hyponatremia independent of the degree of water intake. (See "Causes of hyponatremia 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) [1,3,11]. 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 [5,12]. 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".)
- Sonnenblick M, Friedlander Y, Rosin AJ. Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients. Chest 1993; 103:601.
- 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.
- Ashraf N, Locksley R, Arieff AI. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70:1163.
- Fichman MP, Vorherr H, Kleeman CR, Telfer N. Diuretic-induced hyponatremia. Ann Intern Med 1971; 75:853.
- Chow KM, Szeto CC, Wong TY, et al. Risk factors for thiazide-induced hyponatraemia. QJM 2003; 96:911.
- Chow KM, Kwan BC, Szeto CC. Clinical studies of thiazide-induced hyponatremia. J Natl Med Assoc 2004; 96:1305.
- Mozes B, Pines A, Werner D, et al. Thiazide-induced hyponatremia: an unusual neurologic course. South Med J 1986; 79:629.
- Sonnenblick M, Rosin AJ. Significance of the measurement of uric acid fractional clearance in diuretic induced hyponatraemia. Postgrad Med J 1986; 62:449.
- 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.
- 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.
- Maronde RF, Milgrom M, Vlachakis ND, Chan L. Response of thiazide-induced hypokalemia to amiloride. JAMA 1983; 249:237.
- Sharabi Y, Illan R, Kamari Y, et al. Diuretic induced hyponatraemia in elderly hypertensive women. J Hum Hypertens 2002; 16:631.
- 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.
- Clark BA, Shannon RP, Rosa RM, Epstein FH. Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol 1994; 5:1106.
- 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.
- Johnson JE, Wright LF. Thiazide-induced hyponatremia. South Med J 1983; 76:1363.
- 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.
- Verbalis JG. Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis. Am J Physiol 1994; 267:R1617.
- Leung AA, Wright A, Pazo V, et al. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med 2011; 124:1064.
- Clayton JA, Rodgers S, Blakey J, et al. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Pharmacol 2006; 61:87.
- Rodenburg EM, Hoorn EJ, Ruiter R, et al. Thiazide-associated hyponatremia: a population-based study. Am J Kidney Dis 2013; 62:67.
- Gross P, Palm C. Thiazides: do they kill? Nephrol Dial Transplant 2005; 20:2299.
- Huang CC, Chung CM, Hung SI, et al. Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia. Medicine (Baltimore) 2015; 94:e1422.