Cause Of Hyponatremia In Patients Research Articles

Pramipexole induced syndrome of inappropriate antidiuretic hormone secretion in a patient with young onset Parkinson’s disease

Abstract Pramipexole, a dopaminergic agonist, has rarely been implicated as a cause of hyponatremia in patients with Parkinson’s disease (PD). Pramipexole-induced stimulation of anti-diuretic hormone results in euvolemic hyponatremia. This is often neglected, and hyponatremia may lead to worsening of the motor symptoms with PD and an unnecessary increase in dopaminergic medications, causing disabling dyskinesias. This case report describes a patient with young-onset PD who developed new-onset hyponatremia due to pramipexole-induced syndrome of inappropriate anti-diuretic hormone within 3 months of starting the drug.

Hyponatremia in patients with arterial hypertension: pathophysiology and management.

Sodium is the main cation in the extracellular space. In physiological conditions, sodium concentration in plasma is 135-145 mmol/l. The kidneys play the most important role in the regulation of sodium homeostasis. In recent years, a significant role of glycosaminoglycans, localized mainly in the subcutaneous tissue, and the role of glycocalyx on the surface of vascular endothelial cells, have been documented in the regulation of sodium metabolism. Hyponatremia is defined by a plasma sodium concentration lower than 135 mmol/l. Hyponatremia significantly worsens the prognosis of patients with different chronic diseases. In patients with arterial hypertension, the risk of hyponatremia is 1.5 times higher than in the general population. One of the causes of hyponatremia in patients with arterial hypertension is the use of thiazide or thiazide-like diuretics. The symptoms of hyponatremia are caused mainly by the swelling of cells in the central nervous system. Treatment of hyponatremia depends on the degree and duration (acute or chronic) of hyponatremia as well as presence of clinical symptoms. Too rapid correction of hyponatremia might result in a potentially fatal osmotic demyelinating syndrome. In the present review paper, pathophysiology and management of hyponatremia in patients with arterial hypertension are discussed.

Secondary adrenal insufficiency in patient with COVID-19 and head and neck cancer

Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is an endocrinological disorder which occurs when there is an evidence of continued antidiuretic hormone (ADH) secretion in the absence of an appropriate osmotic volume stimulus. Most commonly it is caused by different types of cancer or medications (eg. diuretics, antidepressants, antipsychotics...). Secondary adrenal insufficiency is caused by the insufficient adrenocorticotropic hormone (ACTH) secretion and cortisol production. In the hypocortisolism, the inhibitory mechanism on ADH secretion vanishes causing increased ADH secretion and leading to SIADH-like state. Both conditions, SIADH and hypocortisolism, manifest in euvolemic hyponatremia, however, its cause can be misdiagnosed and result in an inadequate treatment and potentially fatal outcome. Our case is about fifty-seven-year-old male patient who was treated with chemoradiotherapy for hematological malignancy of the oropharynx and who presented with severe hyponatremia se-veral times that almost ended fatally. Considering his malignant disease, patient was diagnosed with SIADH as a cause of hypona-tremia and was treated with hypertonic saline fluids and fluid intake restriction. However, after having suffered Covid-19 infection the patient was given glucocorticoids according to the protocol at the time. The sodium levels finally corrected, and the secondary adrenal insufficiency has been declared as the real cause of hyponatremia. SIADH is often thought to be the cause of hyponatremia in patients with malignant disease. However, SIADH represents a diagnosis of exclusion. Before making a final diagnosis, thyroid and secondary adrenal insufficiency must be ruled out. Moreover, secondary adrenal insufficiency imitates SIADH and results in euvolemic hyponatremia but the management and potential outcomes of these two conditions differ significantly. In patients who have been previously treated for malignancies with the treatment options that increase the risk of adrenal insufficiency (chemotherapy, neck or skull base radiotherapy, immunotherapy), adrenal reserve must be evaluated. If introduced, the glucocorticoid therapy should be carefully deescalated in these patients because of the risk of previously unrecognized adrenal insufficiency. This especially applies to conditions that include glucocorticoid therapy in the treatment protocol, such as Covid-19 infection.

