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      Severe cyclophosphamide-related hyponatremia in a patient with acute glomerulonephritis

      case-report

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          Abstract

          Cyclophosphamide is frequently used to treat cancer, autoimmune and renal diseases, such as rapidly progressive glomerulonephritis. Its side effects are well-known, including bone marrow depression, infections, alopecia, sterility, bladder malignancy and hemorrhagic cystitis. Moreover, in some cases cyclophosphamide use has been related to the onset of hyponatremia, by development of a syndrome of inappropriate antidiuresis. Indeed, severe hyponatremia has been previously reported in patients treated with high-dose or moderate-dose of intravenous cyclophosphamide, while only few cases have been reported in patients treated with low dose. Here, we discuss a case of a syndrome of inappropriate antidiuresis followed to a single low-dose of intravenous cyclophosphamide in a patient with a histological diagnosis of acute glomerulonephritis, presenting as acute kidney injury. After cyclophosphamide administration (500 mg IV), while renal function gradually improved, the patient developed confusion and headache. Laboratory examinations showed serum sodium concentration dropped to 122 mmol per liter associated with an elevated urinary osmolality of 199 mOsm/kg, while common causes of acute hyponatremia were excluded. He was successfully treated with water restriction and hypertonic saline solution infusion with the resolution of the electrolyte disorder. This case, together with the previous ones already reported, highlights that electrolyte profile should be strictly monitored in patients undergoing cyclophosphamide therapy in order to early recognize the potentially life-threatening complications of acute water retention.

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          Most cited references11

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          The Syndrome of Inappropriate Antidiuresis: Pathophysiology, Clinical Management and New Therapeutic Options

          Hyponatremia is a marker of different underlying diseases and it can be a cause of morbidity itself; this implies the importance of a correct approach to the problem. The syndrome of inappropriate antidiuresis (SIAD) is one of the most common causes of hyponatremia: it is a disorder of sodium and water balance characterized by urinary dilution impairment and hypotonic hyponatremia, in the absence of renal disease or any identifiable non-osmotic stimulus able to induce antidiuretic hormone (ADH) release; according to its definition, it is diagnosed through an exclusion algorithm. SIAD is usually observed in hospitalized patients and its prevalence may be as high as 35%. The understanding of the syndrome has notably evolved over the last years, as reflected by the significant change in the name, once the syndrome of inappropriate secretion of ADH (SIADH), today SIAD. This review is up to date and it analyses the newest notions about pathophysiological mechanisms, classification, management and therapy of SIAD, including vaptans.
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            Cyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney.

            Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4-hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water-loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats. In cyclophosphamide-treated rats, significant increases in renal expression of aquaporin-2 (AQP2) and Na-K-2Cl cotransporter type 2 (NKCC2) were shown by immunoblot analysis and immunohistochemistry. Apical translocation of AQP2 was also demonstrated by quantitative immunocytochemistry. In both rat kidney and primary cultured IMCD cells, significant increases in AQP2 and vasopressin receptor type 2 (V2R) mRNA expression were demonstrated by real-time quantitative PCR analysis. Confocal laser-scanning microscopy revealed that apical translocation of AQP2 was remarkably increased when primary cultured IMCD cells were treated with 4-HC in the absence of vasopressin stimulation. Moreover, AQP2 upregulation and cAMP accumulation in response to 4-HC were significantly reduced by tolvaptan cotreatment in primary cultured IMCD cells and IMCD suspensions, respectively. We demonstrated that, in the rat kidney, cyclophosphamide may activate V2R and induce upregulation of AQP2 in the absence of vasopressin stimulation, suggesting the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
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              Hyponatraemia induced by low-dose intravenous pulse cyclophosphamide.

              Cyclophosphamide is an alkylating agent and was traditionally known to potentiate the renal action of vasopressin. Although low-dose intravenous pulse cyclophosphamide therapy is being used extensively in the treatment of malignant and rheumatological diseases, there have been only a few case reports of cyclophosphamide-induced hyponatraemia. Clinical data were retrospectively analysed from 84 patients (42 lupus nephritis; 42 non-Hodgkin's lymphoma; a total of 112 treatment episodes) admitted for intravenous pulse cyclophosphamide (500-750 mg/m(2)) therapy. In all patients, half-isotonic saline was used for prophylactic hydration. Cyclophosphamide-induced hyponatraemia was defined as serum sodium concentration <135 mEq/L at 24 hours after the therapy in patients whose basal serum sodium concentrations were normal. After the low-dose intravenous pulse cyclophosphamide, serum sodium concentration significantly decreased from 139.9 +/- 3.5 to 137.9 +/- 5.1 mEq/L (P < 0.001). Cyclophosphamide-induced hyponatraemia occurred in 15 treatment episodes (13.4%) from 12 patients (14.3%). Patients with hyponatraemia were significantly older than those without hyponatraemia (57.3 +/- 14.7 vs. 40.0 +/- 17.0 years, P < 0.01). Hyponatraemia was associated with male sex on univariate analysis (P < 0.05), but not on multivariate analysis. No factors were found to independently predict the occurrence of cyclophosphamide-induced hyponatraemia when multivariate analysis was performed including parameters age, sex, underlying disease, presence or absence of comorbidities associated with hyponatraemia, presence or absence of concurrent medications associated with hyponatraemia and dose of cyclophosphamide. Hyponatraemia occurring after low-dose intravenous pulse cyclophosphamide is not rare, especially when hypotonic solutions are adopted for hydration protocol. Thus, the use of hypotonic fluids should be avoided when using cyclophosphamide. Instead, isotonic solutions should be used if a forced diuresis is required.
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                Author and article information

                Journal
                World J Nephrol
                WJN
                World Journal of Nephrology
                Baishideng Publishing Group Inc
                2220-6124
                6 July 2017
                6 July 2017
                : 6
                : 4
                : 217-220
                Affiliations
                Pasquale Esposito, Maria Valentina Domenech, Nicoletta Serpieri, Marta Calatroni, Ilaria Massa, Alessandro Avella, Edoardo La Porta, Luca Estienne, Elena Caramella, Teresa Rampino, Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico “San Matteo” and University of Pavia, 27100 Pavia, Italy
                Author notes

                Author contributions: All authors contributed equally in data acquisition, analysis and interpretation of the data, drafting and critical revision of the manuscript.

                Correspondence to: Pasquale Esposito, MD, PhD, Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico “San Matteo” and University of Pavia, Piazzale Golgi 19, 27100 Pavia, Italy. p.esposito@ 123456smatteo.pv.it

                Telephone: +39-3-82503883 Fax: +39-3-82503883

                Article
                jWJN.v6.i4.pg217
                10.5527/wjn.v6.i4.217
                5500459
                28729970
                d07921b9-dda8-4166-ba4e-231c774ea23c
                ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.

                Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 26 January 2017
                : 12 April 2017
                : 6 June 2017
                Categories
                Case Report

                hyponatremia,cyclophosphamide,syndrome of inappropriate antidiuresis,glomerulonephritis,hypertonic solutions,antidiuretic hormone,urine osmolality

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