Metabolic Acidosis and Hyponatremia in a Patient With Metastatic Melanoma

Abstract

A 72-year-old man with a history of metastatic melanoma and hypertension presented to the hospital with a 2-week duration of weakness and fatigue. He also reported poor appetite and decreased oral intake but no weight loss. He denied shortness of breath, lightheadedness, syncope, nausea, vomiting, or diarrhea. He also denied headache, confusion, polyuria, or polydipsia. Home medications included amlodipine 10 mg once a day, lisinopril 10 mg once a day, and pembrolizumab 200 mg intravenously every 3 weeks. The latter was started 3 months prior to admission and he had recently completed 3 cycles of therapy. On admission, he had blood pressure of 118/78 mm Hg and heart rate of 62 beats per minute. Initial work-up was notable for hyponatremia with serum sodium level of 120 mg/dL and metabolic acidosis with total CO2 of 16 mmol/L. Other laboratory results are shown in Table 1. A spot urinary protein-creatinine ratio was 0.12 mg/mg, and urine pH was 6.0. Urine analysis did not show any microscopic hematuria or pyuria. There was no glycosuria.Table 1Laboratory Findings on Admission and Work-upValueReference RangeSodium, mmol/L120136-145Potassium, mmol/L3.63.5-5.3Bicarbonate, mmol/L1621-32Chloride, mmol/L9098-107Creatinine, mg/dL0.60.5-1.3SUN, mg/dL86-23Phosphorus, mg/dL2.62.5-4.9Aldosterone, ng/dL5.00.0-30.0TSH, mIU/L1.040.44-3.98ACTH, pg/mL5.17.2-63.3Cortisol AM, μg/dL1.02.5-20.0Aldolase, U/L2.43.3-10.3LH, IU/L3.81.5-9.3 (adult male)FSH, IU/L8.22-10 (adult male)DHEA, μg/dL1228-290Urine sodium, mmol/L52Urine potassium, mmol/L19Urine chloride, mmol/L63Urine osmolality, mOsm/kg299200-1,200Abbreviations: ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. Open table in a new tab Abbreviations: ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. Computed tomography scan of the abdomen was normal. Other laboratory studies including titers of serum antinuclear antibody, anti-neutrophil cytoplasmic antibody, and anti-SSA/SSB; tests for hepatitis B and C virus; and levels of C3 and C4 were all unrevealing.•What is the general differential diagnosis for hyponatremia in a patient with cancer?•What is the most likely cause of this patient’s metabolic acidosis?•What is the cause of hyponatremia in this patient? Hyponatremia is frequently associated with cancers and it is commonly caused by inappropriate secretion of antidiuretic hormone, or the syndrome of inappropriate antidiuresis (SIAD). There are various causes of SIAD in a cancer patient: it may be a result of ectopic vasopressin production by tumor cells or a consequence of stimulation of vasopressin secretion or potentiation of vasopressin effects by anticancer drugs or palliative medications. There are many traditional chemotherapeutic treatments that can cause hyponatremia. Recently, immune checkpoint inhibitors have revolutionized the treatment of various solid tumors. There are adverse kidney effects associated with these drugs, including hyponatremia. New targeted therapies have also been associated with the development of hyponatremia and possibly SIAD. Diagnosis of the etiology of hyponatremia is necessary in order to provide appropriate treatment. Laboratory assessments, including measurements of plasma osmolality, urine osmolality, and urine sodium, and clinical assessment of extracellular volume status are critical to the differential diagnosis of hyponatremia. This patient had normal anion gap metabolic acidosis with positive urine anion gap and low positive urine osmolar gap (<150 mOsm/kg). This combination, in the absence of kidney failure, raises the possibility of a renal tubular acidosis (RTA). For this patient, the laboratory work-up is highly suggestive of a distal RTA (high urine pH and absence of features that are typically seen with a proximal RTA and Fanconi syndrome, such as hypophosphatemia and glucosuria). Although this condition is normally associated with hypokalemia, simultaneous adrenal insufficiency could have offset this finding. Distal or type I RTA is a tubulopathy characterized by dysfunction of distal urinary acidification, which subsequently can lead to a normal anion gap metabolic acidosis.1Mustaqeem R. Arif A. Renal Tubular Acidosis. [Updated 2020 Aug 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan.https://www.ncbi.nlm.nih.gov/books/NBK519044/Google Scholar Common causes include autoimmune diseases, drugs, genetic diseases, and tubulointerstitial diseases; however, in many cases a cause is not identified.1Mustaqeem R. Arif A. Renal Tubular Acidosis. [Updated 2020 Aug 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan.https://www.ncbi.nlm.nih.gov/books/NBK519044/Google Scholar In our patient, we suspected the distal RTA to be secondary to a renal immunotherapy-related adverse event (irAE). Distal RTA is an emerging irAE that has not been well recognized. There are only few case reports and case series thus far describing this