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

Disclosures

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

Results

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.

(Enlarge Image)

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).

(Enlarge Image)

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).

1 2 3 4

Next Section

Table 1. Baseline characteristics of patients who received ICIs
Characteristics	Total
Patients, N	2458
Age (years), mean (SD)	64 (13)
Male, n (%)	1422 (58)
Race, n (%)
White	2208 (90)
Black	47 (2)
Asian	27 (1)
Hispanic	80 (3)
Other/unknown	96 (4)
eGFR (mL/min/1.73 m²),^a mean (SD)	81 (22)
Malignancy, n (%)
Thoracic	768 (31)
Melanoma	721 (29)
GI	276 (11)
Other^b	693 (29)
ICI type, n (%)
CTLA-4	263 (11)
PDL-1	225 (9)
PD-1	1742 (71)
Combined (CTLA-4 + PD-1)	228 (9)
Comorbidities,^c n (%)
Diabetes mellitus	445 (18)
Hypertension	1505 (61)
Coronary artery disease	620 (25)
Cirrhosis	87 (4)
CKD (eGFR <60 mL/min/1.73 m²)	463 (19)
Medications,^d n (%)
Diuretic use	714 (29)
Loop diuretics	410 (17)
Thiazides	255 (10)
Potassium-sparing diuretics	59 (2)
ACEi/ARB	622 (25)
SSRI	368 (15)
PPI	1009 (41)
Anticancer agents associated with electrolyte abnormalities^e	323 (13)

^aeGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.
^bOther cancers include genitourinary cancers, gynecological cancers, head and neck cancers, glioblastoma, breast cancers, lymphomas and leukemias.
^cComorbidities were determined by the presence of International Classification of Diseases 9th or 10 Revision codes at the time of ICI administration.
^dMedications were determined by active prescriptions at the time of ICI administration.
^eAnticancer agents associated with electrolyte abnormalities included cisplatin, carboplatin, oxaliplatin, vincristine, vinblastine, cyclophosphamide and ifosfamide.
CKD, chronic kidney disease.

Table 2. Incidence of electrolyte abnormalities in patients receiving ICIs
Electrolyte disorders	Values
Hyponatremia (N = 2456)
Baseline sodium (mEq/L), mean (SD)	137 (3)
Overall incidence, n (%)	1519 (62)
Grade 1 (130–134 mEq/L)	974 (40)
Grade 2 (125–129 mEq/L)	409 (17)
Grade 3 (120–124 mEq/L)	113 (5)
Grade 4 ( <120 mEq/L)	23 (1)
Hypokalemia (N = 2455)
Baseline potassium (mEq/L), mean (SD)	4 (1)
Overall incidence, n (%)	677 (27)
Grades 1 and 2 (3.0–3.3 mEq/L)^a	544 (22)
Grade 3 (2.5–2.9 mEq/L)	114 (5)
Grade 4 ( <2.5 mEq/L)	19 (1)
Hyperkalemia (N = 2455)
Baseline potassium (mEq/L), mean (SD)	4 (1)
Overall incidence, n (%)	643 (26)
Grade 1 (5.1–5.5 mEq/L)	453 (18)
Grade 2 (5.6–6.0 mEq/L)	135 (5)
Grade 3 (6.1–7.0 mEq/L)	47 (0.3)
Grade 4 ( >7.0 mEq/L)	8 (0.3)
Hypophosphatemia (N = 2208)
Baseline phosphorous (mg/dL), mean (SD)	3 (1)
Overall incidence, n (%)	1106 (49)
Grades 1 and 2 (2.0–2.5 mg/dL)	757 (38)
Grade 3 (1.0–1.9 mg/dL)	329 (16)
Grade 4 (<1.0 mg/dL)	20 (1)
Hypocalcemia (N = 2454)
Baseline calcium (mg/dL), mean (SD)	10 (1)
Overall incidence, n (%)	213 (9)
Grade 1 (8.0–8.4 mg/dL)	145 (6)
Grade 2 (7.0–7.9 mg/dL)	63 (3)
Grade 3 (6.0–6.9 mg/dL)^b	5 (0.2)
Grade 4 ( <6.0 mg/dL)	0 (0)

Severity of electrolyte abnormalities was graded per the CTCAE version 5.0 (2017). Baseline values were determined from the entire cohort. N for each electrolyte abnormality includes the total number of patients who had both baseline and at least one follow-up value determined.
^aIn the CTCAE grading criteria, Grades 1 and 2 were differentiated based on symptoms and/or intervention, which were not included in the grading provided in this table. Only laboratory values were used for CTCAE grading in this table.
^bGrade 3 or 4 hypocalcemia was extremely rare, with an incidence of 0.2%, and chart review of each of the five cases of Grade 3 hypocalcemia did not uncover any plausible link to ICI use.

