Clin Exp Nephrol (2007) 11:241–243 © Japanese Society of Nephrology 2007DOI 10.1007/s10157-007-0485-4

A. Onishi · H. Yamamoto · T. Akimoto (*) · O. Saito · M. Inoue · Y. Ando · S. Muto · E. KusanoDivision of Nephrology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, JapanTel. +81-285-58-7346; Fax +81-285-44-4869e-mail: tetsu-a@jichi.ac.jp

CASE REPORT

Akira Onishi · Hisashi Yamamoto · Tetsu Akimoto Osamu Saito · Makoto Inoue · Yasuhiro Ando Shigeaki Muto · Eiji Kusano

Reversible acute renal failure associated with clomipramine-induced interstitial nephritis

Received: March 1, 2007 / Accepted: June 11, 2007

AbstractWe describe a 41-year old man with obsessive-compulsive neurosis who developed acute renal failure (ARF) due to acute interstitial nephritis (AIN) during 6 weeks of treat-ment with clomipramine hydrochloride (CPH). He had a slight fever, mild arthralgia, appetite loss, and diarrhea after taking CPH. On admission, he showed serum creatinine (sCr) of 7.31 mg/dl, and creatinine clearance (Ccr) of 2.5 ml/min. He subsequently became anuric and required hemodi-alysis. Renal biopsy revealed AIN with diffuse mononuclear cell infi ltration. After the withdrawal of CPH and treatment with prednisolone (PSL) 0.5 mg/kg per day, his urinary output improved, along with improvement of his renal func-tion; therefore hemodialysis was fi nally discontinued. To our knowledge, this is the fi rst case report of AIN induced by clomipramine.

Key words Interstitial nephritis · Clomipramine · Obses-sive-compulsive neurosis · Corticosteroid

Introduction

Acute interstitial nephritis (AIN) has been implicated in drug-associated renal damage. Several types of medications, including antibiotics and nonsteroidal anti-infl ammatory drugs, cause AIN.1 This report describes a 41-year-old man with reversible acute renal failure (ARF) due to AIN, prob-ably induced by the use of clomipramine hydrochloride (CPH), which is commonly administered for the treatment of psychosis, neurosis, or panic disorder.2 He required hemo-dialysis; however, his renal function fi nally recovered after the withdrawal of CPH and the administration of cortico-

steroid. To our knowledge, this is the fi rst case report of AIN that was presumably induced by CPH.

Case report

A 41-year-old man was admitted to our hospital in October 2005 because of appetite loss, low-grade fever, and renal failure. Six months previously, he had been diagnosed with obsessive-compulsive neurosis, and had been treated with teprenone (TPN) 150 mg/day for 26 weeks, sodium valpro-ate (VPA) 600 mg/day for 21 weeks, carbamazepine (CBZ) for 19 weeks, perospirone hydrochloride hydrate (PHH) 8 mg/day for 14 weeks, and CPH 50 mg/day for 6 weeks. Three weeks after the initiation of CPH treatment, he pre-sented with fever, mild arthralgia in multiple joints, appetite loss, and diarrhea. Two weeks before admission, laboratory analysis had revealed blood urea nitrogen (BUN) of 25 mg/dl and serum creatinine (sCr) of 2.67 mg/dl, followed by further progressive deterioration of renal function. No data regarding his previous renal function was available.

On admission, his arthralgia and diarrhea had disap-peared, but fever, appetite loss, and diarrhea had persisted. His blood pressure was 140/80 mmHg, pulse rate was 90 beats/min, respiratory rate was 24/min, and temperature was 37.1°C. The lungs were clear and heart sounds were normal. There was no rash, lymphadenopathy, or swelling of joints. Renal sonography showed the right and left kidney to measure 11.1 cm and 11.0 cm, respectively, with normal cortex echogenicity. The laboratory data on admission are shown in Table 1.

In addition to renal dysfunction, hematological and sero-logical studies revealed eosinophilia and an increased level of C-reactive protein (CRP). In addition, neither antiglo-merular basement membrane antibody, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), nor proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) were observed, while the complement levels were also found to be within the normal limits. Urinalysis showed active sediments with 15 to 16 epithelial casts, and 9 to

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10 granular casts per low-power fi eld. His urine con-tained 0.14 g of protein in a 24-h specimen. Fractional excretion of sodium (FENa) was 1.3%. The urinary excre-tion of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) was 1181 µg/l and 11.0 U/l, respectively. Because he was oliguric, the administration of furosemide at 200 mg/day was begun; however, his oliguria worsened steadily. Subsequently, he became anuric and required hemodialysis for progressive azotemia (Fig. 1).

A renal biopsy was performed 6 days after admission. The specimens consisted of three cores of renal parenchyma with eight glomeruli with no histological changes (Fig. 2B). There was marked diffuse infi ltration of lymphocytes and eosinophils, associated with destruction of tubular struc-tures (Fig. 2A). Interstitial edema and mild tubular atrophy were also found. Immunohistochemistry failed to reveal any immune complex deposit in the observed glomeruli. Elec-tron microscopy disclosed focal fusion of the foot processes of the glomerular visceral epithelial cells.

