Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Hyponatraemia: more than just a marker of disease severity?

Nature Reviews Nephrology volume 9, pages 37–50 (2013)Cite this article

Subjects

A Correction to this article was published on 26 February 2013

This article has been updated

Abstract

Hyponatraemia—the most common serum electrolyte disorder—has also emerged as an important marker of the severity and prognosis of important diseases such as heart failure and cirrhosis. Acute hyponatraemia can cause severe encephalopathy, but the rapid correction of chronic hyponatraemia can also profoundly impair brain function and even cause death. With the expanding elderly population and the increased prevalence of hyponatraemia in this segment of society, prospective studies are needed to examine whether correcting hyponatraemia in the elderly will diminish cognitive impairment, improve balance and reduce the incidence of falls and fractures. Given that polypharmacy is also common in the elderly population, the various medications that may stimulate arginine vasopressin release and/or enhance the hormone's action to increase water absorption must also be taken into consideration. Whether hyponatraemia in a patient with cancer is merely a marker of poor prognosis or whether its presence may alter the patient's quality of life remains to be examined. In any case, hyponatraemia can no longer be considered as just a biochemical bystander in the ill patient. A systematic diagnostic approach is necessary to determine the specific aetiology of a patient's hyponatraemia. Therapy must then be dictated not only by recognized reversible causes such as advanced hypothyroidism, adrenal insufficiency, diuretics or other medicines, but also by whether the hyponatraemia occurred acutely or chronically. Information is emerging that the vast majority of cases of hyponatraemia are caused by the nonosmotic release of arginine vasopressin. Now that vasopressin V2-receptor blockers are available, a new era of clinical investigation is necessary to examine whether hyponatraemia is just a marker of severe disease or whether correction of hyponatraemia could improve a patient's quality of life. Such an approach must involve prospective randomized studies in different groups of patients with hyponatraemia, including those with advanced heart failure, those with cirrhosis, patients with cancer, and the elderly.

Key Points

  • Hyponatraemia is the most common electrolyte disturbance in clinical practice and its most common mediator is the nonosmotic release of arginine vasopressin

  • In the elderly, hyponatraemia predisposes to falls and fractures and may worsen cognitive impairment; in patients with heart failure, hyponatraemia reflects severe haemodynamic alterations and is associated with worse morbidity and mortality

  • In patients with liver cirrhosis, hyponatraemia is associated with increased mortality, hepatorenal syndrome, hepatic encephalopathy, and reduced quality of life

  • Hyponatraemia carries a worse prognosis in patients with chronic kidney disease, including those with end-stage renal disease

  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is classified as euvolaemic hyponatraemia, and therefore hypovolaemic or hypervolaemic causes of hyponatremia need to be excluded

  • In addition to fluid restriction, vasopressin-receptor antagonists are now available in some countries to treat hyponatremia in heart failure, cirrhosis and SIADH

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The pivotal role of vasopressin in the pathophysiology of hyponatraemia.
Figure 2: Diagnostic and therapeutic approach to the hypovolaemic, euvolaemic, and hypervolaemic patient with hyponatraemia.

Similar content being viewed by others

Change history

  • 28 January 2013

    In Figure 1 of the version of this article initially published online, "Baroreceptors" was incorrectly written as "Basoreceptors". The error has been corrected for the HTML and PDF versions of the article.

References

  1. Schrier, R. W. Body water homeostasis: clinical disorders of urinary dilution and concentration. J. Am. Soc. Nephrol. 17, 1820–1832 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Hawkins, R. C. Age and gender as risk factors for hyponatremia and hypernatremia. Clin. Chim. Acta 337, 169–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Owen, J. A. & Campbell, D. G. A comparison of plasma electrolyte and urea values in healthy persons and in hospital patients. Clin. Chim. Acta 22, 611–618 (1968).

    Article  CAS  PubMed  Google Scholar 

  4. Hoorn, E., Lindemans, J. & Zietse, R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol. Dial. Transplant. 21, 70–76 (2006).

    Article  PubMed  Google Scholar 

  5. DeVita, M. V., Gardenswartz, M. H., Konecky, A. & Zabetakis, P. Incidence and etiology of hyponatremia in an intensive care unit. Clin. Nephrol. 34, 163–166 (1990).

    CAS  PubMed  Google Scholar 

  6. Ayus, J. C., Achinger, S. G. & Arieff, A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am. J. Physiol. Renal Physiol. 295, F619–F624 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Bradley, E. L., Etheridge, M. S. & Arieff, A. I. Causes of brain damage in patients with severe symptomatic hyponatremia: analysis of 344 patients over 30 years [abstract]. J. Am. Soc. Nephrol. 16, 44A (2005).

