Hyponatremia and Other Electrolyte Abnormalities in Patients Receiving Immune Checkpoint Inhibitors

Harish Seethapathy; Nifasha Rusibamayila; Donald F. Chute; Meghan Lee; Ian Strohbehn; Leyre Zubiri; Alexander T. Faje; Kerry L. Reynolds; Kenar D. Jhaveri; Meghan E. Sise


Nephrol Dial Transplant. 2021;36(12):2241-2247. 

In This Article


In a large real-world cohort of nearly 2500 consecutive patients with a variety of different cancer types, we found that hyponatremia was the most common electrolyte abnormality observed, occurring in 62% of patients, with 6% of patients developing severe (Grade 3 or 4) hyponatremia (serum sodium ≤124 mEq/L) within the first year after ICIs. This is the first and largest study to date that systematically determined the risk and etiology of severe hyponatremia after ICI use. We found that severe (Grade 3 or 4) hyponatremia attributed to immune-related endocrinopathies was rare, affecting only 0.3% of the cohort. We identified important risk factors for severe (Grade 3 or 4) hyponatremia, including ipilimumab (CTLA-4 inhibitor) use, diuretic use and race. It is well known that certain irAEs, particularly hypophysitis, are more common in patients receiving CTLA-4 inhibitors compared with those receiving PD-1 or PDL-1 monotherapy.[12,18] Additionally, in both the FDA reporting system and in the literature, most cases of hyponatremia and hypophysitis were reported in patients on ipilimumab.[14] Gastrointestinal (GI) malignancies were associated with a higher risk of any-grade hyponatremia (Supplementary data, Table S1) and there was a nonsignificant trend toward a higher risk of severe hyponatremia. This is likely due to the association with chronic liver disease or luminal disease that may affect oral intake and nutrient absorption.

Knowledge of hyponatremia associated with ICI is important. In general, in patients with cancer, hyponatremia negatively impacts cancer survival at all stages and its development can signal the presence of new comorbidities or toxicity, such as cardiomyopathy or advanced liver disease, or signal as a biomarker of advanced or unresponsive malignancy.[19,20] In addition, hyponatremia has been shown to impact response to cancer therapy and can affect healthcare costs and utilization. The direct costs of treating hyponatremia in the USA on an annual basis have been estimated to range between $1 and 4 billion.[21–23] Early diagnosis and treatment of ICI-associated hyponatremia might help in mitigating some of the above concerns and outcomes associated with hyponatremia in cancer patients.

Importantly, we found substantially higher rates of other electrolyte abnormalities than other recent reports. A systematic review of clinical trial data found that in patients on PD-1 inhibitors, the pooled incidence of electrolyte abnormalities was only 1.2% (95% CI 0.7–2.1%) while another analysis summarizing clinical trial data reported an incidence of hyponatremia of 8.7%.[15,16] This dramatic difference is likely due to several reasons. The prior studies only included trial participants, who are highly selected with normal or near-normal baseline organ function and closely monitored, making them less prone to adverse events in general. Additionally, patients whose cancer progresses will often be taken off of a trial and their electrolytes may no longer be included in study follow-up data, whereas our study followed patients for 1 year or to death. Because electrolyte abnormalities are common in patients with cancer, with the reported frequency of hyponatremia ranging from 4 to 47%, hypokalemia from 43 to 64%, hypocalcemia from 20 to 30% and hypophosphatemia from 20 to 30% in different cancers and settings, it can be hard to determine causality. This in turn could lead to underreporting in clinical trials, as some trials only report electrolyte abnormalities as adverse events if the investigators attributed it to the study drug.[24–26] In our study, we did not detect an association between ICIs and hypocalcemia that a recently published meta-analysis showed.[16] In fact, Grade 3 or 4 hypocalcemia was extremely rare, with an incidence of 0.2%, and a chart review of each case of severe hypocalcemia did not find a single instance of a plausible link to ICI use.

Our study has several limitations. First, this was a predominantly White population sourced from a single cancer center, limiting generalizability. Practice patterns at our cancer center in terms of frequency of electrolyte monitoring may have influenced the detection rate. Additionally, it is possible that patients had laboratory studies performed at hospitals outside our healthcare network, resulting in an underestimation of the frequency of electrolyte abnormalities. We only included patients who had at least one metabolic panel measured in the 12-month follow-up period to ensure that patients getting the majority of their care outside our healthcare system were not included in the analysis. Furthermore, on average, our cohort had 21 metabolic panel measurements in the 12 months after starting ICIs, suggesting they were followed closely. Retrospective data collection led to limited clinical phenotyping of some cases of Grade 3 or 4 hyponatremia and hypocalcemia; we relied on the available laboratory data and clinical evaluation at the time of the event. All cases of endocrinopathies leading to Grade 3 or 4 hyponatremia had been evaluated by an endocrinologist at the time of diagnosis, strengthening the validity of this diagnosis group. However, it is possible that endocrinopathies were underdiagnosed in patients who did not undergo a full workup, as they can present similarly to SIADH; the uncertainty of this diagnosis group is a limitation. We used the first ICI regimen administered and did not account for sequential therapy, which may have occurred if patients were switched from one ICI regimen to another. Additionally, we did not take into account the dose or total number of ICI doses patients received, duration of therapy nor dose response of ICI on the risk of electrolyte abnormalities. The dose/exposure–toxicity relationship is not well understood, but a large meta-analysis conducted with anti-PD/PD-L1 found no relationship between irAEs and dose of ICI agent.[27] Given the unique mechanism of action and prolonged duration of immunologic activity of even a single dose of an ICI (up to 1 year), we evaluated all electrolyte abnormalities within 1 year of the start date regardless of the duration of treatment.[28]

In conclusion, hyponatremia is very common in patients receiving ICIs; however, immune-related causes of severe hyponatremia were uncommon. Given the widespread use of these drugs in patients with advanced malignancies, it is imperative that clinicians who manage these patients are aware of the high risk of these abnormalities; a focused workup is recommended to establish whether hyponatremia may be immune mediated or related to another cause, because if left uncorrected it could lead to serious consequences. Also, because we found that severe hypophosphatemia is also common, the National Comprehensive Cancer Network guidelines should consider recommending routine phosphate monitoring after ICI. Additional research is required to establish the ideal screening protocol and mechanisms driving electrolyte abnormalities in patients on ICIs.