phenomenon.2El Bitar S, Weerasinghe C, El-Charabaty E, Odaimi M. Renal tubular acidosis an adverse effect of PD-1 inhibitor immunotherapy. Case Rep Oncol Med. 2018 Jan 31;2018:8408015. doi:10.1155/2018/8408015Google Scholar, 3Herrmann S.M. Alexander M.P. Romero M.F. Zand L. Renal tubular acidosis and immune checkpoint inhibitor therapy: an immune-related adverse event of PD-1 inhibitor - a report of 3 cases.Kidney Med. 2020; 2: 657-662Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 4Charmetant X. Teuma C. Lake J. Dijoud F. Frochot V. Deeb A. A new expression of immune checkpoint inhibitors' renal toxicity: when distal tubular acidosis precedes creatinine elevation.Clin Kidney J. 2019; 13: 42-45Crossref PubMed Scopus (9) Google Scholar, 5Atiq S.O. Gokhale T. Atiq Z. Holmes R. Sparks M.A. A case of pembrolizumab induced distal renal tubular acidosis.Journal of Onco-Nephrology. 2021; 5: 23-26Crossref Google Scholar However, distal RTA being an immune-mediated phenomenon is not a novel concept, as there are a range of autoimmune diseases that have been associated with distal RTA. Distal RTA is also perhaps an underdiagnosed disease among patients receiving immune checkpoint inhibitors, as it is typically asymptomatic and associated with concurrent decreased kidney function. There has been extensive literature characterizing the various endocrinopathies associated with immune checkpoint inhibitors, including primary adrenal insufficiency, hypothyroidism, hyperthyroidism, and hypophysitis.6Barroso-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 Although the risk of immune checkpoint inhibitor–associated adrenal insufficiency is less than 1%, it is still associated with significant morbidity and mortality.2El Bitar S, Weerasinghe C, El-Charabaty E, Odaimi M. Renal tubular acidosis an adverse effect of PD-1 inhibitor immunotherapy. Case Rep Oncol Med. 2018 Jan 31;2018:8408015. doi:10.1155/2018/8408015Google Scholar, 3Herrmann S.M. Alexander M.P. Romero M.F. Zand L. Renal tubular acidosis and immune checkpoint inhibitor therapy: an immune-related adverse event of PD-1 inhibitor - a report of 3 cases.Kidney Med. 2020; 2: 657-662Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 4Charmetant X. Teuma C. Lake J. Dijoud F. Frochot V. Deeb A. A new expression of immune checkpoint inhibitors' renal toxicity: when distal tubular acidosis precedes creatinine elevation.Clin Kidney J. 2019; 13: 42-45Crossref PubMed Scopus (9) Google Scholar, 5Atiq S.O. Gokhale T. Atiq Z. Holmes R. Sparks M.A. A case of pembrolizumab induced distal renal tubular acidosis.Journal of Onco-Nephrology. 2021; 5: 23-26Crossref Google Scholar, 6Barroso-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 In our patient, we suspected that the patient had hypophysitis, which precipitated an adrenal insufficiency. This was supported by low levels of ACTH and cortisol. Hyponatremia is common in cancer patients receiving immune checkpoint inhibitors, and acute hyponatremia secondary to pembrolizumab has been reported.7Desikan S.P. Varghese R. Kamoga R. Desikan R. Acute hyponatremia from immune checkpoint inhibitor therapy for non-small cell lung cancer.Postgrad Med J. 2020; 96: 570-571Crossref PubMed Scopus (1) Google Scholar,8Seethapathy H. Rusibamayila N. Chute D.F. et al.Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors.Nephrol Dial Transplant. 2020; (gfaa272)https://doi.org/10.1093/ndt/gfaa272Crossref Scopus (11) Google Scholar However, endocrinopathies are an uncommon cause of severe hyponatremia in patients who receive an immune checkpoint inhibitor.8Seethapathy H. Rusibamayila N. Chute D.F. et al.Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors.Nephrol Dial Transplant. 2020; (gfaa272)https://doi.org/10.1093/ndt/gfaa272Crossref Scopus (11) Google Scholar The combination of hyponatremia, RTA, and adrenal insufficiency in this patient is highly suggestive that his hyponatremia was secondary to adrenal insufficiency, which in turn we considered as an irAE. The patient was started on hydrocortisone 40 mg daily. This was accompanied by improvement in serum sodium and bicarbonate levels. Two days later, the patient’s hyponatremia and metabolic acidosis had resolved. He was eventually discharged on a tapering dose of steroids. Rapid resolution of both conditions upon initiation of steroids suggests that they are both immune-mediated adverse effects associated with pembrolizumab. Immune-mediated central adrenal insufficiency causing hyponatremia and combined with distal RTA secondary to immune checkpoint inhibitor therapy. Dayyan Adoor, MD, Hafsa Tariq, MD, and Arash Rashidi, MD. None. The authors declare that they have no relevant financial interests. The authors declare that they have obtained consent from the patient reported in this article for publication of the information about him that appears within this Case Report. Received April 27, 2021. Direct editorial input from a Deputy Editor. Accepted in revised form May 21, 2021.