Metabolic Acidosis and Hyponatremia in a Patient With Metastatic Melanoma

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.

Influence of osmolality on gastrointestinal fluid volume and drug absorption: potential impact on oral salt supplementation

BackgroundThe syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most frequent cause of hyponatremia in patients with cerebrovascular disease, and is often treated with oral salt tablets. However, we have shown that osmolality-dependent variations in gastrointestinal (GI) fluid volume can alter the concentration of a poorly permeable drug in the GI tract, potentially affecting its absorption. Here, we examined the effect of ingestion of hyperosmotic solution (10% NaCl) on drug concentration and absorption in the GI tract.MethodsThe effects of osmolality on luminal fluid volume and drug absorption in rat intestine (jejunum, ileum and colon) were examined by means of an in situ closed loop method using fluorescein isothiocyanate-dextran 4000 (FD-4) and atenolol. In vivo absorption in rats was determined by measuring the plasma concentration after oral administration of the test compounds dissolved in purified water or hyperosmotic solution (10% NaCl).ResultsAdministration of hyperosmotic solution directly into the GI tract significantly increased the GI fluid volume, owing to secretion of water into the lumen. After administration in hyperosmotic solution, the luminal concentration of non-permeable FD-4 was significantly lower than the initial dosing concentration, whereas after administration in purified water, the luminal concentration exceeded the initial concentration. The fraction absorbed of atenolol was markedly lower after administration in hyperosmotic solution than after administration in purified water. An in vivo pharmacokinetic study in rats was consistent with these findings.ConclusionsAdministration of hyperosmotic NaCl solution increased GI fluid volume and reduced the plasma level of orally administered atenolol. This may imply that oral salt tablets used to treat hyponatremia in SIADH patients could decrease the intestinal absorption of concomitantly administered drugs, resulting in lower plasma exposure.

Risk factors and causes of hyponatremia in patients after radiotherapy for head and neck cancer: A retrospective study

BackgroundHyponatremia is the most frequently encountered electrolyte abnormality which is caused by kinds of reasons including kidney, metabolic and central nervous system diseases. The adverse effects of hyponatremia include but not limit to cerebral edema and seizures, which often aggravate neurological damage. Therefore, early diagnosis and intervention would reduce the risk of adverse effects of hyponatremia. ObjectiveTo investigate the differences between patients with or without hyponatremia after radiotherapy for head and neck cancer, and to explore the risk factors and causes of hyponatremia. MethodsPatients who aged over 18 years old and underwent radiotherapy for head and neck cancer were collected from Department of Neurology, Sun Yat-Sen Memorial Hospital from January 2012 to July 2018. The comorbidities of patients and demographic and serological data were retrospectively collected to investigate the causes and risk factors of hyponatremia in these patients. Differences of the length of hospital stay and the cognitive function between patients with and without hyponatremia were analyzed. ResultsIn this study, 798 patients were reviewed. The incidence of hyponatremia was 17.9%. Risk factors of hyponatremia included age(OR 1.05, 95%CI 1.03–1.07, P ​< ​0.001), gender(OR 0.62, 95%CI 0.39–0.99, P ​= ​0.046), medical history of hypothyroidism(OR 2.42, 95%CI 1.26–4.09, P=0.006), adrenal insufficiency (OR 15.61, 95%CI 2.73–89.07, P ​= ​0.002) or dysphagia (OR 1.81, 95%CI 1.24–2.65, P ​= ​0.002). The most common cause of hyponatremia was cerebral salt-wasting syndrome (CSWS) (32.9%). The insufficient intake due to dysphagia (29.4%), and hypothyroidism (13.3%) were also common in these patients. Clinically, hyponatremia resulted in the prolonged hospitalization time. ConclusionHyponatremia would be common in patients who underwent radiotherapy for head and neck cancer. The importance of distinguishing the etiology of hyponatremia is addressed.

[Clinical Characteristics of Brucellosis Complicated by Syndrome of Inappropriate Secretion of Antidiuresis].

