Hyponatremia in cancer patients receiving immune checkpoint inhibitors: the ARON-MOUSEION-014 meta-analysis.

Abstract

Hyponatremia is the most prevalent electrolyte imbalance in cancer patients. Symptoms potentially signaling hyponatremia include altered mental status, neurological condition, headache, nausea, dizziness, and balance loss. Its management is particularly challenging as it must account for prognosis, treatment-related factors, and quality of life, especially in individuals treated with immune checkpoint inhibitors (ICIs). This systematic review and meta-analysis assessed the incidence of hyponatremia in patients receiving ICIs or immune-based combinations compared with placebo or other anticancer treatments. The review was registered in PROSPERO (CRD420251137412). Eligible studies included randomized clinical trials, quasi-experimental, and observational studies reporting hyponatremia frequency in patients treated with ICIs. Risk of bias was assessed using the ROB 2 tool for randomized studies and ROBINS-I for observational studies. A meta-analysis for proportions was performed using generalized linear mixed models. Proportion was measured for any grade of hyponatremia, grade 1-2, and grade ≥ 3; and three separate subgroup meta-analyses were performed: one for any grade, one for grade 1 or 2, and one for grade ≥ 3. Thirteen studies were included in the quantitative analyses. Any-grade hyponatremia was reported in 7 studies (934 patients, 49 events), with a pooled prevalence of 5.0% (95% CI = [2.3%; 11.9%]; I² = 81.8%). Grade 1-2 hyponatremia was assessed in 7 studies (314 patients, 36 events) with a pooled prevalence of 1.2% (95% CI = [0.03%; 37.8%]; I² = 88.2%). Grade ≥ 3 hyponatremia was evaluated in 14 studies (652 patients, 35 events), yielding a pooled prevalence of 5.5% (95% CI = [3.1%; 9.6%]; I² = 44.8%). No significant small-study effects were detected for grade ≥ 3 events (Egger's test P = 0.313). These findings support routine electrolyte surveillance in patients treated with ICIs and highlight the need for further studies to clarify mechanisms and risk factors and define optimal monitoring strategies to improve both safety and outcomes.