European Journal of Internal Medicine 17 (2006) 343 – 348

www.elsevier.com/locate/ejim

Original article
Penicillamine and nephrotic syndrome
George S. Habib a,⁎, Walid Saliba d , Munir Nashashibi b , Zaher Armali c
a
Department of Medicine, Carmel Medical Center, Faculty of Medicine, Technion, Israel Institute of Technology, 7 Michal Street 34362 Haifa, Israel
b
Department of Pathology, Carmel Medical Center, Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
c
Department of Nephrology and Dialysis, Nazareth Hospital, Nazareth, Israel
d
Department of Medicine C, Emek Medical Center, Afula, Israel
Received 27 September 2005; received in revised form 12 January 2006; accepted 3 March 2006

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.
© 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Keywords: Penicillamine; Nephrotic syndrome; Adverse effects

1. Introduction adverse effects and toxicities including polymyositis [6],

asthma [7], lupus-like disease [8], loss of taste [9],
D-Penicillamine is a beta 1 beta dimethyl cysteine. It has pemphigus [10], thrombocytopenia [11], leukopenia [11],
been used for the treatment of a variety of diseases including myasthenia gravis [12], optic neuritis [13], proteinuria, and
Wilson's disease [1], rheumatoid arthritis (RA) [2], sclero- nephrotic syndrome (NS). It was used for the first time by
derma [3], cysteinuria [4], and heavy metal poisoning [5]. Walshe in 1956 for the treatment of Wilson's disease [14],
Penicillamine (PA) is associated with a wide spectrum of and the first case of PA-induced NS was reported by Fellers
and Shahidi in 1959 [15]. Since then, many case reports and
⁎ Corresponding author. Tel.: +972 4 8250 757; fax: +972 4 6000 803. small series of patients with NS associated with the use of PA
E-mail address: [email protected] (G.S. Habib). treatment have been reported. Initially, it was felt that this
0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2006.03.001
344 G.S. Habib et al. / European Journal of Internal Medicine 17 (2006) 343–348

insult was associated with L-isomer only, but later it was Table 2
found that all isomers could be equally incriminated. Demographics of patients with PA-induced NS
Prior to NS, the first manifestation of PA-induced Parameter Number
nephropathy is usually proteinuria, which may progress to Female/male ratio 40:23
NS in some patients. The time span from the development of Age at diagnosis of NSa (years) 44 ± 17 (4–74)
proteinuria to NS can range from a few weeks to several PA dose at diagnosis of NSa (g) 1.09 ± 0.413 (0.125–2)
PA total dose at diagnosis of NSa (g) 296.3 ± 387.7 (7–2193)
years. The prevalence of proteinuria among patients treated
Duration of PA treatment prior to 11.9 ± 18.8 (3 weeks–11 years)
with PA ranges from 4% to 33% [16,17], and 70% or more of diagnosis of NSa (months)
those with persistent proteinuria may develop NS if PA Duration of PA treatment prior to 7.6 ± 3.9
treatment is continued [16,18]. In most cases, the changes diagnosis of proteinuriab,c (months)
seen at kidney biopsy are similar to idiopathic membranous Patients pretreated with gold 9
Patients with renal failure 20/61 (33%)
glomerulonephritis. Different types of pathology have been
Patients with elevated blood pressure 8/16
reported in a minority of patients. a
Mean ± S.D. and range.
Here we review all of the reported cases of PA-induced b
Mean ± S.D.
NS in the English literature, in addition to our case. c
36/41 patients evaluated for proteinuria.

