A 68-year-old woman was diagnosed with metastatic sarcomatoid non–small cell lung cancer. She was initiated on pembrolizumab therapy and achieved partial remission. Four months later, she was found to have orthostatic hypotension, with blood pressure of 90/50 mm Hg sitting and serum sodium concentration of 123 mmol/L. Serum creatinine level was 0.7 mg/dL, corresponding to estimated glomerular filtration rate > 60 mL/min/1.73 m2. Serum osmolality was 260 mOsm/kg, and urine osmolality was 475 mOsm/kg. Urine sodium excretion was 45 mmol/L. A trial of normal saline solution led to improvement in blood pressure but did not improve the hyponatremia.•What is the differential diagnosis of hyponatremia in this patient?•Which diagnostic tests should be performed?•What are the potential mechanisms for the observed hyponatremia and how might they be related to the treatment regimen? The hyponatremia observed in patients with cancer usually results from nonosmotic release of vasopressin with consequent hypo-osmolar hyponatremia. Nausea, pain, and baroreceptor release of vasopressin (also known as antidiuretic hormone [ADH]) are common causes of excess ADH release, while ectopic production of ADH from tumors such as small cell lung cancer is relatively rare. Paraproteinemias, hyperlipidemia, and lipoprotein X are causes of pseudohyponatremia that are excluded here because of the documented hypo-osmolarity. Hypo-osmolar hyponatremia may result from impaired free-water excretion associated with reduced effective arteriolar blood volume, as seen in this patient with relative hypotension. Other common causes of hyponatremia should also be considered, such as use of thiazide diuretics or other medications. A number of chemotherapeutic agents, including vincristine, vinblastine, cyclophosphamide, cisplatin, and novel targeted therapies, have been associated with enhanced ADH release, but the patient did not receive any of these agents. Finally, adrenal insufficiency consequent to adrenalitis or hypophysitis resulting from cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitor therapies may be observed. An early-morning plasma cortisol test done 48 hours later in the hospital was very low (Table 1), particularly in the setting of hypotension. Corticotropin (ACTH), free thyroxine, and thyroid-stimulating hormone levels were all low, suggesting a central cause. Follicle-stimulating hormone and luteinizing hormone levels were not affected. Brain magnetic resonance imaging focused on the pituitary gland and adrenal computed tomographic scans were unremarkable. In light of these findings, the presumptive diagnosis was hyponatremia resulting from central adrenal insufficiency due to impaired ACTH synthesis. The patient’s hypothyroidism was thought to be at most a minor contributing factor. The patient was treated with hydrocortisone, fludrocortisone, and levothyroxine, with improvement in serum sodium concentration to 133 mmol/L over 5 days. One year later, the cancer was in remission in the context of continuing pembrolizumab treatment and the patient remained on treatment with replacement hydrocortisone and levothyroxine.Table 1Endocrine Laboratory Findings of the PatientTiming Relative to ImmunotherapyTiming Relative to Steroid TreatmentReference Range6 mo Prior1 mo Prior4 mo After5 d After2 mo After4 mo AfterSerum sodium, mmol/L143137123133135139135-145ACTH, pg/mL9<5<55-46Free cortisol (morning), μg/dL22<1<1—0.2-1.8Prolactin, ng/mL——16.9—4-18FSH, IU/L—3.91.5-12.4aIn men.LH, IU/L7.31.7-8.6aIn men.TSH, mlU/L1.380.010.611.00.27-4.2FT4, ng/dL1.50.81.21.20.9-1.8Aldosterone, ng/dL4.7≤23.2Plasma renin direct, pg/mL26.73.7≤33.2Abbreviations: ACTH, corticotropin; FSH, follicle-stimulating hormone; FT4, free thyroxine; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.a In men. Open table in a new tab Abbreviations: ACTH, corticotropin; FSH, follicle-stimulating hormone; FT4, free thyroxine; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. The hypo-osmolar hyponatremia in this patient could have been due in part to baroreceptor-mediated ADH release given her hypotension, but the low aldosterone level and plasma renin activity suggest that this was not a predominant factor. Furthermore, isotonic saline solution infusion decreased the serum sodium concentration further, implying that a primary ADH effect was preventing water excretion. The prompt improvement in urinary dilution and correction of hyponatremia after hydrocortisone administration was thought to be due its suppression of ADH release. Cortisol not only suppresses ACTH secretion but also inhibits secretion of corticotropin-releasing hormone (CRH).1Kalogeras KT Nieman LK Jaovski JA et al.Inferior petrosal venous sampling in healthy subjects reveals a unilateral corticotropin releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.J Clin Invest. 