    Google Scholar 

  8. Waikar, S. S., Mount, D. B. & Curhan, G. C. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am. J. Med. 122, 857–865 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Doshi, S. M., Shah, P., Lei, X., Lahoti, A. & Salahudeen, A. K. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. Am. J. Kidney Dis. 59, 222–228 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Wald, R., Jaber, B. L., Price, L. L., Upadhyay, A. & Madias, N. E. Impact of hospital-associated hyponatremia on selected outcomes. Arch. Intern. Med. 170, 294–302 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Chawla, A., Sterns, R. H., Nigwekar, S. U. & Cappuccio, J. D. Mortality and serum sodium: do patients die from or with hyponatremia? Clin. J. Am. Soc. Nephrol. 6, 960–965 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zilberberg, M. D. et al. Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study. BMC Pulm. Med. 8, 16 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Klein, L. et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure. Circulation 111, 2454–2460 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Biggins, S. W. et al. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 41, 32–29 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Pokaharel, M. & Block, C. A. Dysnatremia in the ICU. Curr. Opin. Crit. Care 17, 581–593 (2011).

    Article  PubMed  Google Scholar 

  16. Stelfox, H. T. et al. The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units. Can. J. Anaesth. 57, 650–658 (2010).

    Article  PubMed  Google Scholar 

  17. DeVita, M. V., Gardenswartz, M. H., Konecky, A. & Zabetakis, P. M. Incidence and etiology of hyponatremia in an intensive care unit. Clin. Nephrol. 34, 163–166 (1990).

    CAS  PubMed  Google Scholar 

  18. Funk, G. C. et al. Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med. 36, 304–311 (2010).

    Article  PubMed  Google Scholar 

  19. Caird, F. I., Andrews, G. R. & Kennedy, R. D. Effect of posture on blood pressure in the elderly. Br. Heart J. 35, 527–530 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miller, M., Hecker, M. S. & Friedlander, D. A. Apparent idiopathic hyponatremia in an ambulatory geriatric population. J. Am. Geriatr. Soc. 44, 404–408 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Anpalahan, M. Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. Q. J. Med. 101, 583–588 (2008).

    Article  Google Scholar 

  22. Miller, M. Hyponatremia: age-related risk factors and therapy decisions. Geriatrics 53, 32–48 (1998).

    CAS  PubMed  Google Scholar 

  23. Kleinfeld, M., Casimir, M. & Borra, S. Hyponatremia as observed in a chronic disease facility. J. Am. Geriatr. Soc. 27, 156–161 (1979).

    Article  CAS  PubMed  Google Scholar 

  24. Sunderam, S. G. & Mankikar, G. D. Hyponatremia in the elderly. Age Ageing 12, 77–80 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Miller, M., Morley, J. F. & Rubinstein, L. Z. Hyponatremia in a nursing home population. J. Am. Geriatr. Soc. 43, 1410–1413 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Bettari, L. et al. Hyponatremia and long-term outcomes in chronic heart failure-an observational study from the Duke Databank for Cardiovascular Diseases. J. Card. Fail. 18, 74–81 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Konstam, M. A. et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 297, 1319–1331 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Shorr, A. F. et al. Burden of sodium abnormalities in patients hospitalized for heart failure. Congest. Heart Fail. 17, 1–7 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. DeWolfe, A., Lopez, B., Arcement, L. M. & Hebert, K. Low serum sodium as a poor prognostic indicator for mortality in congestive heart failure patients. Clin. Cardiol. 33, E13–E17 (2010).

    Article  PubMed  Google Scholar 

  30. Mohammed, A. A. et al. Hyponatremia, natriuretic peptides, and outcomes in acutely decompensated heart failure: results from the International Collaborative of NT-proBNP Study. Circ. Heart Fail. 3, 354–361 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Klein, L. et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation 111, 2454–2460 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Gheorghiade, M. et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch. Intern. Med. 167, 1998–2005 (2007).

    Article  PubMed  Google Scholar 

  33. Solà, E. et al. Factors related to quality of life in patients with cirrhosis and ascites. Relevance of serum sodium concentration and leg edema. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2012.07.020.

  34. Shaikh, S., Mal, G., Khalid, S., Baloch, G. H. & Akbar, Y. Frequency of hyponatraemia and its influence on liver cirrhosis-related complications. J. Pak. Med. Assoc. 60, 116–120 (2010).

