Minimal change nephrotic syndrome associated with rifampicin treatment

Keisuke Kohno, Yoshihiko Mizuta, Tomoyo Yoshida, Hisashi Watanabe, Hidemi Nishida, Kei Fukami, Syuuji Iida, Reiko Haramaki, Yoshifumi Wada, Osamu Tamai, Kiyoshi Tamaki, Seiya Kato1, Minoru Morimatsu1 and Seiya Okuda

Department of Internal Medicine III and 1 Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan

Keywords: minimal change nephrotic syndrome; rifampicin



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Rifampicin is a commonly used anti-tuberculosis agent which has been reported to have some adverse effects, including nephrotoxicity [19]. The most frequent form of nephrotoxicity is a syndrome consisting of acute renal failure, with tubular necrosis as pathological finding, with or without haemolysis and thrombocytopenia, generally occurring during intermittent or interrupted treatment. Other forms of nephrotoxicity are interstitial nephritis with or without mild glomerular lesions, rapidly progressive glomerulonephritis and light chain proteinuria [3]. We herein report a case of minimal change nephrotic syndrome (MCNS) after rifampicin treatment which was not associated with acute interstitial nephritis or any other glomerular lesion, followed by complete remission after discontinuation of rifampicin.



   Case
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 Introduction
 Case
 Discussion
 References
 
A 43-year-old female was admitted to the hospital for further evaluation of a right pleural abnormality detected on a chest X-ray film. She had a history of allergy to penicillin. On admission, her body temperature was 36.5°C, and the blood pressure was 116/70 mmHg. Physical examination was unremarkable. Urinalysis did not reveal any abnormalities. Laboratory investigation showed: haemoglobin 12.7 g/dl, haematocrit 39.6%, blood urea nitrogen (BUN) 13.1 mg/dl, serum creatinine 0.9 mg/dl, Na 141 mEq/l, K 3.9 mEq/l, total protein 8.4 g/dl, albumin 3.9 g/dl, total cholesterol 170 mg/dl. A chest X-ray showed pleural thickening of the right lung. Bronchoalveolar lavage showed no acid-fast bacilli, but PPD (purified protein derivative of tuberculin) skin test showed a positive reaction. Pleural tuberculosis was suspected and antituberculous treatment was started with rifampicin 450 mg/day, isoniazid 300 mg/day and ethambutol hydrochloride 750 mg/day.

After 4 weeks of daily treatment, the patient suddenly developed systemic oedema. Urinalysis showed proteinuria (3+). The urinary sediment did not show either significant red blood cells or granular casts. A 24-h urinary protein value was 7.9 g/day. The selectivity index was 0.01. Other laboratory findings at that time were as follows: haemoglobin 11.2 g/dl, haematocrit 34.2%, white blood cells 5200/l, eosinophils 3%, BUN 14.5 mg/dl, serum creatinine 1.0 mg/dl, creatinine clearance 58.9 ml/min, Na 139 mEq/l, K 3.8 mEq/l, total protein 4.5 g/dl, albumin 1.6 g/dl, total cholesterol 263 mg/dl, and IgE 94 U/ml.

Antinuclear antibody and antiglomerular basement membrane were negative. Serum complements were normal. Patient's lymphocyte was collected for drug lymphocyte stimulating test (DLST) and cultured with each drug in a variety of dosages. The culture was incubated at 37°C for 72 h, and the degree of lymphocytes blast transformation was determined by [3H]thymidine uptake. DLST was negative for rifampicin, isoniazid and ethambutol hydrochloride.

Renal biopsy revealed minor glomerular abnormalities and no interstitial changes by light microscopy (Figure 1Go). No depositions of immunoglobulins or complement components were observed in glomeruli. Electron microscopy showed a fusion of the foot process of glomerular epithelial cells but not the presence of immune complexes in glomeruli or thickening of the glomerular basement membrane (Figure 2Go).



