A case of bucillamine-induced membranous nephropathy presenting with acute kidney injury and requiring hemodialysis

Abstract

We present kidney biopsy findings in a 65-year-old male patient with rheumatoid arthritis who developed severe proteinuria 10 months after bucillamine administration and required hemodialysis 14 days later. Light microscopy revealed no spike formation but showed linear (partially granular) immunoglobulin (Ig)G-positive images (predominantly IgG1) along the capillary wall. Electron microscopy revealed widespread, large subepithelial electron-dense deposits (EDD). Foot process effacement was observed throughout the entire area, including areas with no apparent EDD. Neural epidermal growth factor-like 1 protein-positive images consistent with IgG were observed over a wide area. After administration of 60 mg of glucocorticoid, proteinuria subsided, and dialysis could be discontinued. Fifteen months after discharge, urinary protein was below 0.1 g/day. Even though bucillamine-induced membranous neuropathy may show few subepithelial EDDs, it has been reported cause severe proteinuria; however, no cases of acute kidney injury have been reported. The following mechanism is speculated as the cause of AKI. Although the arteriosclerotic lesions were mild in the kidney biopsy specimen, the severe hypoalbuminemia caused by severe proteinuria, combined with the drop in blood pressure due to losartan administration, led to an ischemic state, which is thought to have led to the onset of AKI.

Introduction

Membranous nephropathy (MN) is characterized by granular deposition of immunoglobulin (Ig)G in the subepithelial region of the glomerular basement membrane (GBM). One approach to distinguish primary from secondary MN is to evaluate IgG subclasses because IgG4-predominant deposition has been reported as a hallmark of primary MN [1]. Furthermore, Beck et al. [2] reported that the M-type phospholipase A2 receptor (PLA2R) is consistent with IgG4-dominant deposition in primary MN, and they suggested it as a marker for the disease. Moroni et al. summarized previously reported cases of secondary MN and found that its causes included viruses, autoimmune diseases, cancer, and hematopoietic stem cell transplantation. They reported that besides IgG4, the predominant IgG subclasses were IgG1, IgG2, and IgG3 [3].

Gold and penicillamine, both of which are administered for the treatment of rheumatoid arthritis (RA), have been known to cause drug-associated secondary MN [4]. In addition, as first reported by Nagahama et al. [5], secondary MN can also be caused by bucillamine, a drug widely used in Japan to treat RA. The group noted the absence of spike formation on light microscopy; the localization of IgG deposits, with a predominance of IgG1, on immunofluorescence staining; and the small number and size of electron-dense deposits (EDDs) on electron microscopy [5]. Later, Hoshino et al. [6] wrote that the first-line treatment for bucillamine-induced MN is to discontinue the drug. Recently, Sawa et al. [7] conducted a large-scale study and reported that in patients treated with bucillamine for a short period of time, only a few EDDs were seen, corresponding to early MN, but with long-term administration, the number of EDDs increased and the findings resembled those in typical primary MN. Furthermore, in early-stage cases, electron microscopy revealed foot process effacement more often in areas without EDDs, a finding that led the group to speculate that foot process impairment occurs first, followed by later EDD formation [7].

Although patients with minimal change disease and nephrotic syndrome can develop acute kidney injury (AKI) because of high levels of proteinuria, few reports have described AKI in patients with MN. Here, we report on a patient receiving bucillamine who developed AKI that required dialysis after the onset of severe proteinuria. Kidney biopsy led to a diagnosis of bucillamine-induced MN.

Case report

A 65-year-old man was admitted to the hospital for further evaluation of AKI. At the age of 64, he developed bilateral shoulder and knee pain. One month later, he was diagnosed with rheumatoid arthritis and started on bucillamine 200 mg and prednisolone 5 mg. This treatment was ineffective, so 9 months later the doses were increased to bucillamine 300 mg and prednisolone (PSL) 10 mg. After receiving the higher doses for one month, the patient developed lower leg edema and was admitted to hospital a few weeks later. He had a smoking history of 40 cigarettes per day for 30 years and had also consumed alcohol for over 30 years. He had been suffering from hypertension for 10 years and had been receiving losartan.

