Pulmonary Renal Syndrome Due to Anti-GBM and IgM C-ANCA Disease Requiring the Use of Novel Therapeutic Agents

Abstract

There are several known causes for the clinical syndrome of pulmonary hemorrhage and acute renal failure. Here, we report a unique case of a 50-year-old man presenting in this manner. The initial diagnosis was one of antiglomerular basement membrane (anti-GBM) disease that responded well to steroids, cyclophosphamide, and plasma exchange (PE). The pulmonary hemorrhage resolved, but he remained dialysis dependent. However, despite falling anti-GBM titers, the symptoms relapsed and standard therapy was reinitiated with limited success. The anti-GBM antibody titer fell to zero despite clinical deterioration, prompting a search for an alternative diagnosis. He was found to be IgM anti-proteinase-3 antineutrophil cytoplasmic antibody (C-ANCA) positive. The pulmonary hemorrhage responded successfully to the use of intravenous immunoglobulin and the antilymphocyte monoclonal antibody CD52. To our knowledge, this is the first known case of IgM C-ANCA in association with anti-GBM disease. As such, it highlights the predominance of pulmonary hemorrhage in this condition, as well as the need to consider alternative therapies in refractory cases.

• antiglomerular basement membrane
• glomerulonephritis
• monoclonal antibody
• antineutrophil cytoplasmic antibodies
• Igm
• pulmonary hemorrhage
• pulmonary renal syndrome

Introduction

The clinical presentation of pulmonary hemorrhage and acute renal failure suggests a broad differential diagnosis that includes conditions such as Goodpasture syndrome, microscopic polyarteritis, Wegener's granulomatosis, and other less common immune complex deposition diseases.[1] The key to making a diagnosis lies in serologic testing and in obtaining a biopsy of an affected organ. Unfortunately, diagnosis and treatment can be challenging because overlap of these conditions can occasionally occur. Here, we present a case that highlights these difficulties.

Case

A 50-year-old man presented to accident and emergency with a month-long history of malaise, recurrent pyrexia, anorexia, nausea, and vomiting. He had a 12-year history of manic depression for which he had been taking lithium and haloperidol decanoate. He was otherwise well, was not taking any other medications, and was a nonsmoker. Clinical examination was entirely unremarkable, except for pyrexia of 38°C. Of note, there was no evidence of a source of sepsis, and abdominal examination was normal.

Laboratory investigation revealed the following abnormalities: urea 40.1 mmol/L, potassium 5.1 mmol/L, creatinine 1397 µmol/L, albumin 20 g/dL, adjusted calcium 2.35 mmol/L, phosphate 2.24 mmol/L, C-reactive protein 166, and hemoglobin 9.19 g/dL with a normochromic, normocytic blood picture. Chest X-ray (CXR) and electrocardiogram were unremarkable. Hemodialysis was initiated.

An autoantibody screen showed a positive antiglomerular basement membrane (anti-GBM) antibody with a titer of > 1200 EU, negative antinuclear factor, negative rheumatoid factor, and negative antineutrophil cytoplasmic antibody (ANCA). Renal ultrasound showed normal-size kidneys, and a renal biopsy was performed, which revealed marked tubulointerstitial inflammation with red cell casts. There was partial or complete sclerosis of the eight glomeruli present, and crescents were present in the nonsclerosed glomeruli. The predominant finding on immunofluorescence was linear deposition of IgG (Figure 1) consistent with the clinical diagnosis of anti-GBM disease.

Figure 1. Immunofluorescence revealing the typical, linear IgG antibody deposition along the glomerular basement membrane.

He was commenced on cyclophosphamide 150 mg daily (2 mg/kg), and the dose was adjusted according to his white cell count. Prednisolone 60 mg daily was also commenced along with a course of 3 1-L plasma exchanges (PE) with 4% albumin as the replacement fluid. He had 12 PE sessions at which point the anti-GBM titer had fallen to 57 EU. He improved clinically and was later discharged on oral immunosuppression. Unfortunately, he did not recover renal function and so attended the hospital for ongoing hemodialysis.

He remained well until a month later when he was readmitted with rigors, vomiting, and frank hemoptysis. The anti-GBM titer had fallen further to 38 EU. Chest X-ray revealed patchy bilateral infiltrates (Figure 2). Clinically, there was no evidence of fluid overload, so a relapse of anti-GBM disease was suspected, although the falling anti-GBM titer was atypical. He was still on prednisolone 30 mg daily and cyclophosphamide 100 mg daily, and sessions of PE were reinitiated. He required a further 18 sessions before clinical and radiologic improvement was achieved.