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Fig. 1. Light microscopic appearance (PAS staining), showing normal glomeruli (original magnification, x400).

 


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Fig. 2. Electron microscopic findings, showing fusion of foot processes (original magnification, x7500).

 
Rifampicin-induced nephrotic syndrome was suspected. Therefore rifampicin alone was suspended and other drugs were continued. Proteinuria started to decrease immediately after the cessation of rifampicin and became negative 4 weeks later. Serum albumin and cholesterol levels became normal 6 weeks after the discontinuation of rifampicin. Pleural tuberculosis was well controlled by isoniazid and ethambutol hydrochloride and recurrence of proteinuria was not observed.



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Fig. 3. Clinical course. TP, total protein; UP, urinary protein.

 


   Discussion
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 Introduction
 Case
 Discussion
 References
 
In terms of drug side-effects, rifampicin is different from other drugs, such as penicillin, ß-lactam or NSAIDs, which usually induce acute interstitial nephritis. De Vriese et al. reported that acute renal failure was the most frequently observed clinical presentation of rifampicin associated nephrotoxicity. In most of cases, the pathological finding was tubular necrosis, while acute interstitial nephritis has been observed in some cases. Furthermore, several cases of rapidly progressive glomerulonephritis (RPGN) and light chain proteinuria have been described. They suggested that acute renal failure during rifampicin therapy most often occurs with interrupted or intermittent treatment and presents as a fulminant systemic reaction sometimes associated with haemolytic anaemia or thrombocytopenia [3].

After 4 weeks of continuous use of rifampicin, our patient suddenly developed nephrotic syndrome, but not acute renal failure. Immunoglobulins and complements were negative in glomeruli. Electron microscopy did not demonstrate either the presence of immune complexes in the glomeruli or thickening of the glomerular basement membrane, leading to the diagnosis of MCNS.

The first case of rifampicin-induced nephrotic syndrome was reported by Neugarten et al. [4]. The glomeruli presented no significant changes whereas interstitial lesions were prominent in that case. Immunoglobulin deposition and complements were not observed in the kidney, while electron microscopy revealed dense deposits in the mesangial matrix and in subendothelial and paramesangial sites. Tada et al. also reported rifampicin-induced MCNS, showing minor glomerular abnormalities and slight interstitial changes [5]. In their patient, electron microscopy showed glomerular changes such as local widening of the subendothelial space which was filled with fine granular or fibrillar materials, irregularity of the endothelial investment, and swelling or shrinkage of the endothelial cells. They speculated that endothelial injury due to rifampicin seemed to play a role in the development of nephrotic syndrome. RPGN associated with nephrotic syndrome was reported in patients treated with rifampicin. Ogata et al. detected antirifampicin antibody in patients with crescentic glomerulonephritis and suggested a relation between the antibody and the renal histology [6]. However, the occurrence of antirifampicin antibody in this case was atypical. De Vriese et al. reported that detection of antirifampicin antibodies was confined to patients who developed acute renal failure, with or without haemolytic anaemia and thrombocytopenia [3].

In addition to the glomerular lesions, rifampicin-induced nephrotic syndrome was reported to be associated with interstitial nephritis [49]. Neugarten et al. suggested that independent cell-mediated and humoral mechanisms could be responsible for the combination of acute interstitial and glomerular lesions. The link between acute interstitial nephritis and MCNS may be supported by rifampicin-induced immunological abnormalities. However, our patient did not show any findings of acute interstitial nephritis such as inflammatory cell infiltration or interstitial edema or fibrosis.

In conclusion, we report a case of rifampicin-induced MCNS. Although this side effect is rare, it may be indicated to check for proteinuria during the follow-up of a patient started on rifampicin.



   Notes
 
Correspondence and offprint requests to: Keisuke Kohno, MD, PhD, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830, Japan. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

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Received for publication: 31. 5.99
Revision received 2. 3.00.



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