Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis

Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis
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   NDT Plus (2008) 5: 286–288doi: 10.1093/ndtplus/sfn076Advance Access publication 24 June 2008 Case Report  Water intoxication induced by low-dose oral cyclophosphamidein a patient with anti-neutrophil cytoplasmic antibody-relatedglomerulonephritis Akihiko Kato 1 , Takeshi Sugiura 2 , Tatsuo Yamamoto 3 , Taro Misaki 4 , Takayuki Tsuji 4 , Yukitoshi Sakao 4 ,Masaaki Sakakima 4 , Hideo Yasuda 4 , Yoshihide Fujigaki 4 and Akira Hishida 4 1 Division of Blood Purification, Hamamatsu University School of Medicine,  2 Department of Nephrology, Seirei Mikatahara GeneralHospital,  3 Department of Health and Nutritional Science, Hamamatsu University and   4 First Department of Medicine, HamamatsuUniversity School of Medicine, Shizuoka, Japan Abstract We reported the case of a 70-year-old woman with mod-erate renal failure due to anti-neutrophil cytoplasmicantibody-related glomerulonephritis who developed symp-tomatic water intoxication (serum Na: 108 mEq/L) fol-lowing treatment with oral low-dose cyclophosphamide(CY) (50mg/day). Estimated glomerular filtration rate was29.5 mL/min/1.73 m 2 . She had drunk  > 2 L of fluid in 12 h prior to the development of cerebral oedema. This rare casesuggests that oral low-dose CY could be an occult cause of water intoxication in patients with chronic kidney diseasetaking large fluid volumes. Keywords:  chronic kidney disease; cyclophosphamide;fluid intake; symptomatic hyponatraemia Introduction Cyclophosphamide (CY) is an alkylating drug often used forrheumatologicdiseasessuchasanti-neutrophilcytoplas-mic antibody (ANCA)-related glomerulonephritis (GN).Water intoxication following intravenous low-dose CY isreported rarely to cause life-threatening water intoxication[1–4]. Herein, we report the case of an elderly womanwith ANCA-related GN who developed symptomatic wa-ter intoxication following low-dose oral CY treatment for 1 month. Correspondence and offprint requests to : Akihiko Kato, Division of Blood Purification, Hamamatsu University School of Medicine, 1-20-1Handayama,Higashi-ku,Hamamatsu,Shizuoka431-3192,Japan.Tel.and Fax: + 81-53-435-2756; E-mail: a.kato@hama-med.ac.jp Case report A 70-year-old woman with ANCA-related GN was emer-gently readmitted to our hospital due to the developmentof nausea, vomiting, confusion and mental disorientationconcomitantly on 9 January 2006. She had previously beenadmitted to our hospital due to anaemia and a rapid in-crement of serum creatinine from 0.69 to 3.08 mg/dLin the previous 3 months on 28 October 2005. After admission, serum creatinine had maximally increased to5.22 mg/dL. Due to the presence of 123 EU of serummyeloperoxidase (MPO)—ANCA titre and crescentic GNin the kidney biopsy—we diagnosed her as having ANCA-related GN. After twice methylprednisolone pulse therapy(500 mg/day), we had started 30 mg/day of oral pred-nisolone (PSL) on 7 November and subsequently added oral CY [50 mg/day, 1.4 mg/kg body weight (BW)/day]since 6 December. She had been discharged from our hospital on 20 December, with 20 mg/day of PSL and 50 mg/day of CP. At discharge, her serum creatinine had decreased to 1.98 mg/dL with normal serum sodium (Na)(138 mEq/L). On 6 January 2006, she first visited our out- patient clinic. After discharge, she had been taking fluids tomaintain urinary flow to avoid haemorrhagic cystitis. Her serum Na had decreased to 130 mEq/L without any clinicalsymptoms.At readmission, blood pressure was elevated to 169/87 mmHg, but there was no pitting oedema in either leg.Her body weight remained at 37 kg. Serum NA decreased to 108 mEq/L with plasma osmolality of 233 mOsm/kgH 2 O, while urinary Na excretion was 55 mEq/L with uri-nary osmolality of 246 mOsm/kg H 2 O. Laboratory exam-ination revealed as follows: haemoglobin 9.9 g/dL, serumcreatinine 1.31 mg/dL, blood urea nitrogen 25.9 mg/dL, potassium 4.1 mEq/L, chloride 79 mEq/L, plasma glucose116 mg/dL and bicarbonate 24.9 mmol/L. Her serum al- bumin decreased to 3.2 g/dL, with 31 mL/min of creati-nineclearance(Ccr)and29.5mL/min/1.73m 2 ofestimated  C  The Author [2008].The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access versionof this article for non-commercial purposes provided that: the srcinal authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the srcinal place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org   b  y g u e  s  t   onM a r  c h 1 2  ,2  0 1 4 h  t   t   p :  /   /   c k  j   . