Hyponatremia Associated with Poorer Overall Survival in Renal Cell Cancer Patients

In metastatic renal cell cancer (mRCC) patients treated with targeted therapy, baseline hyponatremia is associated with poorer overall survival (OS), time to treatment failure (TTF), and disease control rate (DCR), according to a study published in European Urology.

Researchers retrospectively studied 1,661 mRCC patients aged 60 years and older from 18 academic centers worldwide. The majority of patients were treated with a first-line anti-endothelial growth factor (anti-VEGF) agent, such as sunitinib, sorafenib, axitinib, bevacizumab, pazopanib, or tivozanib, though some were treated with mammalian target of rapamycin (mTOR) agents, such as temsirolimus and everolimus.

To compare the DCR in mRCC patients with and without hyponatremia, which was defined as serum sodium <135mmol/l, the researchers used the chi-square test, though they estimated OS and TTF with the Kaplan-Meier method. They found median OS after treatment was 18.5 months, and 552 (33.2%) patients were alive at a median follow-up of 22.1 months.

Hyponatremia was found in 14.6% of mRCC patients at the initiation of targeted therapy. After adjusting for International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk groups, the researchers found that hyponatremic patients in the intermediate- and poor-risk groups had a significantly shorter median OS compared to non-hyponatremic patients.

Hyponatremia patients also had a significantly shorter median TTF and lower DCR compared to the other group. Baseline hyponatremia was also associated with other unfavorable prognostic features, including a time from diagnosis to targeted therapy treatment of <1 year, low hemoglobin levels, high serum calcium levels, elevated lactate dehydrogenase levels, high neutrophil levels, and high platelet counts.

“Antidiuretic hormone (ADH) may play a role as in other cancers, usually from an ectopic production, although it can also be a marker or burden of disease,” the authors speculated. “Patients with mRCC may have some degree of renal dysfunction, especially those submitted to nephrectomy, that could lead to hyponatremia.”

The authors also cited cerebral salt wasting as a possible cause for hyponatremia in cancer patients.

However, “hyponatremia in patients with mRCC could be also just a reflection of the baseline comorbidities, such as renal failure, although prior data from our group showed that renal function at therapy initiation does not adversely affect the efficacy of targeted therapy in advanced RCC,” they wrote.

Other comorbidities like ethnicity, congestive heart failure (CHF), hypertension, diabetes, cirrhosis, adrenal insufficiency, hypothyroidism, diuretics, steroids, antiepileptic drugs, selective serotonin reuptake inhibitors (SSRIs), and alcohol use may impair sodium homeostasis, the authors said.

“It is possible that patients with a higher tumor load have increased ectopic ADH production, leading to hyponatremia,” Joaquim Bellmunt, MD, PhD, and Jeffrey J. Leow, MD, MPH, wrote in an accompanying editorial. “The increased tumor load underlying this observed phenomenon might consequently worsen survival or progression outcomes.”

Bellmunt and Leow added that patients with poorer comorbid status might not be able to tolerate systemic therapy as well, which would explain their poorer DCRs and consequently poor TTF and OS outcomes.