Objective To summarize and analyze the causes of hyponatremia in patients with brucellosis and explore the clinical manifestations of syndrome of inappropriate antidiuresis(SIAD)in patients with brucellosis. Methods The clinical data of 111 patients with acute brucellosis who were treated in Peking Union Medical College Hospital from September 2011 to December 2017 were retrospectively reviewed.Hyponatremia was defined by serum sodium level lower than 135 mmol/L.Clinical characteristics including medical histories,vital signs,and laboratory test findings were collected and analyzed. Results Hyponatremia was found in 14(12.6%)of 111 patients with brucellosis,among whom 3 patients were confirmed to be with SIAD,10 were suspected as SIAD,and 1 was diagnosis as hypopituitarism.Hypoalbuminemia,elevation of erythrocyte sedimentation rate,and high sensitivity C reactive protein were found in brucellosis patients with SIAD,along with severe complications such as infective endocarditis,septic shock,and anemia. Conclusion Hyponatremia is not a rare condition in brucellosis patients and may be caused by SIAD.

Hyponatremia in a Patient With Cancer

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.

Severe Persistent Hyponatremia: A Rare Presentation of Biliary Fluid Loss

Hypotonic hyponatremia is caused by a serum sodium level of <135 mEq/L in the setting of excess solute loss accompanied by free water retention because of antidiuretic hormone release, subsequent to decreased effective arterial blood volume. Acute hyponatremia can have various neurological manifestations, including drowsiness, lethargy, coma, seizures, respiratory depression, and even death. In this article, we present a case of a 41-year-old man who presented with hyponatremia as a result of sodium containing biliary fluid loss and resultant renal free water retention in response to increased antidiuretic hormone secretion. He underwent placement of a cholecystostomy tube for acalculous cholecystitis and was found to be persistently hyponatremic despite repletion with sodium-containing fluids. Once the cholecystostomy tube was removed, the patient’s sodium levels improved, and his symptoms resolved. Our case highlights choleuresis as an unusual but significant cause of hyponatremia in patients who have external biliary drainage.

Hiponatremia in the practice of a psychiatrist. Part 1: SIADH syndrome and drug-induced hyponatremia.

Abstract Introduction. Hyponatremia is an important part of psychiatric practice. In order to analyze its causes and symptoms, the literature on hyponatremia in psychiatric patients has been reviewed. The work has been divided into two separate manuscripts. In the first one the authors discuss the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia occurring with the use of psychotropic drugs (antidepressants, antipsychotics, normotimics), while the second paper discusses research on psychogenic polydipsia. The causes of hyponatremia in patients treated in psychiatric wards include: water intoxication associated with polydipsia, somatic comorbidities, side effect of internal medicine and psychiatric drugs. The most common mechanism leading in these cases to hyponatremia is the syndrome of inappropriate secretion of vasopressin (SIADH). The SIADH syndrome is a group of symptoms, first described in 1967 by Schwartz and Bartter in The American Journal of Medicine, which results from the hypersecretion of antidiuretic hormone, also called vasopressin, which causes patients to develop normovolemic hyponatremia. The phenomenon of drug-induced hyponatremia in psychiatric practice is generally observed with the use of antidepressants, antipsychotics and anti-epileptic drugs (used in psychiatry as normotimic drugs). Aim and method. The first manuscript includes a review of literature on the syndrome of inappropriate secretion of vasopressin (SIADH) and hyponatremia occurring after the use of psychotropic drugs, and is divided into two subsections: 1. The syndrome of inappropriate secretion of vasopressin (SIADH), 2. Hyponatremia and psychotropic drugs (antidepressants, antipsychotics, normotimics). Conclusion. In the view of the reviewed literature it is extremely important to control the natremia level during pharmacotherapy using the above mentioned drugs, especially in the initial period of therapy.