1996; 97: 2045-2050Crossref PubMed Scopus (51) Google Scholar CRH stimulates ADH release; thus, glucocorticoid deficiency is associated with excess CRH and ADH release, which is reversed by administration of cortisol. Cortisol deficiency may also more directly increase ADH release. Adverse kidney effects associated with immune check point inhibitors are well described, as is hyponatremia related to both PD-1 and CTLA-4 inhibitor use.2Wanchoo R. Karam S. Uppal N.N. et al.Adverse renal effects of immune checkpoint inhibitors: a narrative review.Am J Nephrol. 2017; 45: 160-169Crossref PubMed Scopus (195) Google Scholar, 3Rahman O. El Halawani H. Fouad M. Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis.Future Oncol. 2016; 12: 413-425Crossref PubMed Scopus (95) Google Scholar, 4Byun DJ Wolchok JD Rosenberg LM Girotra M Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies.Nat Rev Endocrinol. 2017; 13: 195-207Crossref PubMed Scopus (375) Google Scholar Both these agents can promote endocrine immune-related adverse events, as observed in our patient, which vary in severity and can involve damage to pituitary, adrenal, thyroid, and pancreatic beta cells. This case is unusual in that PD-1 inhibitors have not been associated with hyponatremia and less commonly induce hypophysitis than the anti–CTLA-4 class5Barroso-Sousa R. Barry W.T. Garrido-Castro A.C. et al.Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis.JAMA Oncol. 2018; 4: 173-182Crossref PubMed Scopus (477) Google Scholar,6Caturegli P. Di Dalmazi G. Lombardi M. et al.Hypophysitis secondary to cytotoxic T-lymphocyte–associated protein 4 blockade: insights into pathogenesis from an autopsy series.Am J Pathol. 2016; 186: 3225-3235Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar of drugs. Of the various PD-1 inhibitors, nivolumab has been most frequently reported to have endocrine adverse effects and has been linked to hypophysitis and adrenal insufficiency in 1% and 2% of patients, respectively.5Barroso-Sousa R. Barry W.T. Garrido-Castro A.C. et al.Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis.JAMA Oncol. 2018; 4: 173-182Crossref PubMed Scopus (477) Google Scholar Table 2 summarizes the 16 reports of PD-1 inhibitor–associated hyponatremia: 12 occurred in men, with most patients in their 50s. The majority of patients presented within 6 to 8 weeks after initiation of PD-1 inhibitor therapy. The cause of hyponatremia was adrenalitis in 31% (5/16), hypophysitis in 25% (4/16), and isolated ACTH deficiency in 38% (6/16).Table 2Summary of Cases Reported of Hyponatremia With PD-1 InhibitorsCaseAge, y/SexCancerDrugTiming of Hyponatremia DiagnosisDiagnosisManagement143/MMalignant melanomaNivolumab8 wkAdrenalitisPD-1 inhibitor continued255/MMalignant melanomaPembrolizumab20 wkAdrenalitisPD-1 inhibitor stopped383/MMalignant melanomaNivolumab26 wkHypophysitisPD-1 inhibitor stopped450/MOropharynx cancerNivolumab6 wkHypophysitisPD-1 inhibitor continued555/MMalignant melanomaNivolumab6 wkHypophysitisPD-1 inhibitor continued652/MNSCLCNivolumab2 wkAdrenalitisNot available763/FMalignant melanomaNivolumab + ipilimumab18 wkIsolatedACTH deficiencyDrugs stopped854/MRenal cell cancerNivolumab12 wkIsolatedACTH deficiencyPD-1 inhibitor continued974/FRenal cell cancerNivolumab2 wkHypophysitisPD-1 inhibitor continued1058/FMetastatic melanomaNivolumab4 wkAKI/immune nephritis (IRAE)PD-1 inhibitor stopped1176/FMetastatic melanomaNivolumab9 wkIsolatedACTH deficiencyNot available1254/MPoorly differentiated lung cancerNivolumab8 wkIsolated ACTH deficiencyNot available1364/MLung adenocarcinomaNivolumab7 wkIsolatedACTH deficiencyNot available1457/MLarge cell lung carcinomaNivolumab6 wkIsolatedACTH deficiencyNot available1551/MNSCLCNivolumabNAAdrenal insufficiencySteroids, drug discontinuation1684/MNSCLCNivolumabNAAdrenal insufficiencySteroidsNote: Case 1 from Trainer et al (https://dx.doi.org/10.1530/EDM-16-0108); case 2, from Paepegaev et al (https://dx.doi.org/10.1210/js.2017-00170); case 3, from Kuru et al (https://dx.doi.org/10.4103/IJCIIS.IJCIIS_15_17); case 4, from Okano (https://doi.org/10.1507/endocrj.EJ16-0161); case 5, from Ishikawa & Oashi (https://doi.org/10.1111/1346-8138.13437); case 6, from Akarca et al (https://doi.org/10.1016/j.tjem.2017.05.007); case 7, from Ariyasu et al (https://doi.org/10.21873/anticanres.11814); case 8, from Zeng et al (https://doi.org/10.1097/MD.0000000000008426); case 9, from Seki et al (https://www.ncbi.nlm.nih.gov/pubmed/28871578); case 10, from Vandiver et al (https://doi.org/10.1007/s11523-016-0426-9); cases 11-14, from Cho et al (https://doi.org/10.1507/endocrj.EJ16-0596); case 15, from Grenier et al (https://www.shmabstracts.com/abstract/cant-cope-with-the-stress-of-nivolumab-therapy-immune-mediated-adrenal-insufficiency/); case 