    PubMed  Google Scholar 

  35. Kim, J. H. et al. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J. Intern. Med. 24, 106–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yun, B. C. et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology 49, 1610–1615 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Angeli, P., Wong, F., Watson, H. & Ginès, P. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology 44, 1535–1542 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Berghmans, T., Paesmans, M. & Body, J. J. A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis. Support Care Cancer 8, 192–197 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Doshi, S. M., Shah, P., Lei, X., Lahoti, A. & Salahudeen, A. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. Am. J. Kidney Dis. 59, 222–228 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Nair, V., Niederman, M. S., Masani, N. & Fishbane, S. Hyponatremia in community-acquired pneumonia. Am. J. Nephrol. 27, 184–190 (2007).

    Article  PubMed  Google Scholar 

  41. Kovesdy, C. P. et al. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 125, 677–684 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Waikar, S. S., Curhan, G. C. & Brunelli, S. M. Mortality associated with low serum sodium concentration in maintenance hemodialysis. Am. J. Med. 124, 77–84 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Almond, C. S. et al. Hyponatremia among runners in the Boston Marathon. N. Engl. J. Med. 352, 1550–1556 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Knechtle, B., Knechtle, P. & Rosemann, T. Low prevalence of exercise-associated hyponatremia in male 100 km ultra-marathon runners in Switzerland. Eur. J. Appl. Physiol. 111, 1007–1016 (2011).

    Article  PubMed  Google Scholar 

  45. Kipps, C., Sharma, S. & Pedoe, D. T. The incidence of exercise-associated hyponatraemia in the London marathon. Br. J. Sports Med. 45, 14–19 (2011).

    Article  PubMed  Google Scholar 

  46. Mettler, S. et al. Hyponatremia among runners in the Zurich Marathon. Clin. J. Sport Med. 18, 344–349 (2008).

    Article  PubMed  Google Scholar 

  47. Gankam Kengne, F., Andres, C., Sattar, L., Melot, C. & Decaux G. Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM 101, 583–588 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Sandhu, H. S., Gilles, E., DeVita, M. V., Panagopoulos, G. & Michelis, M. F. Hyponatremia associated with large-bone fracture in elderly patients. Int. Urol. Nephrol. 41, 733–737 (2009).

    Article  PubMed  Google Scholar 

  49. Beck, L. H. Changes in renal function with aging. Clin. Geriatr. Med. 14, 199–209 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, L. K., Lin, M. H., Hwang, A. J. & Chen, T. W. Hyponatremia among the institutionalized elderly in 2 long-term care facilities in Taipei. J. Chin. Med. Assoc. 69, 115–119 (2006).

    Article  PubMed  Google Scholar 

  51. Schrier, R. W., Berl, T. & Anderson, R. J. Osmotic and non-osmotic control of vasopressin release. Am. J. Physiol. 236, F321–F322 (1979).

    CAS  PubMed  Google Scholar 

  52. Rudman, D. et al. Hyponatremia in tube-fed elderly men. J. Chronic Dis. 39, 73–80 (1986).

    Article  CAS  PubMed  Google Scholar 

  53. Goldstein, C. S., Braunstein, S. & Goldfarb, S. Idiopathic syndrome of inappropriate antidiuretic hormone secretion possibly related to advanced age. Ann. Intern. Med. 99, 185–188 (1983).

    Article  CAS  PubMed  Google Scholar 

  54. Renneborg, B., Musch, W., Vandemergel, X., Manto, M. & Decaux, G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am. J. Med. 119, 71.e1–71.e8 (2006).

    Article  CAS  Google Scholar 

  55. Gosch, M., Joosten-Gstrein, B., Heppner, H. J. & Lechleitner, M. Hyponatremia in geriatric inhospital patients: effects on results of a comprehensive geriatric assessment. Gerontology 58, 430–440 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Thaler, S. M., Teitelbaum, I. & Berl, T. “Beer potomania” in non-beer drinkers: effect of low dietary solute intake. Am. J. Kidney Dis. 31, 1028–1031 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Kugler, J. P. & Hustead, T. Hyponatremia and hypernatremia in the elderly. Am. Fam. Physician 61, 3623–3630 (2000).

    CAS  PubMed  Google Scholar 

  58. Clayton, J. A., Rodgers, S., Blakey, J., Avery, A. & Hall, I. P. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br. J. Clin. Pharmacol. 61, 87–95 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Berl, T. & Schrier, R. Disorders of water metabolism. In Renal and Electrolyte Disorders 6th edn (ed. Schrier, R.) (Philadelphia, Lippincott Williams & Wilkins, 2003).

