Why Sodium Levels Might Matter for Patients with Advanced Kidney Cancer Treated with Nivolumab

A recent study by Catalano et al. (1) has cast a light on an underappreciated factor that may hold a potential target for improved outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab: serum sodium (SNa) levels. The study was a retrospective cohort study, including patients treated with nivolumab as second-line or subsequent therapy from October 2015 to November 2019 across multiple Italian oncology centers. The main focus was on the association of pre- and post-immune checkpoint inhibitor (ICI) sodium levels with overall survival, progression-free survival, objective response rate, and disease control rate. The study's findings indicate that a higher SNa (≥140 mEq/L) before and/or after treatment with nivolumab was associated with better clinical outcomes, including overall survival, progression-free survival, and disease control rate. While previous research has hinted at the prognostic value of SNa among patients with mRCC (2), the association of SNa and outcomes in patients with mRCC receiving ICI has not been studied.

There are, of course, limitations to any retrospective analysis. A notable aspect of this study is the examination of SNa before and after ICI (approximately 4 weeks). Immunotherapy toxicity may develop within this period, but it is important to note that complications such as hyponatremia can occur even several months after the initial exposure to immunotherapy. Furthermore, an unreported number of patients received combination therapy of nivolumab plus ipilimumab as a first-line option for patients with intermediate-risk and poor-risk disease.

There are several mechanisms by which hyponatremia could develop in this population. Hyponatremia could be the direct result of mRCC, usually by causing the syndrome of inappropriate antidiuresis, or it could appear as a complication of immunotherapy, including the syndrome of inappropriate antidiuresis, hypovolemia from diarrhea in the setting of colitis, and less commonly, adrenalitis and hypophysitis (3, 4). Hyponatremia can also be the result of comorbidities such as advanced heart failure or cirrhosis, which were not considered in the analysis. Furthermore, most patients in this cohort had undergone prior nephrectomy, adding a layer of complexity. This is because a reduced glomerular filtration rate can be associated with increased use of medications, including diuretics and the presence of additional comorbidities that may influence both SNa and survival. The surprising aspect of this report is the observation that SNa levels, even when within the conventional, normal range of 135–139 mEq/L, are correlated with decreased survival probabilities in mRCC. Since SNa determinations are frequently obtained, perhaps a method that examined SNa over time using a mixed-effects model would have been more indicative of the impact of SNa on survival.

The study indicates that the International mRCC Database Consortium (IMDC) score significantly influences the hazard rate, possibly driven by the Karnofsky performance status score, which is an element of the IMDC score. Further analysis of variables driving the score could offer valuable insights into the interplay among these factors, SNa, and survival rates. To elucidate further, it is worth considering that elements contributing to a reduced score might also affect SNa values, such as limited solute intake. Conversely, a low SNa might in turn contribute to a diminished risk score. To deepen our understanding, follow-up investigations could explore additional factors such as hemodynamic status, medications (especially diuretics), the presence of liver disease or heart failure, and urinary indices, including urine osmolality.

Ultimately, the work by Catalano et al. (1) should be commended because the study highlights the potential importance of SNa as a predictor of outcomes among patients with mRCC. At the very least, we can hypothesize that those at low risk for developing hyponatremia before nivolumab treatment have a stronger likelihood of improved outcomes. Additionally, patients who maintain a normal SNa after exposure to nivolumab tend to fare better. This raises the possibility of integrating SNa into patient risk assessments and may be an impetus to involve consultants, such as nephrologists, earlier who can focus on managing hyponatremia.

While several questions remain about the mechanisms underlying this association, whether this phenomenon is present with other ICI therapies, and whether it can be generalized to other cancers, these findings open the possibility for further studies unlocking modifiable avenues for enhancing the care and outcomes for patients with cancer.

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