On admission, the patient was 165 cm tall and weighed 80 kg (an increase from 74 kg previously). His blood pressure was 144/95 mmHg. Fine crackles could be heard in all lung fields, and he was diagnosed with interstitial pneumonia. He had significant lower leg edema. Minimal deformity was seen in the joints of both hands, and no swelling or pain was observed. Serum creatinine was 1.23 mg/dL; albumin, 1.1 g/dL; CRP, 1.23 mg/dL. The immunoglobulin (Ig)G measurement was 960 mg/dL; IgA, 194 mg/dL; IgM, 148 mg/dL; IgE,494 IU/mL; antinuclear factor, negative; anti-double-stranded DNA antibody, 1.6 IU/mL;CH50, 64 U/mL; rheumatic factor,7 U/mL; anti citrullinated protein/peptide (CCP) antibody, 0.5 U/mL;anti-SS-A (Ro) antibodies, negative; and anti-SS-B (La) antibodies, negative,and matrix metalloproteinase-3 (MPP-3), 276 ng/mL (normal: < 121). Urinary protein, 12.8 g/day; urinary erythrocyte sediment, < 1/high power field.

There were no clinical findings such as dry eyes or dry mouth that would suggest Sjögren syndrome, and no skin lesions that would suggest systemic lupus erythematosus.

Computed tomography scans showed ground-glass opacity and honeycombing throughout the entire lung field. Several days after admission, the patient’s renal function worsened (serum creatinine, 7.8 mg/dL), so hemodialysis was initiated and a kidney biopsy was performed. The kidney biopsy was evaluated with the standard methods used in Japan [8, 9].

Kidney biopsy findings

Light microscopy of the kidney biopsy specimen revealed 14 glomeruli, two of which had complete global glomerular sclerosis. In the majority of the proximal tubules, the tubular epithelium was degenerated, swollen, and sloughed. Brush border loss was also evident (Fig. 1a). The glomeruli were intact, with no visible spikes (Fig. 1b). There was no hyalinosis of the arterioles, and fibroelastosis of the interlobular arteries was mild. Immunofluorescence staining revealed linear and partially granular IgG deposits along the GBM (Fig. 1c). The predominant IgG subclass was IgG1 (Fig. 1d), although IgG2 and IgG4 were also slightly positive. C3c (Fig. 1e) and C4d were also positive, C1q was very weakly positive (Fig. 1f), and kappa and lambda light chains were equally positive (Fig. 1g + ih). PLA2R, thrombospondin type-1 domain-containing (THSD)7A, and exostosin 1/2 were all negative, but neural epidermal growth factor-like 1 protein (NELL-1), a protein encoding neural tissue with epidermal growth factor-like repeats, was positive (Fig. 1i–k). In the GBM, electron microscopy revealed widespread subepithelial EDDs, some of which were rod shaped (Fig. 1l). Foot process effacement was observed not only in areas where EDDs were present (Fig. 1l), but also widely in areas where no EDD were apparent (Fig. 1m).

Fig. 1.

Kidney biopsy findings. a + b: Light microscopy findings (original magnification × 400). a: The tubular epithelium in the majority of proximal tubules was degenerated, swollen, or sloughed. Periodic acid-Schiff stain (PAS) stain. b: The glomeruli were intact, with no visible spikes. Periodic acid-methenamine-silver stain (PAM) stain. c–k: Immunofluorescent microscopy findings. c: Immunoglobulin (Ig)G was deposited linearly (some in a granular form) along the glomerular basement membrane (GBM). d: IgG1 was the predominant IgG subclass. e: C3c was also positive along the GBM. f: C1q was weakly positive along the GBM. g + h: Kappa and lambda light chains were equally positive. i–k: Double staining (ik) for IgG (i) and neural epidermal growth factor-like 1 protein (j) showed consistent positive images along the GBM. l, m: Electron microscopy findings (original magnification × 6000). l: Extensive electron-dense deposits (EDDs) was observed in the GBM subepithelium. Some of these EDDs were rod shaped. Foot process effacement was widely present in areas where EDD was present (arrow). m: Foot process effacement was widely present also in areas where EDD were not seen (arrow)

These findings were consistent with bucillamine-induced MN and acute tubular necrosis.

Clinical course

After admission, hemodialysis was initiated and PSL 40 mg was administered at the same time, but this was not effective, so the dose was increased to PSL 60 mg four weeks later. Two weeks after that, proteinuria began to decrease. The prednisolone dose was gradually tapered thereafter. Five months after admission, urinary protein levels had decreased to less than 1 g/day, and 15 months later, to less than 0.1 g/day. However, when the prednisolone dose was reduced to 6 mg, interstitial pneumonia worsened, so treatment subsequently focused on the interstitial pneumonia. Renal function and proteinuria remained stable (Fig. 2). Rheumatoid arthritis also stabilized with prednisolone treatment.