2. Materials and methods

or 5 months after discontinuing PA treatment [28,30]. In
In a Medline search for the years 1963 through 2004, we 8 patients, NS developed while the patient was on low-dose
reviewed all of the cases of PA-induced NS reported in the corticosteroid (CS) treatment [23,24,30,32,33,41,43]. Five
English literature. The key words used in the search were patients had other side effects attributed to PA treatment:
“nephrotic” and “penicillamine” or “proteinuria” and three had rash [21,22,44], one pemphigus [27], and one
“penicillamine”. Other reports and those reported earlier patient had stomatitis and a decrease in taste sensation [33].
than 1963 were located using article references. Cases were In most of the patients who developed renal failure, it was
included in our study only if they had enough clinical and mild to moderate, except in one patient who had acute renal
laboratory data and if, in the author(s)' opinion, PA was failure and died within a few days [20].
considered the cause or main reason for NS. Epidemiologic, Laboratory features of the patients are shown in Table 3.
clinical, and laboratory parameters, including type of The mean peak 24-h urine protein was 10.79 g with a
disease, dose of treatment, duration of treatment, type of maximal level of 50 g, and most of the patients had active
renal involvement on biopsy, renal function, amount of sediment in the urine. Some 5/8 patients had positive
proteinuria, treatment, and course of proteinuria, were
documented. Table 3
Laboratory features of the patients with PA-induced NS
3. Results
Parameter (no. of patients evaluated) Number (%)
Peak level of 24-h proteinuria 10.79 ± 9.436 g, 2.2–50
A total of 74 cases were identified. Ten patients did not
(mean ± S.D., range)
have enough data [16,19]. In one patient, the NS was, in the Albumin level (mean ± S.D.) 2.2 ± 0.747 g
authors' opinion, due more to renal amyloidosis than to PA Cholesterol level (mean ± S.D.) 413 ± 93 mg/dl
treatment [28]. Thus, 63 cases, including our own, were Urine analysis (44)
reviewed [15,18,20–44]. Table 1 summarizes the different + WBC and RBC 14 (32)
+ RBC (alone) 8 (18)
types of diseases for which PA was prescribed. Most of the
+ WBC (alone) 8 (18)
patients (75%) had RA and 10% had Wilson's disease. Table + Casts
2 summarizes demographic and clinical variables of the Hyaline + granular 2 (5)
patients. In 27 patients (43%), NS developed within 7 months Hyaline 2 (5)
after starting PA treatment. In 3 patients, NS developed 1, 3, Granular 5 (11)
Granular + RBC 1 (2)
Cylindrical 1 (2)
Table 1 Patients with + ANA (8) 5
Types of diseases in patients with PA-induced NS Patients with + ANCA (2) 1
C3 level (17) 13—normal
Disease Number (%)
3—high
Rheumatoid arthritis 47 (75) 2—low
Wilson's disease 6 (9) C4 level (13) 13—normal
Scleroderma 3 (5) Patients with + C3 breakdown products (5) 1—traces
Chronic active hepatitis 3 (5) Patients with + platelet aggregation test (10) 3
Cysteinuria 2 (3) Patients with + C1q precipitation test (9) 0
Primary biliary cirrhosis 1 (1.5)
ANA = antinuclear antibodies, ANCA = antineutrophil cytoplasmic antibo-
RA/scleroderma overlap 1 (1.5)
dies, C3 = complement 3, C4 = complement 4, C1q = complement 1q.
 G.S. Habib et al. / European Journal of Internal Medicine 17 (2006) 343–348 345