    Google Scholar 

  60. Jencks, S. F., Williams, M. V. & Coleman, E. A. Rehospitalizations among patients in the Medicare fee-for-service program. N. Engl. J. Med. 360, 1418–1429 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Allen, L. A. et al. Identifying patients hospitalized with heart failure at risk for unfavorable future quality of life. Circ. Cardiovasc. Qual. Outcomes 4, 389–398 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Gottlieb, S. S. et al. The prognostic importance of different definitions of worsening renal function in congestive heart failure. J. Card. Fail. 8, 136–141 (2002).

    Article  PubMed  Google Scholar 

  63. Schrier, R. W. Blood urea nitrogen (BUN) and serum creatinine: not married in heart failure. Circ. Heart Fail. 1, 2–5 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Lilly, L., Dzau, V., Williams, G., Rydstedt, L. & Hollenberg, N. Hyponatremia in congestive heart failure: implications for neurohumoral activation and responses to orthostasis. J. Clin. Endocrinol. Metab. 52, 924 (1984).

    Article  Google Scholar 

  65. Szatalowicz, V. L. et al. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N. Engl. J. Med. 305, 263–266 (1981).

    Article  CAS  PubMed  Google Scholar 

  66. Riegger, G. A., Leibau, G. & Kochsiek, K. Antidiuretic hormone in congestive heart failure. Am. J. Med. 72, 49 (1982).

    Article  CAS  PubMed  Google Scholar 

  67. Goldsmith, S. R., Francis, G. S., Cowley, A. W., Levine, T. B. & Cohn, J. N. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J. Am. Coll. Cardiol. 1, 1385 (1983).

    Article  CAS  PubMed  Google Scholar 

  68. Kim, J. K. et al. Arginine vasopressin gene expression in chronic cardiac failure in rats. Kidney Int. 38, 818–822 (1990).

    Article  CAS  PubMed  Google Scholar 

  69. Abraham, W. T. Hormones and hemodynamics in heart failure. N. Engl. J. Med. 341, 577–585 (1999).

    Article  PubMed  Google Scholar 

  70. Schrier, R. W. Body fluid regulation in health and disease: a unifying hypothesis. Ann. Intern. Med. 113, 155–159 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. Riegger, G. A., Liebau, G., Bauer, E. & Kochsiek, K. Vasopressin and renin in high output heart failure of rats: hemodynamic effects of elevated plasma hormone levels. J. Cardiovasc. Pharmacol. 7, 1–5 (1985).

    Article  CAS  PubMed  Google Scholar 

  72. Forfia, P. R. et al. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 177, 1364–1369 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Scherz, N. et al. Prognostic importance of hyponatremia in patients with acute pulmonary embolism. Am. J. Respir. Crit. Care Med. 182, 1178–1183 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Crestanello, J. A. et al. Preoperative hyponatremia predicts outcomes after cardiac surgery. J. Surg. Res. http://dx.doi.org/10.1016/j.jss.2012.06.004.

  75. Abraham, W., Shamshirsaz, A., McFann, K., Oren, R. & Schrier, R. W. Aquaretic effect of lixivaptan, an oral non-peptide selective V2 receptor vasopressin antagonist, in the New York Heart Association Functional class II and III chronic failure patients. J. Am. Coll. Cardiol. 47, 1615–1621 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Kindermann, I. et al. Cognitive function in patients with decompensated heart failure: the Cognitive Impairment in Heart Failure (CogImpair-HF) study. Eur. J. Heart Fail. 14, 404–413 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Gheorghiade, M. et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 297, 1332–1343 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Ginés, P. & Schrier, R. W. Renal failure in cirrhosis. N. Engl. J. Med. 361, 1279–1290 (2009).

    Article  PubMed  Google Scholar 

  79. Ginés, P. et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology 28, 851–864 (1998).

    Article  PubMed  Google Scholar 

  80. Martin, P. Y., Gines, P. & Schrier, R. W. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N. Engl. J. Med. 339, 533–541 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Bichet, D., Szatalowicz, V., Chaimovitz, C. & Schrier, R. W. Role of vasopressin in abnormal water excretion in cirrhotic patients. Ann. Intern. Med. 96, 413–417 (1982).