Fig. 2.

Clinical course. The change in urinary protein level was shown by UPCR (urinary protein creatinine ratio, urinary protein/ creatinine)

Discussion

We described a case of AKI requiring hemodialysis because of severe proteinuria after bucillamine administration. Compared with previous cases of bucillamine-induced MN, in the present case kidney biopsy revealed more proteinuria, abundant subepithelial deposits, and more extensive foot process effacement, which resulted in widespread proximal tubular damage. These factors are thought to have contributed to the AKI. Although bucillamine-induced MN has been reported to improve with drug discontinuation alone [6, 7], this patient had severe nephrotic syndrome, so drug discontinuation was ineffective and renal failure progressed rapidly, necessitating high dose of glucocorticoid therapy.

Recently, antigens associated with secondary MN have begun to be identified. Sethi et al. [10] reported a case of PLA2R-negative MN with IgG1-dominant MN in which positive staining for NELL-1 coincided with IgG deposition. NELL-1-positive patients were also found to have lung cancer, urothelial carcinoma, and breast cancer, raising concerns about the relationship of NELL-1 to cancer [10]. Subsequently, Miyazaki et al. [11] performed staining for NELL-1 in 221 MN patients; 6 were NELL-1-positive, and 3 of these patients were taking bucillamine. The EDDs were only present in a portion of the GBM, and the treatment course was similar to that reported in the above-mentioned articles [5–7], with many cases resolving with discontinuation of bucillamine alone [11]. Hyodo et al. [12] also reported that a high proportion of NELL-1-positive patients were receiving bucillamine, which was similar to the findings of Sawa et al. [7]. Takahashi et al. [13] reported that only 1 of 4 patients treated with bucillamine was NELL-1-positive, and Dirim et al. [14] reported that penicillamine, which has a similar structure to bucillamine, also caused NELL-1-positive secondary MN. Andeen et al. [15] wrote that because of the availability of bucillamine in Japan, it is frequently used there in patients with NELL-1-positive MN. In other countries, the use of high-mercury compounds has attracted attention. Discontinuing administration of these drugs tends to lead to improvement of MN, but the relationship with malignant tumors has not been fully evaluated [15].

Since glucocorticoid administration reduced proteinuria and improved renal function, it is clear that glucocorticoids were effective. The following mechanism is speculated as the cause of AKI. Although the arteriosclerotic lesions were mild in the kidney biopsy specimen, the severe hypoalbuminemia caused by severe proteinuria, combined with the drop in blood pressure due to losartan administration, led to an ischemic state, which is thought to have led to the onset of AKI [16].This case demonstrates that even in patients with severe nephrotic syndrome who have transitioned to hemodialysis due to AKI, continued glucocorticoid treatment for six to eight weeks can produce good results and allow dialysis to be discontinued.

We reported a case of secondary MN caused by bucillamine. This case was characterized by IgG1 positivity, but negative PLA2R and THSD7A. Primary MN is positive for PLA2R and IgG4. Meanwhile, Iida et al. reported a 61-year-old female case of MN specific to RA associated with high RA disease activity. In the case of Iida et al., PLA2R and THSD7A were negative, but IgG2 was positive, and high MMP-3 levels were noted as a contributing factor [17]. In our case, it is presumed that the drug-induced factors of bucillamine, as well as the high disease activity of RA and hypoalbuminemia due to severe nephrotic syndrome with large amounts of deposits, contributed to the development of AKI requiring dialysis.

In our case, many cases of bucillamine-induced MN are mild, with kidney biopsies showing few EDDs, and in most cases, the condition appears to be diagnosed at an early stage. Some cases of MN are NELL-1-positive, but the frequency of this subtype remains unknown and requires further research. In the present case, severe interstitial pneumonia and chronic hypoxemia were present as underlying conditions, which may have contributed to the specific presentation of this case.

Declarations

Conflict of interest

The authors declare no competing financial interests and no conflicts of interest.

Ethics approval

The present report was produced in conformity with the Declaration of Helsinki, and the patient gave his written informed consent for the case report to be published.