In December 2005, the first effective vasopressin antagonist, conivaptan, was approved. Several months later when I spoke to my hospital’s Pharmacy and Therapeutic committee, I described the dangers of hyponatremia and the effectiveness of conivaptan at raising the sodium. It can be frustrating managing severe cases of SIADH, especially in situations where fluid restriction fails. After I finished my argument, I was asked a simple question, “Does this drug affect patient care?” At that point, I repeated what we knew about hyponatremia and how it was associated with falls, hip fractures, and poor hospital and overall mortality. Conivaptan had increased the sodium, but had it changed mortality? At that time, I had no answer.
Seven years later, we still don’t know if correcting hyponatremia prevents the morbidity that is associated with low sodium levels. In the July issue of AJKD, Hoorn and Zietse shed some light on the question by asking if hyponatremia is a marker for, or a cause of, the increased mortality. The review looks at 15 articles on mortality in hospitalized patients with hyponatremia, spanning 35 years and 401,693 patients. Reading through the disparate findings of the studies, it is amazing that the conclusions are varied when describing a single entity. The final scorecard shows 9 articles in favor of a direct contribution of hyponatremia to mortality, while 6 note nothing more than an incidental association.
The authors then review specific diseases for which hyponatremia has been determined to be an independent risk factor: heart failure (both ischemic and non-ischemic), cirrhosis, myocardial infarction, pulmonary embolism, pulmonary hypertension, pneumonia, and chronic kidney disease. Across these varied conditions, hyponatremia was reliably associated with increased mortality.
The authors further discuss our understanding of hyponatremia among dialysis patients. This special population lacks kidney function as a confounding means to generate hyponatremia, and provides a purer picture of the effect of sodium concentration alone on outcomes. The data in this situation points to a causative role for hyponatremia in mortality.
Management of hyponatremia feels like the management of anemia in the final years of the 20th century. It’s a disease that has a newly effective but expensive drug. We understand the disease is dangerous, but studies have been almost entirely observational with few randomized controlled trials. The expensive wonder drug was approved based on its ability to fix the number, not on any patient-oriented outcome. We need to see if in a randomized, placebo-controlled study correcting the sodium concentration improves the mortality of hyponatremia.
Joel Topf, MD
eAJKD Advisory Board member