1 Renal Unit, Sir Charles Gairdner Hospital, Nedlands and 2 Department of Pathology, University of Western Australia and PathCentre, Western Australia, Australia
Correspondence and offprint requests to: Dr George Chin, Department of Nephrology, Derriford Hospital NHS Trust, Derriford, Plymouth, Devon PL6 8DH, UK. Email: george.chin{at}phnt.swest.nhs.uk
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Abstract |
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Keywords: drug-induced; infliximab; nephrotic syndrome
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in the adult population. It is conventionally classified into primary idiopathic and secondary forms. Drugs and toxins constitute an important aetiological subgroup of the latter. Drugs that are well known to be associated with MN include gold, penicillamine, captopril and non-steroidal anti-inflammatory agents (NSAIDS). This list will be expected to expand as increasing numbers of new drugs become available in the pharmaceutical market. Clinicians must be vigilant about the use of new therapeutic agents and the possibility of their potential side effects including MN. We describe a case of renal biopsy-proven MN in which infliximab is the suspected cause.
SJ is a 29-year-old Australia-born Vietnamese who presented with nephrotic syndrome. Her past medical history is significant for previous intravenous drug use, depression and severe psoriasis. She has had psoriasis for many years and her disease has been resistant to various topical therapies including glucocorticoids, tar, and coconut compound. Methotrexate and mycophenolate mofetil were tried with minimal success. In March 2002, a single dose of infliximab was given, followed by a dramatic clinical improvement within 1 week. She become pregnant shortly after and no further infusion was given until November the same year, followed by infusions in January and April 2003. The doses administered averaged 812 mg/kg: 450, 500, 400 and 400 mg respectively.
When reviewed in the Dermatology outpatient clinic 1 month after her last dose of infliximab, she complained of a short history of dyspnoea associated with a non-productive cough, accompanied by increasing abdominal and periorbital swelling. There were no fevers, chills or rigors. She denied intravenous drug use and had no recent history of travel. She was on no other medications besides the infliximab.
On examination, she was tachycardiac with a pulse rate of 108, blood pressure 110/70, and oxygen saturation 100% on room air. Her temperature was 37.3°C. Physical findings were remarkable for extensive peripheral pitting oedema, ascites and a right-sided pleural effusion. Urinalysis showed the presence of proteinuria (+++) without haematuria. A spot urine protein:creatinine ratio (PCR) was 1330 mmol/mg, equivalent to approximately 13 g of proteinuria daily. Serum albumin was 10 g/l, total cholesterol was 12.3 mmol/l with LDL of 9.4 mmol/l. Serum creatinine was normal during the entire period. A diagnosis of acute nephrotic syndrome was made. Anti-nuclear factors, hepatitis B/C and HIV serology, as well as serum/urine electrophoresis were all negative.
A renal biopsy was performed. Light microscopy showed non-specific changes, the capillary loops somewhat rigid and minimally thickened. Silver staining confirmed patchy thickening of the glomeruli basement membrane, but neither spikes nor double contours were seen. There was no evidence of vasculitis. Immunofluoresence demonstrated strong membranous fine granular IgG and C3 deposition, and electron microscopy (Figure 1) showed small electron dense sub-epithelial deposits dispersed at intervals along the lamina rara externa, confirming the diagnosis of membranous glomerulopathy.
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Infliximab, a chimeric anti-tumor necrosis factor-alpha (TNF-) monoclonal antibody, has been used in a number of inflammatory conditions. It has an established role in controlling disease activities in rheumatoid arthritis and inflammatory bowel disease. Its effectiveness appears to extend to the treatment of psoriasis, psoriatic arthropathy and ankylosing spondylitis [14]. The use of infliximab continues to grow. A number of case reports have been noted in the literature where the drug was used in patients with significant proteinuria secondary to AA amyloidosis [5,6]. This agent also appears to be safe in patients undergoing haemodialysis [7].
One of the more serious side effects of infliximab is infection, a not uncommon reason for temporary or permanent cessation of the therapy. Little is known of renal complications that may result from its use. A lupus-like syndrome has been described in association with infliximab therapy [8,9]. The absence of the typical serological results and immunofluorescence findings on the renal biopsy in our patient exclude lupus nephritis. An unusual hypersensitivity vasculitis with leucocytoclastic vasculitis secondary to infliximab has been described in a case report by McIlwain et al. [10]. Our patient at no stage developed any vasculitic rash, nor did the renal biopsy demonstrate any features of a vasculitis.
The temporal relationship between the initiation of infliximab and the subsequent development of biopsy-proven MN, along with slow resolution upon withdrawal of infliximab, suggested the possibility of a drug related phenomenon. It is, however, difficult to exclude the possibility of idiopathic MN with spontaneous remission. Approximately 50% of patients with idiopathic MN enter remissions, half of which will have complete remission within 35 years. This has resulted in difficulty in selecting patients who would otherwise benefit from treatment. Various prognostic factors have been used to predict outcomes in patients with MN. Older age, male sex, the presence of hypertension, nephrotic syndrome, and hypoalbuminaemia are among the predictors of poor outcome [11].
When MN is drug induced, the disease almost always resolves, but can take years to do so [12]. The patient described received a total of four infusions of infliximab over 13 months. It took 5 months for the patient to enter remission after infliximab was ceased. The course of MN might have been altered by the use of glucocorticoids, though it is well known that high-dose oral steroids alone are usually ineffective in MN.
Understanding of the pathogenesis of idiopathic MN largely comes from studies of animal models of passive Heymann nephritis (PHN), which can be induced in rats by administrating antibodies to antigens expressed on the membranes of the glomerular epithelial cells (GEC) [13]. The antigen has been identified as megalin-receptor associated protein complex in experimental MN [14]. The immune complexes then activate the complement cascade, which subsequently generates the terminal complement complex, C5b-9 or membrane attack complex (MAC), responsible for glomerular injury. Damage to glomeruli by C5b-9 is predominantly a non-lytic process. MAC induces activation of GEC with increased production of nephritogenic molecules such as oxidants, cytokines, vasoactive molecules, and extracellular matrix [12]. Tumor necrosis factor, has been demonstrated as a pro-inflammatory cytokine in the pathogenesis of a number of human and animal models of glomerulonephritis. Passive immunization of anti-TNF antibodies reduced levels of albuminuria in animals [15]. Theoretically, infliximab, being an antibody to TNF-, would not be expected to induce significant proteinuria from glomerular injury. It may represent an idiosyncratic reaction, although the evidence for this is far from conclusive.
The pathogenesis of drug-induced MN is poorly understood, but is probably different from that of idiopathic MN. Nagahama et al. [16] described renal biopsy findings in patients with Bucillamine induced MN. Immunofluorescence microscopy showed granular deposition of IgG2, IgG3 and IgG4 along the glomerular capillary walls, as compared with the predominant diffuse IgG4 deposition in idiopathic MN. In our patient, we did not analyse IgG subclass deposition with immunofluorescence microscopy.
Clinicians need to consider infliximab as a potential cause of renal injury in patients to whom it is given. This report describes a probable case of infliximab induced-membranous nephropathy which we believe to be the first case described in the literature.
Conflict of interest statement. None declared.
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