Hyponatremia and Cancer: From Bedside to Benchside

Abstract

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients. This applies also to cancer patients. Multiple causes can lead to hyponatremia, but most frequently this electrolyte disorder is due to the syndrome of inappropriate antidiuresis. In cancer patients, this syndrome is mostly secondary to ectopic secretion of arginine vasopressin by tumoral cells. In addition, several chemotherapeutic drugs induce the release of arginine vasopressin by the hypothalamus. There is evidence that hyponatremia is associated to a more negative outcome in several pathologies, including cancer. Many studies have demonstrated that in different cancer types, both progression-free survival and overall survival are negatively affected by hyponatremia, whereas the correction of serum [Na+] has a positive effect on patient outcome. In vitro studies have shown that cells grown in low [Na+] have a greater proliferation rate and motility, due to a dysregulation in intracellular signalling pathways. Noteworthy, vasopressin receptors antagonists, which were approved more than a decade ago for the treatment of euvolemic and hypervolemic hyponatremia, have shown unexpected antiproliferative effects. Because of this property, vaptans were also approved for the treatment of polycystic kidney disease. In vitro evidence indicated that this family of drugs effectively counteracts proliferation and invasivity of cancer cells, thus possibly opening a new scenario among the pharmacological strategies to treat cancer.

Hyponatremia Promotes Cancer Growth in a Murine Xenograft Model of Neuroblastoma

“…Furthermore, in agreement with the many clinical observations that both PFS and OS are reduced in hyponatremic cancer patients [1,2], we observed a trend to a reduced survival in hyponatremic mice compared to normonatremic ones.…”

“…The awareness that hyponatremia may represent a negative prognostic factor in different pathologies has increased in the last decennium [13]. Experimental and clinical evidence clearly indicate that this apply also to cancer [1]. Interestingly, pre-treatment low serum [Na + ] have been related to a worse response to chemotherapy [14,15].…”

“…In this setting, the prevalence of hyponatremia is about 30%. The same considerations apply to cancer patients, in which low serum sodium ([Na + ]) is present in around 40% of cases at admission [1]. In addition, roughly half of cancer patients experience one or more episodes of hyponatremia during their disease.…”

“…Interestingly, hyponatremia has a negative impact on both Progression-Free Survival (PFS) and Overall Survival (OS) in many types of tumors, including lung, gastrointestinal, liver, renal, prostatic, pancreatic, genitourinary cancer, mesothelioma and lymphoma [1]. In a large series of patients admitted to a University Cancer Center, an almost three-fold higher hazard ratio for death in hyponatremic patients than in normonatremic ones was observed [5].…”

“…Noteworthy, the gene that showed the highest increase in the expression level in low [Na + ] was the heme oxigenase-1 (HMOX-1) gene. HMOX-1 has an antioxidant activity that represents a response to oxidative stress and is also associated with anti-apoptotic effects [1].…”