antinuclear antibodies (ANA) at the time of diagnosis of NS, represent the EDD seen at EM, and there is a close
including one patient with PA-induced lupus [25]. Only a correlation between these two findings. In some patients,
few patients were evaluated for immune complexes in the for whom kidney biopsy was done 6 or more months after
serum, and most of them had negative results [18,37]. HLA stopping PA treatment, the IF was still positive while the EM
studies were done in four patients: one patient had A2+, findings were negative for EDD. Among patients with
A31+, B40+, DR4+ [37], another had B8+, DR3− [38], a persistent proteinuria, the IF and the EDD findings would
third had A1+, A3+, B7+, B8+, DR15+, DR3+ [43], and the still be there, even if biopsy was taken 1 year or more after
fourth patient had B8− and DR3− [39]. stopping PA treatment.
Kidney biopsy was obtained from 52 patients. In three Two patients with RA had renal amyloidosis in addition
patients, it was done twice [18,23,37] and in two patients it to perimembranous glomerulonephritis [28] and one patient
was done three times [18,36]. One patient had no with RA had renal amyloidosis in addition to mesangial
documentation of biopsy results. As expected, the majority glomerulopathy [42]. In all three, the amyloidosis was
of patients (55%) had membranous glomerulonephritis and considered not to be the main cause of NS [28].
27% had minimal change disease. The rest of the patients PA was stopped immediately after the diagnosis of NS
had different pathologies (Table 4). The mean time that in most of the patients or up to 7 months in a few of them
elapsed between the last PA treatment and the kidney biopsy (in three patients PA treatment was stopped before the
was 1.9 ± 2.3 months (range 0–8 months). development of NS). However, 12 patients were also
Typically, light microscopy detects either no abnormality treated with CS after the diagnosis of NS was made
or minimal hypercellularity of mesangial or different types of [21,22,25,27,31,32,34,36,37,40,44]. The dose of CS ranged
cells. On the other hand, the findings at electron microscopy from 40 to 90 mg/day of prednisone. In 8 of these 12
(EM) are much more prominent. In classic membranous patients, there was a significant decrease (< 1 g protein in the
glomerulonephritis, numerous electron-dense deposits 24-h urine) or disappearance of the proteinuria within 1–
(EDD) on the epithelial side (outer layer) of the basement 5 weeks after starting CS treatment [21,22,31–33, 36,37,44].
membrane are seen. These deposits are slowly covered and In two patients, there was some decrease in proteinuria
later incorporated into the glomerular basement membrane [27,34]. In one patient, there was no documentation of the
(GBM) by new basement membrane-like material, appar- response [40]. In the PA-induced lupus patient, the lupus
ently formed by the covering epithelial cells. These epithelial symptoms resolved within 3 months after stopping PA
cells lay down new basement membrane-like material over treatment; however, the NS was grossly unchanged.
and between the deposits. With time, a new lamina rara- Prednisone was started at a dose of 40 mg/day and then
externa is formed above the deposits and the accumulated reduced to a maintenance dose of 15 mg/day with some
deposits, which appear to widen the basement membrane, decrease in the level of proteinuria after 9 months.
lose their density, and move in a subendothelial direction. One patient had a recurrence of NS and edema less than
These dynamics of change were formulated based on the 1 month after stopping the CS [34]. CS at a higher dose
changes seen on biopsies taken on different dates after (60 mg of prednisone) was reinstituted with a slow response
stopping PA treatment from different or the same patients. In over half a year. Two patients among those treated with CS
the cases of minimal change disease, the usual finding is died of sepsis and pulmonary aspergillosis [31,27].
complete fusion of the foot processes. Among those patients treated by cessation of PA
Immunofluorescence (IF) findings usually show a finely treatment, follow-up of 24-h urine protein levels was
brilliant, granular fluorescence situated in or around the available for only 35. In many of these patients, there was
capillary loops. The granular florescence was positive, no systematic sequential measurement of 24-h urine pro-
mainly for IgG and complement. Staining can also be teinuria and, in some of them, the follow-up was for a few
positive for IgM, IgA, and fibrin, but is usually less months only. The mean time of disappearance or significant
prominent than for IgG. These granules most probably reduction (< 1 g of 24-h urine protein) of proteinuria from the
time PA was stopped was 7.137 ± 5.912 months (range 0.5–
21 months). In seven patients, there was either a disappear-
Table 4 ance or a significant reduction in proteinuria within 1 month
Histopathologic findings of 51 patients with PA-induced NS
[24,30,33,35,40,41]. In one study [30], it was found that,
Type of nephropathy Number (%) after stopping PA treatment, proteinuria further increased
Membranous glomerulonephritis 28 (55) over 1–4 months in nearly half of the patients; however,
Minimal change disease 14 (27) following the maximal level, it fell to less than 2 g/24 h
Perimembranous glomerulonephritis with amyloid 2 (4)
during the following 2 months. In another report [18], 5/11
IgM nephropathy 2 (4)
Mesangioproliferative glomerulonephritis 1 (2) patients with NS due to PA treatment had a further increase
Mesangial nephropathy with amyloid 1 (2) in proteinuria 3–9 months after stopping PA treatment (some
Membranoproliferative glomerulonephritis 1 (2) of them had no follow-up of proteinuria after the peak level).
Focal interstitial nephritis 1 (2) Three patients in the non-CS treated group died: one
Focal glomerulonephritis 1 (2)
patient died a few days after stopping PA of acute renal
346 G.S. Habib et al. / European Journal of Internal Medicine 17 (2006) 343–348

