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 our cancer center, 2749 patients were started on ICIs between 2011 and 2018. After applying the above exclusions, 2458 patients were included (Figure 1). The baseline characteristics of the included patients are listed in Table 1. The average age was 64 years (SD 13), 58% were male and 90% identified as White. The mean estimated glomerular filtration rate (eGFR) was 81 mL/min/1.73 m2 and 19% of patients had an eGFR <60 mL/min/1.73 m2 at baseline. The breakdown of malignancy types is shown in Table 1; thoracic malignancies were most common (31%), followed by melanoma (29%). PD-1 inhibitors were the most commonly used ICI class (71%), followed by CTLA-4 inhibitors (11%), PDL-1 inhibitors (9%) and PD-1/CTLA-4 combination therapy (9%). Diuretic, ACE/ARB, PPI and SSRI use was prevalent in 29, 25, 41 and 15% of patients, respectively. Thirteen percent of patients also received other anticancer agents known to be associated with electrolyte abnormalities. On average, patients in the included cohort had 21 (SD 15) metabolic panels measured in the first year after starting ICI.

Figure 1.

Patient flow. Flow sheet of patients on ICIs investigated for electrolyte abnormalities. Excluded patients were those without electrolyte results within 3 months prior to starting an ICI, those who did not have at least one follow-up laboratory value after the start date and those with end-stage kidney disease on dialysis. The final cohort included 2458 patients.

Incidence of Hyponatremia and Other Electrolyte Abnormalities

The overall incidence of Grade 1 or higher hyponatremia (≤134 mEq/L) was 62% (n = 1519) within the first year after ICI therapy; 136 patients (6%) experienced Grade 3 or 4 hyponatremia (≤124 mEq/L). Among other electrolytes, severe hypophosphatemia was very common, while severe hypocalcemia was uncommon (Table 2).

Predictors of Severe (Grade 3 or 4) Hyponatremia

In univariable analyses, age, gender, race, ICI class, malignancy type, cirrhosis, PPI use and diuretic use were associated with severe (Grade 3 or 4, serum sodium ≤124 mEq/L) hyponatremia. In the adjusted multivariable analyses, White race was associated with a lower risk of severe hyponatremia {adjusted odds ratio [aOR] 0.50 [95% confidence interval (CI) 0.32–0.80], P < 0.01}. Among the different ICI classes, being on anti-CTLA-4 monotherapy was associated with a higher risk of Grade 3 or 4 hyponatremia [aOR 2.69 (95% CI 1.42–5.09), P < 0.01, PD-1 inhibitors as the reference group]. There was a nonsignificant trend toward increased risk of severe hyponatremia among patients receiving combination (CTLA-4/PD-1) therapy [aOR 1.72 (95% CI 0.97–3.05), P = 0.06] and any-grade hyponatremia was significantly more common in patients receiving combination therapy (Supplementary data, Table S1). Malignancy type was not associated with an increased risk of severe hyponatremia in the adjusted model. Finally, diuretic use, including loop, thiazide or potassium-sparing diuretics, was associated with a higher risk of severe hyponatremia [aOR 1.57 (95% CI 1.09–2.28), P = 0.02]. Diuretics use was also an important predictor of any-grade hyponatremia, as was ICI type, diabetes and concurrent use of other anticancer agents associated with hyponatremia. Predictors of any-grade (Grades 1–4) hyponatremia are shown in Supplementary data, Table S1 (Table 3).

Etiology of Severe (Grade 3 or 4) Hyponatremia

Each case of Grade 3 or 4 hyponatremia was reviewed manually to determine the etiology; the breakdown of etiologies is shown in Figure 2. Endocrinopathies led to Grade 3 or 4 hyponatremia in a total of nine cases (7% of Grade 3 or 4 hyponatremia and 0.3% of the overall cohort). Each of these patients had been evaluated by an endocrinologist. Adrenal insufficiency was secondary in all cases; eight patients had hypopituitarism, with abnormal levels of other pituitary hormones, and one patient had isolated low adrenocorticotropic hormone (ACTH; Table 4). The average time from ICI initiation to diagnosis of adrenal insufficiency–induced hyponatremia was 164 days (SD 100). Of these nine patients, five also had immune-mediated thyroiditis. The other common causes of Grade 3 or 4 hyponatremia were SIADH (35%) and hyponatremia due to a hemodynamic disturbance (20%). Grade 3 or 4 hyponatremia occurring at the time of a terminal decline (hospice enrollment or death) explained many cases of Grade 3 or 4 hyponatremia (34%), and only 4% were related to other/unknown causes (Figure 2).

Figure 2.

Etiology of Grade 3 and 4 hyponatremia. Grade 3 or 4 hyponatremia was present in 136 patients (6% of the overall cohort). SIADH was the most common etiology (36%), followed by hyponatremia occurring in the context of terminal illness leading to death or hospice enrollment (34%) and hyponatremia due to hemodynamic disturbances (20%). ICI-related autoimmune adrenal insufficiency was the cause of 7% of the cases of Grade 3 or 4 hyponatremia. About 4% of the cases (n = 5) were due to other causes [drug-induced (n = 2), polydipsia (n = 1)] or due to unknown causes (n = 2).