    Article  CAS  PubMed  Google Scholar 

  82. Porcel, A. et al. Dilutional hyponatremia in patients with cirrhosis and ascites. Arch. Intern. Med. 162, 323–328 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Gines, A. et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 105, 229–236 (1993).

    Article  CAS  PubMed  Google Scholar 

  84. Guevara, M. et al. Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration. Liver Int. 30, 1137–1142 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Schrier, R. W. et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N. Engl. J. Med. 355, 2099–2112 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Gines, P. et al. Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial. Hepatology 48, 204–213 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Cárdenas, A. et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J. Hepatol. 56, 571–578 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Hackworth, W. A. et al. Effect of hyponatraemia on outcomes following orthotopic liver transplantation. Liver Int. 29, 1071–1077 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Dawwas, M. F. et al. The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study. Liver Transpl. 13, 1115–1124 (2007).

    Article  PubMed  Google Scholar 

  90. Yun, B. C. et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology 49, 1610–1615 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. DiScala, V. A. & Kinney, M. J. Effects of myxedema on the renal diluting and concentrating mechanism. Am. J. Med. 50, 325–335 (1971).

    Article  CAS  PubMed  Google Scholar 

  92. Chen, Y. C. et al. Nonosmotic release of vasopressin and renal aquaporins in impaired urinary dilution in hypothyroidism. Am. J. Physiol. Renal Physiol. 289, F672–F678 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Warner, M. H., Holding, S. & Kilpatrick, E. S. The effect of newly diagnosed hypothyroidism on serum sodium concentrations: a retrospective study. Clin. Endocrinol. (Oxf.) 64, 598–599 (2006).

    Article  Google Scholar 

  94. Oelkers, W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N. Engl. J. Med. 321, 492–496 (1989).

    Article  CAS  PubMed  Google Scholar 

  95. Diringer, M. N. & Zazulia, A. R. Hyponatremia in neurologic patients: consequences and approaches to treatment. Neurologist 12, 117–126 (2006).

    Article  PubMed  Google Scholar 

  96. Dhar, R. & Murphy-Human, T. A bolus of conivaptan lowers intracranial pressure in a patient with hyponatremia after traumatic brain injury. Neurocrit. Care 14, 97–102 (2011).

    Article  PubMed  Google Scholar 

  97. Dubovsky, S. L., Grabon, S., Berl, T. & Schrier, R. W. Syndrome of inappropriate secretion of antidiuretic hormone with exacerbated psychosis. Ann. Intern. Med. 79, 551–554 (1973).

    Article  CAS  PubMed  Google Scholar 

  98. Hill, A. R., Uribarri, J., Mann, J. & Berl, T. Altered water metabolism in tuberculosis: role of vasopressin. Am. J. Med. 88, 357–364 (1990).

    Article  CAS  PubMed  Google Scholar 

  99. Breuer, R. & Rubinow, A. Inappropriate secretion of antidiuretic hormone and mycoplasma pneumonia infection. Respiration 42, 217–219 (1981).

    Article  CAS  PubMed  Google Scholar 

  100. Farber, M. O. et al. Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Arch. Intern. Med. 142, 1326–1330 (1982).

    Article  CAS  PubMed  Google Scholar 

  101. Kaskavage, J. & Sklansky, D. Hyponatremia-associated rhabdomyolysis following exercise in an adolescent with cystic fibrosis. Pediatrics 130, e220–e223 (2012).

    Article  PubMed  Google Scholar 

  102. Baratz, R. A. & Ingraham, R. C. Renal hemodynamics and antidiuretic hormone release associated with volume regulation. Am. J. Physiol. 198, 565–570 (1960).

    Article  CAS  PubMed  Google Scholar 

  103. Letmaier, M. et al. Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme. Int. J. Neuropsychopharmacol. 15, 739–748 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Wilkinson, T. J., Begg, E. J., Winter, A. C. & Sainsbury, R. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people. Br. J. Clin. Pharmacol. 47, 211–217 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Moyses, Z. P., Nakandakari, F. K. & Magaldi, A. J. Fluoxetine effect on kidney water reabsorption. Nephrol. Dial. Transplant. 23, 1173–1178 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Burgess, C., O'Donohoe, A. & Gill, M. Agony and ecstasy: a review of MDMA effects and toxicity. Eur. Psychiatry 15, 287–294 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Tang, W. W., Kaptein, E. M., Feinstein, E. I. & Massry, S. G. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. Am. J. Med. 94, 169–174 (1993).