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om  Hyponatraemia associated with oral cyclophosphamide 287 Fig. 1.  Cerebral oedema due to water intoxication. Plain brain CT scan revealed marked swelling of the sulcus at the frontal lobe and narrowingof cerebral ventricles at re-admission. Following the discontinuation of CY treatment and fluid restriction, hyponatraemia was promptly restored by72 h without any disorientation. CT scan also revealed no cerebral oedema at hospital Day 10. Abbreviations are CT: computed tomography and CY:cyclophosphamide. glomerular filtration rate (eGFR) calculated by the Modi-fication of Diet in Renal Disease (MDRD) Study equation[5]. Plain brain computed tomography (CT) scan revealed  brain oedema such as swelling of the sulcus at the frontallobe and ventricular narrowing (Figure 1A).Endocrine hormone examination at early morning on10 January disclosed as follows: plasma ACTH 155 pg/mL(normal, 7.4–55.7), cortisol 17.7 µ g/dL (normal, 5.3–11.0)and aldosterone 311 pg/mL (normal, 29.9–159). Thyroid function was within normal range. Plasma renin activ-ity was suppressed to 0.2 ng/mL/h (normal, 0.3–2.9), and  plasma human atrial natriuretic peptide (ANP) was ele-vated to 80 pg/mL (normal,  ≤ 40), a compatible findingwith overhydration. Plasma antidiuretic hormone (ADH)was 2.7 pg/mL (normal, 0.3–3.5), despite the presence of hyponatraemia (Na: 119 mEq/L).We diagnosed the patient as having water intoxication inview of hyponatraemia with an inappropriately high urineosmolarity. We first suspected the CY-induced water intox-ication combined with massive hydration. After stoppingoral CY, the fluid intake was restricted by 1 L/day of 0.9%saline solution. By 72 h after readmission, she was fullyoriented with normal electrolyte concentrations. In retro-spective, she reported that she had drunk   > 2 L of fluid in the 12 h prior to the readmission. Plain brain CT scanon day 10 showed the improvement of sulcus swelling and ventricular narrowing (Figure 1B).One month after the cessation of CY, we conducted awater-loading test (20 mL/kg body weight) by infusing5% glucose solution for 30 min (Scr: 1.54 mg/dL, eGFR:26.8 ml/min/1.73 m 2 ). By 4 h, a total of 85% of the loaded volume was excreted into the urine, and urinary osmolalitydecreased from 369 to 150 mOsm/kg H 2 O. Plasma ADHalso decreased to 1.2 pg/mL with 130 mEq/L of serum Na at 2 h after the loading. Until April 2008, she has notexperienced any episode of hyponatraemia. Discussion It was initially thought that water intoxication developed in doses  > 50 mg/kg BW of CY [6]. However, this is nottrue, since some observations have shown that low-doseCY also, but rarely, causes water intoxication [1–4]. To the best of our knowledge, there were five cases that devel-oped symptomatic water intoxication following low-doseCY ( < 15 mg/kg BW) (Table 1). In all of the cases, thedrug was given intravenously. In this case, we first experi-enced severe hyponatraemia in an elderly women with oraladministration of low-dose CY (daily dose: 1.4 mg/kg) for 1 month.That CY was responsible for hyponatraemia in this patient is supported by some observations. First, her hyponatraemia had first become evident 1 month after oralCY treatment. By stopping CY and water restriction, her hyponatraemiasoondissolvedandhavenotoccurredagain.Second, the water-loading test at 1 month after CY cessa-tion revealed normal excretion of free water, indicating no prior impairment of water excreting ability. Third, no other cause of hyponatraemia was apparent. Nausea is a potentstimulus to release ADH, but her plasma ADH remained within normal range. In addition, nausea soon dissolved concomitantlywiththecorrectionofhyponatremiabywater restriction.Otherstudyalsoshowedthatnoriseofplasmais   b  y g u e  s  t   onM a r  c h 1 2  ,2  0 1 4 h  t   t   p :  /   /   c k  j   . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om  288 Kato  et al  . Table 1.  Patient characteristics of water intoxication following low-dose CYAge (years) Sex Original diseases CY dosage Scr (mg/dL) Serum Na (mEq/L) Fluid intake Ref.68 M MM 500 mg, iv 0.96 108 3 L/day [1]59 F SLE 10 mg/kg, iv 0.63 116 2.4 L/day [2]57 F Sj¨ogren 780 mg, iv 0.6 117  > 0.95 L/6 h [3]48 F SLE 750 mg, iv (12.5 mg/kg) 0.72 119 3 L/day [4]53 F SLE 500 mg, iv ND 119 3 L/2 h [4]70 F ANCA-related GN 50 mg (1.4 mg/kg) 1.31 108  > 2 L/12 h This caseCY: cyclophosphamide, MM: multiple myeloma, SLE: systemic lupus erythematosus, ANCA-related GN: anti-neutrophil cytoplasmic antibody-related glomerulonephritis, Scr: serum creatinine, Na: sodium and ND: not determined. observed during moderate-dose CY infusion [7]. However,the water-loading test when recovered from hyponatraemiadecreased plasma ADH to 1.2 pg/mL, indicating that thelevel of plasma ADH (2.7 pg/mL) at readmission wasrelatively high in association with CY therapy. Since acase has been reporte of an 8-year-old girl with established diabetes inspipidus with hyponatraemia caused by CYinfusion despite an inability to secrete ADH [8], one or more CY metabolites may directly alter water permeabilityin the kidney.One certain factor that possibly may contribute to water intoxication was excess fluid intake in this case. Previouslyreportedcasesthatdevelopedseverehyponatraemiabylow-dose CP also received oral hydration > 2–3 L of fluid a day.Other causative factors responsible for water intoxicationwere the presence of renal failure and hypoalbuminaemia.Moderate renal failure (Ccr: 25–50 mL/min) prolongs thehalf-life of CY (50–100 mg/m 2 as a 1-h infusion) from4.8 to 6.4 h [9]. Since hyponatraemia was already evident3 days before re-admission, accumulated CY metabolites by continuous oral regimen may gradually progress to hy- ponatraemia.In summary, we experienced the case of an elderlywoman with impaired renal function who developed symp-tomatic hyponatraemia following oral CY administrationfor 1 month. In this case, the patient had been taking over 2 L of fluid per day according to the general advice to avoid the risk of cystitis, which may contribute to water intoxica-tion.Thus,nephrologistsshouldbeawarethatorallow-doseCY could be an occult cause of water intoxication in renalfailurepatientsandshouldadvisethepatienttotakesodiumchloride when using oral hydration. Conflict of interest statement  . None declared. References 1. Webberley MJ, Murray JA. Life-threatening acute hyponatremia in-duced by low dose cyclophosphamide and indomethacin.  Postgrad  Med J   1989; 65: 950–9522. McCarron MO, Wright GD, Roberts SD. Water intoxication after lowdose cyclophosphamide.  BMJ   1995; 311: 2923. Spital A, Ristow S. Cyclophosphamide induced water intoxication in awoman with Sj¨ogren’s syndrome.  J Rheumatol   1997; 24: 2473–24754. Salido M, Macarron P, Hernandez-Garcia C  et al  . Water intoxicationinduced by low-dose cyclophosphamide in two patients with systemiclupus erythematosus.  Lupus  2003; 12: 636–6395. Imai E, Horio M, Nitta K   et al  . Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan.  Am J Kidney Dis  2007; 50: 927–9376. DeFronzo RA, Braine H, Colvin M. Water intoxication in man after cyclophosphamidetherapy.Timecourseandrelationtodrugactivation.  Ann Intern Med   1973; 78: 861–8697. Bressler RB, Huston DP. Water intoxication following moderate-doseintravenous cyclophosphamide.  Arch Intern Med   1985; 145: 548–5498. CampbellDM,AtkinsonA,GillisD etal  .Cyclophosphamideandwater retention: mechanism revisited.  J Pediatr Endocrinol Metab  2000; 13:673–6759. Haubitz M, Bohnenstengel F, Brunkhorst R   et al  . Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insuffi-ciency.  Kidney Int   2002; 61: 1495–1501  Received for publication: 15.4.08 Accepted in revised form: 30.5.08   b  y g u e  s  t   onM a r  c h 1 2  ,2  0 1 4 h  t   t   p :  /   /   c k  j   . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om


Apr 28, 2018
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