failure [20], another patient died more than a month after related to NS, we recommend a monthly evaluation of 24-
stopping PA of pulmonary emboli [26], and a third died a few h urine protein in those who develop proteinuria; once
months after the diagnosis due to “non-renal” causes without significant progress is noted, PA treatment should be
further clarifications [42]. One patient developed acute renal stopped. We also recommend not restarting PA treatment
failure with anti-GBM antibodies 2 years after recovery from in any patient who has already developed NS due to PA
NS [43]. treatment that resolved later.
PA treatment was reinstituted in smaller doses in five The NS that develops after PA treatment is similar to
patients after the NS had resolved [15,21,33,36,37]. In three the classic NS that develops from more familiar causes
patients, NS redeveloped quickly (after 2 weeks to 2 months) seen in different types of nephropathy or diabetes with
[15,21,37]. In a fourth patient, restarting just one dose of PA peripheral edema, low albumin, and high cholesterol
resulted in an immediate doubling of urine protein [35]. The levels. It is interesting to note that, in 11 out of 17
fifth patient was still without proteinuria 8 months after patients for whom information was given about the way
reinstitution of PA treatment [33]. NS developed, it was described as either progressive or
quite sudden [15,23,27,33,35,37,40,41,43,44]. Nearly one-
4. Discussion third of our patients developed renal failure that improved
later with the improvement in the proteinuria. One patient
Most of our patients who had PA-induced NS were RA died of acute renal failure.
patients. This is not surprising since RA is the most Serological markers were documented in only a few
prevalent of the diseases that can be treated with PA. patients. Perinuclear antineutrophil cytoplasmic antibodies
Fortunately, nowadays, PA is rarely used in RA due to the (P-ANCA) were positive in one out of two patients (our
availability of newer, less toxic, and more efficacious types patient). In the last few years, there have been more and more
of treatment for this disease. Since most RA patients are reports of p-ANCA seroconversion associated with PA
female, the ratio of the gender is in favor of females. The treatment in scleroderma and non-scleroderma patients [47–
average dose of PA treatment prior to the development of 50]. Many of these patients developed rapidly progressive
NS was 1.09 g/day. PA-induced nephropathy is not dose- glomerulonephritis and some of them pulmo-renal syn-
dependent and may develop with daily doses of PA as low drome. This marker may help elucidate the pathogenesis of
as 125 mg. According to our study, NS developed on the renal adverse effects of PA treatment.
average 1 year after starting PA treatment; however, 43% of The overwhelming majority of patients had membranous
the patients developed NS within 7 months after starting PA glomerulonephritis, and nearly one-quarter of them had
treatment. Also, NS developed on the average 5 months minimal change disease. It is interesting to note that in one
from the time proteinuria was first noticed. Yet, this figure is report [30], which included both NS patients and patients with
not accurate since many patients were not evaluated for proteinuria due to PA treatment, the overwhelming majority of
proteinuria before developing NS and, for those who did patients with just proteinuria had minimal change disease.
have this type of evaluation, it was random and not Thus, this finding may be one that precedes progression to
systematic. Nevertheless, NS can develop as early as membranous glomerulonephritis in patients with NS.
3 weeks after starting PA treatment. The brilliant granules seen at IF and the EDD seen at EM
One of the important questions that this study raises is most probably represent immune complexes. This immuno-
what we, the physicians, should do when we find proteinuria logical/allergic mechanism of reaction is supported by
in a patient treated with PA. Unfortunately, the cases in our positive staining for immunoglobulin and complement at
study cannot fully answer this question. Known risk factors the kidney biopsy, co-development of other allergic
for the development of proteinuria include HLA-B8+, DR3+ reactions, development of different serologic markers, and
patients, prior gold-induced proteinuria, poor sulfoxidizers, redevelopment of proteinuria or NS within a short period of
higher age, and low titer of rheumatoid factor [45,46]. time after reinstitution of PA treatment. However, only a few
Proteinuria may develop even months after stopping PA patients had evidence of immune complexes in the serum,
treatment [30]. It can be transient in up to 66% of patients but the diagnostic tests used in these patients are less
[42]. The percentage of those with persistent proteinuria who sensitive than recent ones [51]. Since the kidney is nearly the
have progressed to NS is more than 70% in some series only organ involved, it could be that the immune complexes
[42,43]. Nine patients in our study were treated with gold are formed in the kidney itself, with circulating antibodies
prior to PA treatment, and one of them developed proteinuria becoming attached to local antigen in the kidney. Another
that resolved after stopping gold treatment. In addition, one less accepted theory is the “toxic” theory, supported by the
of our patients was treated concomitantly with both PA and fact that the toxic effect of gold and mercury in the kidneys
gold, and the NS resolved after discontinuing PA treatment yields the same findings on EM.
[42]. Looking at both groups – patients with NS versus those We cannot explain why some patients with NS due to PA
with just proteinuria in the largest case series in our patients treatment develop different types of nephropathy. There was
[30] – we could not find risk factors for developing NS. a patient who developed interstitial nephritis twice due to PA
Taking into account 6% mortality directly or indirectly treatment, so it could be that genetic, and possibly
 G.S. Habib et al. / European Journal of Internal Medicine 17 (2006) 343–348 347

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