    Article  CAS  PubMed  Google Scholar 

  108. Verbalis, J. G. et al. Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion. Eur. J. Endocrinol. 164, 725–732 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rosenthal, S. M. et al. Nephrogenic syndrome of inappropriate antidiuresis. N. Engl. J. Med. 352, 1884–1890 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Chung, H. M., Kluge, R., Schrier, R. W. & Anderson, R. J. Clinical assessment of extracellular fluid volume in hyponatremia. Am. J. Med. 83, 905–908 (1987).

    Article  CAS  PubMed  Google Scholar 

  111. Decaux, G. & Musch, W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin. J. Am. Soc. Nephrol. 3, 1175–1184 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Fenske, W. et al. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. J. Clin. Endocrinol. Metab. 93, 2991–2997 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Fenske, W. et al. Copeptin in the differential diagnosis of hyponatremia. J. Clin. Endocrinol. Metab. 94, 123–129 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Ellison, D. H. & Berl, T. Clinical practice. The syndrome of inappropriate antidiuresis. N. Engl. J. Med. 356, 2064–2072 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Fenske, W., Maier, S. K., Blechschmidt, A., Allolio, B. & Störk, S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am. J. Med. 123, 652–657 (2010).

    Article  PubMed  Google Scholar 

  116. Young, M., Sciurba, F. & Rinaldo, J. Delirium and pulmonary edema after completing a marathon. Am. Rev. Respir. Dis. 136, 737–739 (1987).

    Article  CAS  PubMed  Google Scholar 

  117. Noakes, T. D., Goodwin, N., Rayner, B. L., Branken, T. & Taylor, R. K. Water intoxication: a possible complication during endurance exercise. Med. Sci. Sports Exerc. 17, 370–375 (1985).

    Article  CAS  PubMed  Google Scholar 

  118. Speedy, D. B. et al. Hyponatremia in ultradistance triathletes. Med. Sci. Sports Exerc. 31, 809–815 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. Petzold, A., Keir, G. & Appleby, I. Marathon related death due to brainstem herniation in rehydration-related hyponatraemia: a case report. J. Med. Case Rep. 1, 186 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Siegel, A. J. et al. Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion. Am. J. Med. 120, 461.e11–461.e17 (2007).

    Article  Google Scholar 

  121. Hew-Butler, T. et al. Changes in copeptin and bioactive vasopressin in runners with and without hyponatremia. Clin. J. Sport Med. 21, 211–217 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Ayus, J. C., Varon, J. & Arieff, A. I. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann. Intern. Med. 132, 711–714 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Wakui, A. Electrolyte abnormalities associated with cancer: a review [Japanese]. Gan. To. Kagaku Ryoho 13, 2031–2038 (1986).

    CAS  PubMed  Google Scholar 

  124. Gill, G. et al. Characteristics and mortality of severe hyponatraemia—a hospital-based study. Clin. Endocrinol. (Oxf.) 65, 246–249 (2006).

    Article  Google Scholar 

  125. Berghmans, T. Hyponatremia related to medical anticancer treatment. Support Care Cancer 4, 341–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Bennett, H. E., Bishop, M., Zadik, T. D. & Lincoln, N. B. Cognitive impairment after transurethral resection of the prostate (TURP). Disabil. Rehabil. 26, 1381–1387 (2004).

    Article  Google Scholar 

  127. Sorensen, J. B., Andersen, M. K. & Hansen, H. H. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J. Intern. Med. 238, 97–110 (1995).

    Article  CAS  PubMed  Google Scholar 

  128. Schwartz, W. B., Bennett, W., Curelop, S. & Bartter, F. C. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am. J. Med. 23, 529–542 (1957).

    Article  CAS  PubMed  Google Scholar 

  129. Morton, J. J., Kelly, P. & Padfield, P. L. Antidiuretic hormone in bronchogenic carcinoma. Clin. Endocrinol. (Oxf.) 9, 357–370 (1978).

    Article  CAS  Google Scholar 

  130. Shapiro, J. & Richardson, G. E. Hyponatremia of malignancy. Crit. Rev. Oncol. Hematol. 18, 129–135 (1995).

    Article  CAS  PubMed  Google Scholar 

  131. List, A. F. et al. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J. Clin. Oncol. 4, 1191–1198 (1986).

    Article  CAS  PubMed  Google Scholar 

  132. Odell, W. D. & Wolfsen, A. R. Humoral syndromes associated with cancer. Annu. Rev. Med. 29, 379–406 (1978).

    Article  CAS  PubMed  Google Scholar 

  133. Ferlito, A., Rinaldo, A. & Devaney, K. O. Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature. Ann. Otol. Rhinol. Laryngol. 106, 878–883 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Onitilo, A. A., Kio, E. & Doi, S. A. R. Tumor-Related Hyponatremia. Clin. Med. Res. 5, 228–237 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hamdi, T. et al. Cisplatin-induced renal salt wasting syndrome. South Med. J. 103, 793–799 (2010).

