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Kim, Yim, Sung, Lee, and Suh: Bucillamine-induced Nephropathy
Original Article

J Korean Rheum Assoc 2009;16(3):197-203.

Published online: 20 September 2009

DOI: https://doi.org/10.4078/jkra.2009.16.3.197

Bucillamine-induced Nephropathy

Hyoun-Ah Kim1, Hyun-Ee Yim2, Jun-Mo Sung1, Jin-Woo Lee1, Chang-Hee Suh1

1Department of Allergy and Rheumatology, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea

2Department of Pathology, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea

Received 15 June 2009       Revised 15 July 2009       Accepted 27 July 2009

Copyright © 2009 The Korean Rheumatism Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Bucillamine is a disease-modifying antirheumatic drug that's widely used in Korea and Japan, and it is reported to be a cause of proteinuria. However, the clinical course of the nephropathy associated with the use of bucillamine in rheumatoid arthritis patients has not been described in detail in Korea.

Methods

We examined clinical records of 835 patients who were treated with bucillamine for rheumatoid arthritis at least 2 months at Ajou University Hospital from 2003 to 2008, and we found 23 patients (2.75%) with proteinuria. Each patient was followed up until the proteinuria had resolved.

Results

At the time the proteinuria developed, the mean age of patients was 53.8±11.0 years. Only one patient had marked hypoalbuminemia (＜3.0 g/dL). The mean value of the random urine protein-creatinine ratio was 3.44±2.99. The proteinuria appeared 4∼18 months after the initiation of the treatment with bucillamine. Among the patients, renal biopsy was carried out in 18 patients, and pathological findings were 17 cases of membranous glomerulopathy and 1 case of focal segmental glomerulosclerosis. On the follow-up of the 18 patients, the proteinuria in all the patients had resolved completely without deterioration of renal function. But the time to resolution of the proteinuria was positively correlated with the length of bucillamine treatment after the onset of proteinuria (p＜0.001, r=0.744).

Conclusion

Prevalence of proteinuria in patients receiving bucillamine was 2.75%, and bucillamine-induced nephropathy showed a good prognosis in Korea. The most important thing for resolving the bucillamine-induced proteinuria is to discontinue the bucillamine.

Keywords: Rheumatoid arthritis, Bucillamine, Nephropathy

References

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Fig. 1.
Correlation between interval to remission of proteinuria and bucillamine exposure time after onset of proteinuria.
jkra-16-197f1.tif
Table 1.
Clinical characteristics of patients
  Number (%) or Mean±SD
Total patients 23 (100)
Age (years) 53.83±10.97
Sex (F/M) 21 (91)/2 (9)
Disease duration (months) 18.35±25.01
Rheumatoid factor positivity 8 (34.8)
ESR (mm/hr) 15.73±19.06
CRP (mg/dL) 0.29±0.73
Total protein (g/dL) 6.48±0.52
Albumin (g/dL) 3.80±0.4
Serum creatinine (mg/dL) 0.77±0.09
Total cholesterol (mg/dL) 206.3±50.6
Proteinuria (g/day) 3.44±2.99
Combination therapy with methotrexate 6 (26.1)

ESR: erythrocyte sedimentation rate, CRP: C-reactive protein

Table 2.
Bucillamine treatment and proteinuria
  Mean±SD
Length of bucillamine treatment (months) 7.39±3.72
Dose of bucillamine (mg/day) 200
Length of bucillaminetreatment after onset of proteinuria (months) 8.25±3.16 (3.12±1.83∗)
Time to resolution of proteinuria (months) 6.5±4.84 (5.13±3.4∗)

∗ This data was assessed with excluding 3 patients with tapering of bucillamine

Table 3.
Pathologic findings in renal biopsy specimens of patients with bucillamine-induced nephropathy
Case No. LM IF EM Histologic diagnosis
GBM thickening Spikes IgG C3 Electron dense deposit Stage
1 + – 3+ – Segmental II Membranous glomerulopathy
2 – – 1+ – Segmental I Membranous glomerulopathy
3 Equivocal – 3+ – Segmental I Membranous glomerulopathy
4 Equivocal + 2+ – Segmental I Membranous glomerulopathy
5 Equivocal – 2+ 2+ Segmental II Membranous glomerulopathy
6 Equivocal – 1+ – Segmental I Membranous glomerulopathy
7 Equivocal – 1+ 2+ Segmental II Membranous glomerulopathy
8 Equivocal – 2+ 2+ Segmental II Membranous glomerulopathy
9     1+ 1+     Focal segmental glomerulosclerosis
10 – – 2+ 1+ Segmental I Membranous glomerulopathy
11 Equivocal – 3+ 1+ Segmental II Membranous glomerulopathy
12 Equivocal – 3+ 2+ Segmental I Membranous glomerulopathy
13 Equivocal – 2+ 1+ Diffuse II Membranous glomerulopathy
14 Equivocal – 3+ 1+ Segmental I Membranous glomerulopathy
15 + + 2+ 1+ Segmental II Membranous glomerulopathy
16 – – 2+ – Segmental II Membranous glomerulopathy
17 – – 2+ 1+ Segmental I Membranous glomerulopathy
18 – – 2+ 1+ Segmental I Membranous glomerulopathy

LM: light microscopy, IF: immunofluorescence, EM: electron microscopy, GBM: glomerular basement membrane

Table 4.
Factors influencing interval to remission
Factors Interval to remission (months) p-value
Pathologic stage Stage I (n=8) Stage II (n=7) 0.613
4.75±2.05 7.71±7.01  
Therapeutic medicines (+) (−)  
Cyclosporine A (C) 6.1±3.69 (n=10) 7.0±6.23 (n=8) 0.897
Mizoribine (M) 3.33±2.08 (n=3) 7.13±5.02 (n=15) 0.164
C or M 9.2±7.04 (n=13) 5.46±3.53 (n=5) 0.336
Steroid dose Low dose (n=10) Moderate to high dose (n=8) 0.360
7.7±5.9 5.0±2.72  

These data were assessed using a Mann-Whitney U test. Low dose of steroid was defined as taking ≤10 mg/d of prednisolone equivalent. Moderate to high dose of steroid was defined as taking over 10 mg of prednisolone equivalent

Table 5.
Relationship between clinical parameters and the interval to remission
Factors Correlation coefficient, r (p-value)
Maximum proteinuria 0.151 (0.549)
Total amount of bucillamine 0.126 (0.617)
Bucillamine exposure time 0.154 (0.542)
Bucillamineexposure time after onset of proteinuria 0.744 (＜0.001)
Disease duration −0.006 (0.982)

These data were assessed using a Pearson correlation

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