After the analysis of his renal specimen, drug-induced AIN was suspected. Although all drugs which he had

Table 1. Laboratory data on admission

Urinalysis Urine volume 600 ml/day Chemistry Specifi c gravity 1.015 Total protein 5.5 g/dl Protein 2+ (0.138 g/day) Albumin 2.8 g/dl Glucose – BUN 51 mg/dl Occult blood ± Cr 7.31 mg/dl Ccr 2.5 ml/min Uric acid 8.2 mg/dl FENa 1.3% Sodium 134 mEq/l NAG 11.0 U/l Potassium 4.9 mEq/l β2MG 1181.0 µg/l Chlorine 100 mEq/l Calcium 7.7 mg/dlHematology Phosphorus 4.5 mg/dl White blood cells 8500/µl Stab cells 9% Serology Segmented cells 63% CRP 12.14 mg/dl Eosinophils 15% IgG 447 mg/dl Monocytes 10% IgA 159 mg/dl Lymphocytes 3% IgM 25 mg/dl Red blood cells 317×104/µl C3 129 mg/dl Hemoglobin 10.1 g/dl C4 37 mg/dl Hematocrit 30.1% CH50 47.1 U/ml Platelets 281×103/µl MPO-ANCA Negative PR3-ANCA Negative

Fig. 1. Changes in serum creatinine (sCr), creatinine clearance (Ccr), urine β2 -microglobulin (β2MG), and urine N-acetyl-beta-D-glucosaminidase (NAG). TPN, teprenone; VPA, sodium valproate; CBZ, carbamazepine; PHH, perospirone hydrochloride hydrate; CPH, clomipramine; PSL, prednisolone

Fig. 2A,B. Renal biopsy section, showing A diffuse interstitial infi ltration of lymphocytes and eosinophils associated with destruction of tubular structures and B normal-appearing glomeruli. Periodic acid-Schiff stain

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received were negative for the drug lymphocyte stimulation test (DLST), CPH and PHH were discontinued on the eleventh day after admission. TPN, VPA, and CBZ were continued to avoid deterioration of his psychogenic disorder. Because anuria persisted despite the discontinua-tion of CPH and PHH, oral prednisolone (PSL), at a dose of 30 mg/day, was initiated from day 14. His urine output began to increase 3 days after the initiation of steroid treat-ment, and this was followed by a constant decrease in sCr, along with an improvement of creatinine clearance (Ccr; Fig. 1). Hemodialysis was stopped 6 days after the initiation of PSL, and subsequently his renal function continued to improve. The urinary excretion of β2MG and NAG was also decreased along with the improvement of his renal function.

In April 2007, his sCr had decreased to 1.57 mg/dl, despite the tapering of the PSL dose to 2.5 mg/day and the continu-ation of TPN, VPA, and CBZ.

Discussion

AIN is a common cause of ARF.3 Immune-mediated mecha-nisms, including hypersensitivity to drugs, are the main eti-ologies of AIN. The DLST has been considered to be a useful diagnostic procedure for drug-induced AIN; however, this test may sometimes be negative in situations in which the number of sensitized lymphocytes in the peripheral blood is low or the stage of AIN is advanced.4,5 Therefore, it is not surprising that all the medications prescribed for our patient before admission were negative for the DLST.

CBZ and VPA have been implicated to be associated with AIN in several reports;6–9 however, the appearance of hypersensitivity reactions such as fever, arthralgia, and eosinophilia after the initiation of treatment with CPH led us to consider that CPH-mediated hypersensitivity seemed to be the cause of the AIN in the present patient. Skin lesions and interstitial lung disease due to hypersensitivity reactions to CPH have been reported consistently.10–13 In addition, there has been experimental observation of CPH-mediated nephrotoxicity.14

The primary mode of treatment for AIN is withdrawal or discontinuation of the offending agents.15 Although there is no clear advantage of corticosteroid therapy following the discontinuation of the offending agents, there are several anecdotal reports suggesting that the administration of cor-ticosteroids may shorten the course of the renal failure.3,16–18 The most common regimen consists of 1 mg/kg per day or 60 mg/day of PSL in patients with no infection.3,15–18

As described above, a total of fi ve agents were used for the treatment of obsessive-compulsive neurosis in the present patient. To avoid deterioration of the psychogenic disorder, medications other than TPN, VPA, and CBZ were initially discontinued.

However, the discontinuation of the drugs alone seemed insuffi cient to resolve the patient’s problems. Therefore, a relatively low dose of PSL, 30 mg/day (0.5 mg/kg per day), was administered. Because the patient’s renal function then recovered promptly without any psychogenic exacerbation, we considered the administration of PSL to be safe, while also having a benefi cial effect in this patient.

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