Original article
Penicillamine and nephrotic syndrome

https://doi.org/10.1016/j.ejim.2006.03.001Get rights and content

Abstract

Background

Penicillamine (PA) treatment may be associated with a wide spectrum of adverse effects. There are many case reports and small series of PA-induced nephrotic syndrome (NS). In addition to our patient, in this study, we review all the cases of NS due to PA treatment in the English literature.

Methods

A retrospective Medline search was done for the years 1963–2004 using the terms “penicillamine” and “proteinuria” or “penicillamine” and “nephrotic”. Cases were also located through article references. Cases were included in our review only if they had enough clinical and laboratory data and if the NS was considered by the authors to be mainly or solely due to PA treatment. Diagnosis of the patient, dose and duration of PA treatment, maximal amount of proteinuria, kidney function, urine analysis, serological markers, clinical data, kidney biopsy results, treatment, and course of proteinuria were documented.

Results

Sixty-three patients met our criteria. The female/male ratio was 40:23. Seventy-five percent of the patients had rheumatoid arthritis (RA). Mean age at diagnosis of NS was 44 (± S.D. 14) years. Mean dose of PA at diagnosis was 1.09 (± S.D. 0.413) g. Mean duration of PA treatment prior to proteinuria was 7.6 (± S.D. 3.90) months and mean duration of PA treatment until diagnosis of NS was 11.9 (± S.D. 18.8) months. Peak level of proteinuria was 10.79 (± S.D. 9.436) g. Some 33% of the patients developed mild to moderate renal failure at the time of diagnosis of NS, and one patient developed acute renal failure. Fifty-five percent of the patients had membranous glomerulonephritis and 27% had minimal change disease. Twelve patients were treated with corticosteroids (CS) at a dose ranging from 40 to 90 mg/day. In the overwhelming majority of patients, the proteinuria decreased significantly or disappeared within 7 months after stopping PA treatment. Patients treated with CS had a faster response. Five patients died, two of them from the CS-treated group, due to sepsis.

Conclusion

The mean duration of PA treatment prior to the development of NS is nearly 1 year (5 months after the development of proteinuria). The most common histopathological finding is membranous glomerulonephritis. Most patients will have a significant reduction in, or disappearance of, proteinuria within 7 months after stopping PA treatment. The decrease in proteinuria is faster with CS treatment.

Introduction

d-Penicillamine is a beta 1 beta dimethyl cysteine. It has been used for the treatment of a variety of diseases including Wilson's disease [1], rheumatoid arthritis (RA) [2], scleroderma [3], cysteinuria [4], and heavy metal poisoning [5]. Penicillamine (PA) is associated with a wide spectrum of adverse effects and toxicities including polymyositis [6], asthma [7], lupus-like disease [8], loss of taste [9], pemphigus [10], thrombocytopenia [11], leukopenia [11], myasthenia gravis [12], optic neuritis [13], proteinuria, and nephrotic syndrome (NS). It was used for the first time by Walshe in 1956 for the treatment of Wilson's disease [14], and the first case of PA-induced NS was reported by Fellers and Shahidi in 1959 [15]. Since then, many case reports and small series of patients with NS associated with the use of PA treatment have been reported. Initially, it was felt that this insult was associated with L-isomer only, but later it was found that all isomers could be equally incriminated.

Prior to NS, the first manifestation of PA-induced nephropathy is usually proteinuria, which may progress to NS in some patients. The time span from the development of proteinuria to NS can range from a few weeks to several years. The prevalence of proteinuria among patients treated with PA ranges from 4% to 33% [16], [17], and 70% or more of those with persistent proteinuria may develop NS if PA treatment is continued [16], [18]. In most cases, the changes seen at kidney biopsy are similar to idiopathic membranous glomerulonephritis. Different types of pathology have been reported in a minority of patients.

Here we review all of the reported cases of PA-induced NS in the English literature, in addition to our case.

Section snippets

Materials and methods

In a Medline search for the years 1963 through 2004, we reviewed all of the cases of PA-induced NS reported in the English literature. The key words used in the search were “nephrotic” and “penicillamine” or “proteinuria” and “penicillamine”. Other reports and those reported earlier than 1963 were located using article references. Cases were included in our study only if they had enough clinical and laboratory data and if, in the author(s)' opinion, PA was considered the cause or main reason

Results

A total of 74 cases were identified. Ten patients did not have enough data [16], [19]. In one patient, the NS was, in the authors' opinion, due more to renal amyloidosis than to PA treatment [28]. Thus, 63 cases, including our own, were reviewed [15], [18], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]. Table 1 summarizes the different types of diseases for which PA was prescribed. Most of the

Discussion

Most of our patients who had PA-induced NS were RA patients. This is not surprising since RA is the most prevalent of the diseases that can be treated with PA. Fortunately, nowadays, PA is rarely used in RA due to the availability of newer, less toxic, and more efficacious types of treatment for this disease. Since most RA patients are female, the ratio of the gender is in favor of females. The average dose of PA treatment prior to the development of NS was 1.09 g/day. PA-induced nephropathy is

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