Table 3. Predictors of severe hyponatremia (Grade 3 or 4) in patients receiving ICIs
Variables	Univariable analysis		Multivariable analysis
	OR (95% CI)	P-value	Adjusted OR (95% CI)	P-value
Age	0.99 (0.97–0.10)	0.03	0.99 (0.97–1.00)	0.04
Male	1.45 (1.01–2.09)	0.04	1.35 (0.93–1.97)	0.12
White	0.50 (0.32–0.80)	<0.01	0.52 (0.32–0.84)	<0.01
ICI class		0.01
CTLA4	2.01 (1.24–3.23)	<0.01	2.69 (1.42–5.09)	<0.01
Combined (CTLA4 + PD-1)	1.71 (1.01–291)	0.05	1.72 (0.97–3.05)	0.06
PD-L1	1.03 (0.54–1.96)	0.94	1.04 (0.54–2.00)	0.92
Malignancy type		0.02
Thoracic	1.01 (0.65–1.56)	0.65	1.54 (0.86–2.75)	0.15
GI	1.65 (0.98–2.77)	0.98	1.63 (0.84–3.18)	0.15
Other^a	0.65 (0.39–1.07)	0.39	0.99 (0.53–1.85)	0.98
Diabetes	1.42 (0.94–2.14)	0.09	1.34 (0.87–2.06)	0.18
Hypertension	0.99 (0.70–1.41)	0.96
Cirrhosis	2.60 (1.35–5.02)	<0.01	1.99 (0.96–4.13)	0.06
CKD (eGFR <60 mL/min/1.73 m²)	0.69 (0.42–1.23)	0.14
Diuretic use	1.71 (1.20–2.44)	<0.01	1.57 (1.09–2.28)	0.02
Loop diuretics	1.45 (0.95–2.20)	0.09	–	–
Thiazides	1.34 (0.80–2.24)	0.26	–	–
Potassium-sparing diuretics	1.60 (0.63–4.08)	0.32	–	–
ACE/ARB	1.34 (0.92–1.95)	0.13	–	–
SSRIs	0.75 (0.44–1.27)	0.28	–	–
PPI	1.51 (1.07–2.14)	0.02	1.33 (0.92–1.90)	0.13
Anticancer agents associated with hyponatremia^b	1.45 (0.91–2.29)	0.11	–	–

Predictors that reached a P-value threshold of 0.10 were included in the multivariable analysis.
^aOther cancers include genitourinary, gynecological, head and neck, glioblastoma, breast, lymphomas and leukemias.
^bAnticancer agents associated with electrolyte abnormalities included cisplatin, carboplatin, oxaliplatin, vincristine, vinblastine, cyclophosphamide and ifosfamide.
CKD, chronic kidney disease.

Table 4. Case summaries of patients with hyponatremia caused by ICI-related adrenal insufficiency
Age (years)/sex	Drug	Cancer	Baseline sodium (mEq/L)	Minimum sodium (mEq/L)	Days from ICI start	Hypophysitis on MRI	Cosyntropin test	ACTH	Other endocrine hormones	Resolution with steroids	Concomitant irAE	Other Grade 3 or 4 electrolyte abnormalities
70/F	Pembrolizumab	Thoracic	135	124	148	No	Normal	Low	Normal	Yes	None	None
90/F	Ipilimumab	Melanoma	140	121	155	Yes	Failed	Not checked	↓FSH, LH, TSH	Yes	Hypothyroidism	None
65/M	Nivolumab	Thoracic	134	123	175	No	Failed	Low	↓FSH, LH, prolactin, TSH	Partial	Hypothyroidism, diabetes, skin rash	Hypophosphatemia Grade 3
80/M	Ipilimumab	Melanoma	137	123	70	Yes	Failed	Low	↓FSH, LH, testosterone, TSH	Yes	Hypothyroidism	Hypokalemia Grade 3
75/M	Ipilimumab	Melanoma	131	121	72	Yes	Failed	Low	↓FSH, LH, testosterone	Yes	None	Hypophosphatemia Grade 3
50/M	Nivolumab	Thoracic	138	118	309	Yes	Failed	Low	↓TSH	Yes	Hypothyroidism	Hypophosphatemia Grade 3
40/M	Ipilimumab	Melanoma	137	123	29	No	Not done	Low	↓FSH, LH, testosterone, TSH (later)	Yes	None, hypothyroidism later	Hypophosphatemia Grade 3
80/M	Pembrolizumab	Melanoma	138	122	347	Not definitive	Failed	Low	↓FSH, LH	Yes	None	None
70/M	Ipilimumab and nivolumab	Melanoma	140	124	175	No	Failed	Low	↓Testosterone (FSH, LH not checked)	Yes	Hypothyroidism	None

Adjudication (primary/secondary) was made by an endocrine physician in all cases. Secondary: pituitary cause of adrenal insufficiency; primary: adrenalitis leading to adrenal insufficiency. Ages were rounded to the nearest 5 years.
Grading of electrolyte abnormalities is per CTCAE version 5.0.
F, female; M, male; MRI, magnetic resonance imaging; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.