16, from Neril et al (https://doi.org/10.4158/EP161491.CR).Abbreviations: ACTH, corticotropin; AKI, acute kidney injury; IRAE, immune-related adverse event; NSCLC, non–small cell lung cancer; PD-1, programmed cell death protein 1. Open table in a new tab Note: Case 1 from Trainer et al (https://dx.doi.org/10.1530/EDM-16-0108); case 2, from Paepegaev et al (https://dx.doi.org/10.1210/js.2017-00170); case 3, from Kuru et al (https://dx.doi.org/10.4103/IJCIIS.IJCIIS_15_17); case 4, from Okano (https://doi.org/10.1507/endocrj.EJ16-0161); case 5, from Ishikawa & Oashi (https://doi.org/10.1111/1346-8138.13437); case 6, from Akarca et al (https://doi.org/10.1016/j.tjem.2017.05.007); case 7, from Ariyasu et al (https://doi.org/10.21873/anticanres.11814); case 8, from Zeng et al (https://doi.org/10.1097/MD.0000000000008426); case 9, from Seki et al (https://www.ncbi.nlm.nih.gov/pubmed/28871578); case 10, from Vandiver et al (https://doi.org/10.1007/s11523-016-0426-9); cases 11-14, from Cho et al (https://doi.org/10.1507/endocrj.EJ16-0596); case 15, from Grenier et al (https://www.shmabstracts.com/abstract/cant-cope-with-the-stress-of-nivolumab-therapy-immune-mediated-adrenal-insufficiency/); case 16, from Neril et al (https://doi.org/10.4158/EP161491.CR). Abbreviations: ACTH, corticotropin; AKI, acute kidney injury; IRAE, immune-related adverse event; NSCLC, non–small cell lung cancer; PD-1, programmed cell death protein 1. The potential causes of hyponatremia in patients receiving immune check point inhibitors include hypovolemia, adrenal insufficiency, hypophysitis, isolated ACTH deficiency, and thyroid disorders. The level of adrenal insufficiency can be calibrated with appropriate dosing of glucocorticoids. Because of a substantial mineralocorticoid effect, hydrocortisone may not require supplemental fludrocortisone. PD-1 inhibitors can generally be continued as part of antitumor therapy with concurrent appropriate hormone replacement, which may need to be continued even after cancer treatment has been completed. Knowledge of endocrine-related causes of hyponatremia is important for the nephrologists managing patients who are receiving check point inhibitors. Pembrolizumab-induced isolated ACTH deficiency leading to hyponatremia.Fellowship Program Highlight Description:Program: Zucker School of Medicine at Hofstra/Northwell Nephrology training program (North Shore University Hospital and Long Island Jewish Medical Center).Website: https://professionals.northwell.edu/graduate-medical-education/fellowship-nephrology-nsuh-lij/Program Director: Hitesh H. Shah, MDProgram Description: The nephrology fellowship program at the Zucker School of Medicine at Hofstra/Northwell is acclaimed for its innovation in medical education. This fellow-centric program provides outstanding opportunities for training, learning, and professional growth under the close supervision of highly talented and nurturing faculty members. Research opportunities exists in areas of CKD, podocyte biology, glomerular diseases, women’s health in nephrology, onconephrology, and POCUS, among others. Fellows are trained in hand-held ultrasound, offered at only a handful of training programs in the nation. Finally, fellows benefit from employment opportunities within the various Northwell Health facilities. Program: Zucker School of Medicine at Hofstra/Northwell Nephrology training program (North Shore University Hospital and Long Island Jewish Medical Center). Website: https://professionals.northwell.edu/graduate-medical-education/fellowship-nephrology-nsuh-lij/ Program Director: Hitesh H. Shah, MD Program Description: The nephrology fellowship program at the Zucker School of Medicine at Hofstra/Northwell is acclaimed for its innovation in medical education. This fellow-centric program provides outstanding opportunities for training, learning, and professional growth under the close supervision of highly talented and nurturing faculty members. Research opportunities exists in areas of CKD, podocyte biology, glomerular diseases, women’s health in nephrology, onconephrology, and POCUS, among others. Fellows are trained in hand-held ultrasound, offered at only a handful of training programs in the nation. Finally, fellows benefit from employment opportunities within the various Northwell Health facilities. Nupur N. Uppal, MD, Rimda Wanchoo, MD, Richard Barnett, MD, Avani Sinha, MD, and Kenar D. Jhaveri, MD. None. Dr Jhaveri serves as a consultant for Astex Pharmaceuticals. The remaining authors declare that they have no relevant financial interests. Dr Jhaveri serves as an AJKD Blog advisory board member. Received July 14, 2019. Direct editorial input from the Education Editor and a Deputy Editor. Accepted in revised form September 23, 2019.