    Article  PubMed  Google Scholar 

  136. Iihoshi, M., Sakuragi, T., Higa, K. & Hamada, T. Severe hyponatremia during transurethral resection of prostate [Japanese]. Masui 54, 414–417 (2005).

    PubMed  Google Scholar 

  137. Issa, M. M., Young, M. R., Bullock, A. R., Bouet, R. & Petros, J. A. Dilutional hyponatremia of TURP syndrome: a historical event in the 21st century. Urology 64, 298–301 (2004).

    Article  PubMed  Google Scholar 

  138. Hwang, C. B. et al. Absorption of irrigating fluid during transcervical resection of endometrium—a report of two cases. Acta Anaesthesiol. Sin. 35, 45–50 (1997).

    CAS  PubMed  Google Scholar 

  139. Ayus, J. C., Wheeler, J. M. & Arieff, A. I. Postoperative Hyponatremic Encephalopathy in Menstruant Women. Ann. Intern. Med. 117, 891–897 (1992).

    Article  CAS  PubMed  Google Scholar 

  140. Choong, K. et al. Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial. Pediatrics 128, 857–866 (2011).

    Article  PubMed  Google Scholar 

  141. Yung, M. & Keeley, S. Randomised controlled trial of intravenous maintenance fluids. J. Paediatr. Child. Health. 45, 9–14 (2009).

    Article  PubMed  Google Scholar 

  142. Moritz, M. L. & Ayus, J. C. Prevention of hospital-acquired hyponatremia: a case for using isotonic saline. Pediatrics 111, 227–230 (2003).

    Article  PubMed  Google Scholar 

  143. Bergstrom, W. H. The participation of bone in total body sodium metabolism in the rat. J. Clin. Invest. 34, 997–1004 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Bergstrom, W. H. & Wallace, W. M. Bone as a sodium and potassium reservoir. J. Clin. Invest. 33, 867–873 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Verbalis, J. G. et al. Hyponatremia-induced osteoporosis. J. Bone Miner. Res. 25, 554–563 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Barsony, J., Sugimura, Y. & Verbalis, J. F. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J. Biol. Chem. 286, 10864–10875 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Kinsella, S., Moran, S., Sullivan, M. O., Molloy, M. G. M. & Eustace, J. A. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin. J. Am. Soc. Nephrol. 5, 275–280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hoorn, E. J. et al. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J. Bone Miner. Res. 26, 1822–1828 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Ziere, G. et al. Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J. Clin. Psychopharmacol. 28, 411–417 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Barsony, J., Manigrasso, M. B., Xu, Q., Tam, H. & Verbalis, J. G. Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats. Age (Dordr). http://dx.doi.org/10.1007/s11357-011-9347-9.

  151. Hoorn, E. J., Liamis, G., Zietse, R. & Zillikens, M. C. Hyponatremia and bone: an emerging relationship. Nat. Rev. Endocrinol. 8, 33–39 (2011).

    Article  PubMed  Google Scholar 

  152. Verbalis, J. G., Goldsmith, S. R., Greenberg, A., Schrier, R. W. & Sterns, R. H. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am. J. Med. 120 (11 Suppl. 1), S1–S21 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Moritz, M. L. & Ayus, J. C. 100 cc 3% sodium chloride bolus: a novel treatment for hyponatremic encephalopathy. Metab. Brain Dis. 25, 91–96 (2010).

    Article  PubMed  Google Scholar 

  154. Koenig, M. A. et al. Reversal of transtentorial herniation with hypertonic saline. Neurology 70, 1023–1029 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Ayus, J. C. & Arieff, A. I. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA 281, 2299–2304 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Miller, P. D., Linas, S. L. & Schrier, R. W. Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients. JAMA 243, 2513–2515 (1980).

    Article  CAS  PubMed  Google Scholar 

  157. Bichet, D. G. What is the role of vaptans in routine clinical nephrology? Clin. J. Am. Soc. Nephrol. 7, 700–703 (2012).

