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

Abstract and Introduction


Background: Hyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies.

Methods: This was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review.

Results: A total of 2458 patients were included. Their average age was 64 years [standard deviation (SD) 13], 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%.

Conclusions: Hyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia.


Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key negative regulators on T cells, unleashing anti-tumor T-cell responses that can lead to durable responses in cancers that were previously treatment refractory.[1] ICIs were approved by the US Food and Drug Administration (FDA) to treat 18 different cancer types and their use is rapidly increasing.[1–5] Approved agents include those that target programmed cell death-1 (PD-1) receptor, including pembrolizumab, nivolumab and cemiplimab; PD-1 ligand (PDL-1), including atezolizumab, avelumab and durvalumab; or cytotoxic T lymphocyte antigen-4 (CTLA-4), including ipilimumab. Combination therapy with a PD-1 inhibitor and a CTLA-4 inhibitor is increasingly used, as it is superior to monotherapy in several cancers.[6] However, inhibition of immune checkpoints may disrupt immunologic homeostasis, unleashing autoreactive T cells that can attack host tissues and produce autoimmune side effects called immune-related adverse events (irAEs), which may affect any organ system, commonly involving the skin, intestinal tract, lungs, endocrine organs and kidney.[7]

While acute interstitial nephritis causing acute kidney injury (AKI) is now a well-recognized side effect of ICIs, other important adverse events such as hyponatremia and other electrolyte abnormalities in patients receiving ICIs have not been well characterized.[8–10] Endocrinopathies such as hypothyroidism, adrenalitis and hypophysitis have been widely reported with ICIs and these can be associated with hyponatremia.[11–13] In a query of the FDA Adverse Event Reporting System Database (2011–15), Wanchoo et al.[14] found that hyponatremia was commonly reported with ICIs and another study looking at lung cancer patients[15] reported a higher incidence of hyponatremia with ICIs when compared with standard chemotherapy. However, a recent meta-analysis of patients receiving PD-1 inhibitors in clinical trials concluded that the pooled incidence of electrolyte abnormalities was only 1.2%, with a total of 52 events in ~4300 patients.[16] We and others have also noted higher rates of irAEs from real-world data compared with those previously reported from clinical trials.[8,10] In this study we aimed to define the risk of electrolyte abnormalities over the first year of ICI use and determine the risk factors and etiology of severe hyponatremia in a real-world population of patients receiving ICIs.