D-penicillamine-induced glomerulonephritis with crescent formation: Remission following drug discontinuation.

We report a 71-year-old female who presented with rheumatoid arthritis complicated by proteinuria. She had been receiving D-penicillamine (D-Pc) for two years prior to presentation. A urinalysis showed proteinuria and hematuria which disappeared within 3 months after D-Pc was stopped. The renal histological findings showed focal proliferative glomerulonephritis with crescent formation. A total of 10 cases of D-Pc-induced glomerulonephritis with crescent formation without alveolar hemorrhage have previously been reported in the literature. To the best of our knowledge, this is the first case report in which the patient did not require any treatment.

Introduction

D-penicillamine (D-Pc) is a thiol drug, which has been used in the treatment of Wilson’s disease, rheumatoid arthritis (RA), and systemic sclerosis (SSc). Renal complications as a result of D-Pc treatment have been well recognized; the most common is the development of proteinuria due to membranous nephropathy, but there have also been rare cases of glomerulonephritis with crescent formation. A total of 10 cases of D-Pc-induced glomerulonephritis with crescent formation without alveolar hemorrhage have been reported since 1983. We herein describe a rare case of D-pc-induced glomerulonephritis and review the previous literature.

Case Report

A 71-year-old Japanese female who had 12-year history of RA was admitted to our hospital in January 2011 because of progressive proteinuria and microscopic hematuria. A diagnosis of RA had been made in 2004, and since then, she had been receiving bucillamine, salazosulfapyridine, or minocycline as disease-modifying antirheumatic drugs (DMARDs). She also received low-dose steroid therapy (prednisolone, 5 mg/day). In November 2008, D-Pc was started at 100 mg/day to control the RA activity, and the dose was progressively increased to 200 mg/day. Her urinalysis gave a 2+ result for protein and microscopic hematuria in November 2010, and a 3+ test for protein and microscopic hematuria in December 2010. D-pc was stopped in December 2010. Her previous history included bronchiectasis and bronchiolitis. She was a never-smoker.

On admission to our hospital, the D-pc had been discontinued for 40 days. A physical examination revealed a 45 kg female with a normal blood pressure (125/67 mmHg). She had edema in her legs, and arthritis in her wrists and metacarpophalangeal joints. There was no fever, rash, hemoptysis or diarrhea. Investigations showed a hemoglobin of 10.4 g/dl with normal white blood cell and platelet counts. Her serum creatinine level was elevated from 0.74 mg/dl in 2010 to 1.16 mg/dl. Her blood urea nitrogen concentration was 19.4 mg/dl and the serum albumin concentration was 2.8 g/dl. The level of anti-cyclic citrullinated peptide antibody was >100 U/ml, rheumatoid factor was 23 IU/ml, C-reactive protein was 1.21 mg/dl, and serum amyloid A was 60.7 μg/ml. Her C3 and C4 levels were normal. The anti-nuclear antibody titer was 1:40. She was negative for serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), proteinase-3 anti-neutrophil cytoplasmic antibody (PR3-ANCA), and anti-glomerular basement membrane antibody were negative, which were confirmed by an immunoenzymometric assay (EIA). Urinalysis showed proteinuria of 1,863 mg/day. The patient’s red blood cell count was >100 cells per high power field, her hyaline cast count was two per low power field, and the granular cast count was two per low power field. Radiographs showed Steinbrocker stage III joint deformity, and her lungs had bilateral reticular shadows. Esophagogastroduodenoscopy showed an ulcer scar in the stomach, and the histopathological findings showed amyloid A deposits in the duodenal mucosa.

In February 2011, a percutaneous renal biopsy was performed. The kidneys showed sclerotic changes in half of the glomeruli [Figure 1a]. In the other half of the glomeruli, focal and segmental endocapillary proliferation was observed with segmental necrotizing lesions of the capillary wall. One glomerulus had a fibrous crescentic change [Figure 1b]. There was mild interstitial fibrosis with a mononuclear cell infiltrate. The region of the interlobular artery had amyloid deposition. An immunofluorescence (IF) study revealed deposits of IgG and C3 in the arteries.

Figure 1

(a) There were sclerotic changes of the glomeruli (PAS × 200); (b) There was a fibrous crescentic change (right glomerulus), segmental intracapillary proliferative glomeruli with a necrotizing lesion of the capillary wall (left glomerulus) and mild interstitial fibrosis with mononuclear cell infiltration (PAS ×200)

A few weeks later, the patients’ proteinuria disappeared, hematuria decreased, and her serum creatinine level became normal. We did not add any immunosuppressants, and therefore we concluded that this nephropathy had not been induced by amyloidosis, but by D-pc.

Discussion

D-pc is a thiol drug, which is used for the treatment of Wilson’s disease, SSc, and RA, and its complications include renal damage in 5 to 30% of patients.[1] Proteinuria is usually associated with membranous nephropathy, and it is rarely associated with minimal change disease or mesangioproliferative glomerulonephritis.[2-4] The nephropathy with extrarenal symptoms induced by D-pc has been reported to include Goodpasture-like syndrome, systemic lupus erythematosus syndrome, and vasculitis.[35-7]

Ten cases of D-pc-induced nephropathy with crescent formation without alveolar hemorrhage have so far been reported [Table 1],[5-13] including four patients with SSc and six with RA. These nephropathies had the following features; nine of the nine evaluated cases had necrotizing lesions, five of the five evaluated cases had proliferative glomerulonephritis, five of the six evaluated cases had granular (nonlinear) deposits of IgG and/or C3 along the capillary walls, three of five cases had MPO-ANCA or perinuclear antineutrophilic cytoplasmic antibody (P-ANCA), and antiglomerular basement membrane antibodies were not detected in any of six cases that were evaluated. In most of these cases, immunosuppressant drugs, and/or glucocorticoids, and/or hemodialysis were required for the treatment of renal failure. In summary, the pathological features of D-pc-induced nephropathy with crescent formation were necrotizing lesions, proliferative glomerulonephritis, and granular deposits of IgG and C3. The MPO-ANCA or P-ANCA (EIA or indirect IF) positive rate was about 60%. Moreover, the prognosis of the patients was poor when they did not receive additional treatments.

Table 1

A summary of the previous reports on D-pc-induced nephropathy with crescent formation without alveolar hemorrhage

We described a patient who developed D-pc-induced glomerulonephritis with crescent formation. This case had an atypical clinical course, compared to past reports. It is the first case report in which the patient did not require any treatment. In our case, there were necrotizing lesions of glomeruli, proliferative glomerulonephritis, and crescent formation. However, no granular deposits along the capillary wall or MPO-ANCA were detected. We could not measure the ANCA by an indirect IF assay. This patient had a history of bronchiectasis; therefore, it might have been possible to detect the anti-neutrophil cytoplasmic antibody against bactericidal/permeability-increasing protein (BPI-ANCA).[14]