Cerebral Salt-Wasting Syndrome: Diagnosis by Urine Sodium Excretion

BackgroundCerebral salt-wasting syndrome (CSWS) was initially described over 60 years ago in hyponatremic patients with a cerebral lesion. However, the diagnostic criteria for CSWS have not been fully established. Thus, when hyponatremia is observed in patients with CSWS, they may be misdiagnosed as having the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Thus, it is critical to differentiate between these 2 conditions because their treatments are diametrically opposed. Materials and MethodsWe carried out a retrospective study of 45 patients with CSWS and compared them to 60 normonatremic control patients, and 28 patients with SIADH. All patients had their 24-hour urine volumes and sodium (Na) excretion measured. ResultsIn patients with CSWS, urinary Na excretion was 394 ± 369mmol/24 hours and urinary volume was 2,603 ± 996mL/24 hours; both values significantly greater than in controls (P < 0.01). By contrast, in patients with SIADH, the urine Na excretion was only 51 ± 25mmol/24 hours and urine volume was 745 ± 298mL/24 hours; values significantly lower than in patients with CSWS (P < 0.01). ConclusionsCSWS was diagnosed in patients with cerebral lesion who had (1) symptomatic hyponatremia, (2) urine Na excretion 2 standard deviations above controls and (3) increased urine volume. Patients with SIADH also had symptomatic hyponatremia but, in contrast to patients with CSWS, they had decreased Na excretion and urine volume. Thus urine Na excretion and volume are very important for diagnosing the cause of hyponatremia in patients with cerebral lesions.

Diagnosis and management of hyponatremia in cancer patients

Hyponatremia is among the metabolic disturbances encountered in oncology. Risk factors for hyponatremia include chemotherapy, treatment-induced nausea and vomiting, hydration, pain, narcotic drugs, and physical and emotional stress. A common cause of hyponatremia in patients with cancer is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), which may result from ectopic production of arginine vasopressin (AVP) by the tumor tissue. The AVP-receptor antagonists, a new class of agents, correct hyponatremia by directly blocking the binding of AVP with its receptors. In clinical trials, conivaptan, lixivaptan, tolvaptan, and satavaptan have increased serum osmolality and normalized the serum [Na(+)] in hyponatremia associated with SIADH, cirrhosis, or congestive heart failure. These drugs may have a potential in cancer-related hyponatremia as well.

Syndrome of inappropriate antidiuretic hormone secretion and Kawasaki disease

Sirs, I read with interest the Letter to the Editor entitled “Kawasaki disease and hyponatremia” by Lee et al. [1]. The authors suggested that the syndrome of inappropriate antidiuretic hormone secretion (SIADH) was one of the causes of hyponatremia in patients with Kawasaki disease (KD) and that serum cytokines such as interleukin (IL)-6 or IL-1 beta might contribute to the development of SIADH in such circumstances [1]. I agree with the comments of Dr. Lee et al. that SIADH has sometimes been reported in KD [2, 3] and cerebral vasculitis is thought to be a cause of SIADH in patients with KD [4]. On the other hand, Mine et al. recently suggested that inflammatory cytokines may be involved in the pathogenesis of SIADH in KD [5]. Many inflammatory cytokines, including IL-6 and IL-1 beta, are elevated during the acute phase of KD [4] and these cytokines may activate vasopressin secretion. As Dr. Lee et al. pointed out, further studies are necessary to confirm the possible relationship between serum cytokines and hyponatremia due to SIADH in KD [1], and there is a need to examine the various parameters, such as plasma vasopressin levels, concentrations of serum cytokines, serum osmolality, and urinary electrolytes and osmolality.

SIADH Caused by the Synergistic Effect of S-1 and Thiazide

Hyponatremia is a dangerous electrolyte disturbance in patients on chemotherapy and may cause sudden death if not detected early. SIADH (syndrome of inappropriate antidiuretic hormone) is one of the known causes of hyponatremia in patients undergoing chemotherapy. Few chemotherapeutic agents, however, are reported to cause SIADH. The current study reports that SIADH developed in a 55 year old woman on S-1 () and cisplatin () chemotherapy for the peritoneal metastasis of gastric cancer. The patient underwent a total gastrectomy, a splenectomy, and a segmental resection of the transverse colon for gastric cancer. She had used thiazide and to treat hyperiension for 12 years. She admitted to our hospital with complaining of general weakness, dysarthria, loss of appetite, and urinary discomfort. The serum level of sodium and potassium were 94 mEq/L and 2.2 mEq/L respectively. The hyponatremia completely resolved uneventfully after 3% saline infusion, which led to normalized electrolyte balance. The patient was discharged on the 13th hospital day.