    Article  PubMed  Google Scholar 

  158. Decaux, G., Andres, C., Gankam Kengne, F. & Soupart, A. Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit. Care 14, R184 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Soupart, A., Coffernils, M., Couturier, B., Gankam-Kengne, F. & Decaux, G. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin. J. Am. Soc. Nephrol. 7, 742–747 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Hantman, D., Rossier, B., Kohlman, R. & Schrier, R. W. Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Ann. Intern. Med. 78, 870–875 (1973).

    Article  CAS  PubMed  Google Scholar 

  161. Anderson, R. J., Chung, H. M., Kluge, R. & Schrier, R. W. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann. Intern. Med. 102, 164–168 (1985).

    Article  CAS  PubMed  Google Scholar 

  162. Verbalis, J. G., Zeltser, D., Smith, N., Barve, A. & Andoh, M. Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study. Clin. Endocrinol. (Oxf.) 69, 159–168 (2008).

    Article  CAS  Google Scholar 

  163. Berl, T. et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J. Am. Soc. Nephrol. 21, 705–712 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Gullans, S. R. & Verbalis, J. G. Control of brain volume during hyperosmolar and hypoosmolar conditions. Annu. Rev. Med. 44, 289–301 (1993).

    Article  CAS  PubMed  Google Scholar 

  165. Sterns, R. H., Cappuccio, J. D., Silver, S. M. & Cohen, E. P. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J. Am. Soc. Nephrol. 4, 1522–1530 (1994).

    CAS  PubMed  Google Scholar 

  166. Cluitmans, F. H. & Meinders, A. E. Management of severe hyponatremia: rapid or slow correction? Am. J. Med. 88, 161–166 (1990).

    Article  CAS  PubMed  Google Scholar 

  167. Ayus, J. C., Krothapalli, R. K. & Arieff, A. I. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N. Engl. J. Med. 317, 1190–1195 (1987).

    Article  CAS  PubMed  Google Scholar 

  168. Soupart, A., Schroëder, B. & Decaux, G. Treatment of hyponatraemia by urea decreases risks of brain complications in rats. Brain osmolyte contents analysis. Nephrol. Dial. Transplant. 22, 1856–1863 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Soupart, A., Silver, S., Schroöeder, B., Sterns, R. & Decaux, G. Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myo-inositol) in azotemic rats after correction of chronic hyponatremia. J. Am. Soc. Nephrol. 13, 1433–1441 (2002).

    Article  CAS  PubMed  Google Scholar 

  170. Ayus, J. C., Armstrong, D. & Arieff, A. I. Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents. Kidney Int. 69, 1319–1325 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Schaffer, S., Solodushko, V., Pastukh, V., Ricci, C. & Azuma, J. Possible cause of taurine-deficient cardiomyopathy: potentiation of angiotensin II action. J. Cardiovasc. Pharmacol. 41, 751–759 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Desai, K. V. et al. Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema. Am. J. Physiol. Heart Circ. Physiol. 294, H2428–H2434 (2008).

    Article  CAS  PubMed  Google Scholar 

  173. Dongaonkar, R. M., Stewart, R. H., Geissler, H. J. & Laine, G. A. Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function. Cardiovasc. Res. 87, 331–339 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Okada, K., Ishikawa, S., Caramelo, C., Tsai, P. & Schrier, R. W. Enhancement of vascular action of arginine vasopressin by diminished extracellular sodium concentration. Kidney Int. 44, 755–763 (1993).

    Article  CAS  PubMed  Google Scholar 

  175. Otsuka Pharmaceutical Ltd. Direct Healthcare Professional Communication on the risk of increases in serum sodium with tolvaptan which are too rapid [online], (2012).

  176. Gross, P. A., Wagner, A. & Decaux, G. Vaptans are not the mainstay of treatment in hyponatremia: perhaps not yet. Kidney Int. 80, 594–600 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Colorado School of Medicine, 12700 East 19th Avenue C281, Aurora, 80045, CO, USA

    Robert W. Schrier, Shailendra Sharma & Dmitry Shchekochikhin

Authors
  1. Robert W. Schrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shailendra Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dmitry Shchekochikhin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Robert W. Schrier.

Ethics declarations

Competing interests

R. W. Schrier declares associations with the following companies: Janssen Pharmaceuticals (consultant), Otsuka Pharmaceuticals (consultant). The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schrier, R., Sharma, S. & Shchekochikhin, D. Hyponatraemia: more than just a marker of disease severity?. Nat Rev Nephrol 9, 37–50 (2013). https://doi.org/10.1038/nrneph.2012.246

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.246

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing