American Journal of Kidney Diseases
Volume 59, Issue 2 , Pages 168-169, February 2012

Hyponatremia and Mortality in Patients With Cancer: The Devil Is in the Details

  • Fadi Fakhouri, MD, PhD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Fadi Fakhouri, MD, PhD, Nephrology Department, Institut de Transplantation Urologie et Nephrologie, INSERM U643, CHU de Nantes, Nantes, France
    • ,
  • Frédéric Lavainne, MD

CHU de Nantes, Nantes, France

Hôpital Européen Georges Pompidou, Paris, France

Article Outline

 

Related Article, p. 222

Clinicians usually agree that hyponatremia is the most frequently encountered electrolyte abnormality in hospitalized patients, occurring in 5%-30% of patients in various reports.1, 2 They also acknowledge that, even though hyponatremia may arise in the setting of various medical conditions ranging from liver cirrhosis to heart failure, medications (and thus doctors) remain one of the main causes of hyponatremia. In contrast, the clinical impact of hyponatremia per se on the morbidity and mortality of patients remains a matter of heated debate. In particular, it remains unclear whether “patients die from or with hyponatremia,” a conundrum elegantly formulated by Chawla and colleagues in a recent study.3 In other words, does the underlying disease causing hyponatremia account for the mortality rather than hyponatremia per se?

In this issue of the American Journal of Kidney Diseases, Doshi and colleagues4 add a new piece of evidence to the ongoing debate, by assessing the incidence of hyponatremia in hospitalized patients with cancer and its impact on the clinical outcomes of these patients. Hyponatremia in patients with cancer may occur mostly as a consequence of an inappropriate antidiuretic hormone secretion by the neoplasm, side effects of chemotherapy (including cisplatin), and hydration protocols.5 Mortality may possibly be affected by each of these factors.

Doshi and colleagues provide a large-scale assessment of hyponatremia in patients with cancer. They prospectively collected and retrospectively analyzed data regarding hyponatremia in a large cohort of 3,357 hospitalized patients with cancer and report an impressive 47% rate of hyponatremia (<135 mEq/L). This rate of hyponatremia does not come as a surprise as patients with cancer are usually older with several comorbid conditions. Hyponatremia was mild (130-134 mEq/L) in more than three-quarters of cases and it was acquired during hospitalization in roughly half of the cases. Severe hyponatremia (<120 mEq/L) was more frequent in patients with head, neck, and lung cancers (47%) compared with other types of neoplasia (5%-21%), probably a consequence of the severe malnutrition usually encountered in the first group of patients. A complete correction of hyponatremia was not achieved in roughly one-third of patients during hospitalization. More interestingly, after adjusting for several confounding factors (age, chemotherapy, serum creatinine, etc), hyponatremia was associated with a longer hospital stay (on average, 4 to 8 additional days) and with an increased 90-day mortality. For instance, even moderate hyponatremia (120-129 mEq/L) was associated with a hazard ratio of 4.7 for 90-day mortality compared with a hazard ratio of 2 in cases of mild hyponatremia (130-134 mEq/L). Interestingly, the hazard ratio was only 3.4 in cases with severe hyponatremia (<120 mEq/L). However, only 19 patients had severe hyponatremia (<1% of all patients with hyponatremia). Similarly, the mean duration of hospital stay increased from 5.6 days in patients with eunatremia to 9.9 and 13 days in patients with mild and moderate hyponatremia, respectively. However, paradoxically the mean hospital stay was lower (11.5 days) for patients with severe hyponatremia.

The study by Chawla and colleagues3 previously provided convincing arguments suggesting that the nature of the underlying illness rather than the severity of hyponatremia correlates with mortality. In their cohort of more than 45,000 hospitalized patients, they found a parabolic relationship between hyponatremia and mortality, with lower mortality with severe hyponatremia (<120 mEq/L). This trend has been reported in other, but not all, previous studies.6, 7 More interestingly, Chawla and colleagues analyzed the causes of deaths in patients with hyponatremia. They found that less than 6% of all cases of death were directly related to neurological (cerebral edema) complications of hyponatremia. The main message of their study was that a patient has a better chance to survive if he or she presents with a severe hyponatremia (<110 mEq/L) and a benign underlying cause (medications in 72% of the surviving patients) compared with a milder hyponatremia (≤130 mEq/L) and a severe underlying disorder (70% of patients who died had sepsis, acute kidney injury, or other acute illnesses).

Do the data presented by Doshi and colleagues make the picture clearer? Doshi et al provide a strong statistical association between hyponatremia and mortality in patients with cancer, but from our point of view, no hard evidence of a causal link exists between hyponatremia and mortality. Of note, their analysis of an independent association between hyponatremia and mortality did not take into account several relevant confounding factors including heart failure, liver disease, and most importantly, performance status and malnutrition, which have been associated with both hyponatremia and mortality. By the same token, comorbid conditions and cancer-related causes of hyponatremia, if any, are not provided. In addition, the causes of death in patients with hyponatremia are not reported. Elegant statistics are important but reviewing medical files remains a helpful tool in clinical studies. Linking the death of patients with cancer directly to hyponatremia-induced complications would be a clear argument supporting a causal link between hyponatremia and mortality. Moreover, one should be careful in linking the correction of hyponatremia to improved patient survival. Some patients with advanced cancer and/or end-stage organ failure (heart, lung, kidney, etc) may have received comfort care, which does not necessarily include aggressive correction of hyponatremia. Finally, apart from the probably rare neurological complications of mainly acute hyponatremia,3 there is no definite proof of an impact of acute/chronic hyponatremia on the function of vital organs. The frequently cited effect of hyponatremia on osteoporosis and bone fractures can hardly account for the impressive association of hyponatremia with mortality suggested by some studies.

The question of whether hyponatremia has a direct impact on mortality, including the mortality of patients with cancer, is not merely academic and may have practical implications. If such a link is to be proven, aggressive correction of hyponatremia may improve the outcome of patients, including those with cancer. Moreover, antagonists of the arginine vasopressin receptor 2 (antidiuretic hormone), a potent new class of drugs for the correction of hyponatremia, are available and are readily used in heart failure–associated severe hyponatremia. So, yes we have the means to aggressively correct hyponatremia, but is it cost-effective? The debate is clearly not settled. Doshi and colleagues have provided a large-scale sketch of hyponatremia in patients with cancer, yet crucial details remain to be drawn.

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Acknowledgements 

Financial Disclosure: The authors declare that they have no relevant financial interests.

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References 

  1. Adrogue HJ , Madias NE . Hyponatremia . N Engl J Med . 2000;342(21):1581–1589
  2. Upadhyay A , Jaber BL , Madias NE . Epidemiology of hyponatremia . Semin Nephrol . 2009;29(3):227–238
  3. Chawla A , Sterns RH , Nigwekar SU , Cappuccio JD . Mortality and serum sodium: do patients die from or with hyponatremia? . Clin J Am Soc Nephrol . 2011;6(5):960–965
  4. Doshi SM , Shah P , Lei X , Lahoti A , Salahudeen A . Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes . Am J Kidney Dis . 2012;59(2):222–228
  5. Lameire N , Van Biesen W , Vanholder R . Electrolyte disturbances and acute kidney injury in patients with cancer . Semin Nephrol . 2010;30(6):534–547
  6. Clayton JA , Le Jeune IR , Hall IP . Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome . QJM . 2006;99(8):505–511
  7. Waikar SS , Mount DB , Curhan GC . Mortality after hospitalization with mild, moderate, and severe hyponatremia . Am J Med . 2009;122(9):857–865

PII: S0272-6386(11)01668-4

doi:10.1053/j.ajkd.2011.12.004

Refers to article:

  • Hyponatremia in Hospitalized Cancer Patients and Its Impact on Clinical Outcomes , 17 October 2011

    Simit M. Doshi, Pankaj Shah, Xiudong Lei, Amit Lahoti, Abdulla K. Salahudeen
    American Journal of Kidney Diseases February 2012 (Vol. 59, Issue 2, Pages 222-228)

American Journal of Kidney Diseases
Volume 59, Issue 2 , Pages 168-169, February 2012

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