Figure 2. Chest X-ray revealing bilateral diffuse alveolar infiltrates characteristic of pulmonary hemorrhage.

Unfortunately, he promptly developed hemoptysis with bilateral pulmonary infiltrates on CXR when PE was stopped. The anti-GBM antibody had become negative, and the ANCA also remained negative. PE was continued with intermittent improvement, but overall there was a chronic decline with development of type one respiratory failure, increasing oxygen requirements, and intermittent hemoptysis. He was too unwell for bronchoscopy or pulmonary function testing.

Because there was no response to conventional therapy and the anti-GBM titers were persistently negative, an alternative diagnosis had to be considered. IgM ANCA is not routinely checked in most laboratories, so this was performed in collaboration with Dr. C.M. Lockwood's laboratory at Addenbrooke's Hospital in Cambridge. It was positive with antibodies against proteinase-3, although the exact titer was not reported.

The patient had not responded to recommended therapies, so 0.4 mg/kg of intravenous immunoglobulin was given daily for 4 days. The antilymphocyte monoclonal antibody CD52 (anti-CD52) was then commenced at an initial dose of 2 mg intravenously and then 4 mg, 10 mg, and 40 mg on subsequent days. No adverse events were noted.

The respiratory symptoms and signs resolved completely, and he became independent of PE. Serial IgM ANCA assays were not performed because of the difficulty in having this investigation performed on a routine basis. He had no further episodes of hemoptysis, but unfortunately did remain dialysis dependent and received a renal transplant in 2000. He remains well with no recurrence of either disease.

Discussion

There are a number of unusual aspects to this case of pulmonary renal syndrome that make it unique.

The initial diagnosis was one of anti-GBM disease where circulating autoantibodies are targeted against the NC1 domain of the alpha-3 chain of type IV collagen.[2] This results in a rapidly progressive glomerulonephritis, and when associated with pulmonary hemorrhage, it is referred to as Goodpasture syndrome.[3] The recommended treatment is PE along with prednisolone and cyclophosphamide.[4-6] He initially responded well to this with a marked reduction in his anti-GBM antibody titer. However, within a month he had developed recurrent hemoptysis, which is unusual, as the antibody titer had fallen to 57 EU. The anti-GBM level became negative with reinitiation of treatment, but the symptoms persisted. All previous reports of recurrent anti-GBM had been in the presence of a positive antibody.[7-11] Because this was not the case, it prompted the search for an alternative diagnosis for the ongoing pulmonary hemorrhage.

Included in the differential diagnosis of pulmonary renal syndrome is Wegener's granulomatosis, a vasculitis affecting small to medium-size vessels.[12] This is a condition characterized by the development of granulomatous inflammation that can result in the development of a multisystem disorder potentially affecting the chest, kidneys, and other organs.[13] It is usually characterized by the presence of antineutrophil cytoplasmic antibodies, typically of the IgG isotype, and targeted against proteinase-3[14] with a cytoplasmic staining pattern (C-ANCA). As a result, most laboratories do not routinely check for IgM ANCA antibodies; however, they have been shown to occur in isolation[15&16] and also to be of clinical importance with a greater association with pulmonary hemorrhage.[17] In this case, routine testing for ANCA was persistently negative. IgM ANCA testing was performed given the persistent hemoptysis, and the patient was found to have positive IgM C-ANCA.

The coexistence of ANCA and anti-GBM in sera is well reported and varies between 2% and 38%; however, the clinical consequences of this have not been completely elucidated. Indeed, there is the suggestion that the presence of ANCA confers a favorable prognosis.[18&19] There are also several case reports describing the sequential development of anti-GBM disease and ANCA disease;[20-23] however, the clinical scenario of IgM ANCA disease in association anti-GBM disease has only been reported once previously.[24] On that occasion the antibodies were specific for myeloperoxidase, but this is the first case report of the sequential development of anti-GBM disease and IgM C-ANCA.

Therapy for ANCA-related disease usually consists of steroids and cyclophosphamide, but PE is also recommended if dialysis is required.[25] Despite receiving PE, the patient continued to have recurrent, increasingly severe episodes of hemoptysis, so alternative therapy was sought. There have been reports of the successful use of several other novel therapies in ANCA-associated vasculitis, including antitumor necrosis alpha and antiadhesion molecule agents,[26] in such refractory cases. Antilymphocyte monoclonal antibodies (CD52/CD4) and immunoglobulin (believed to work by interfering with antibody-neutrophil binding and neutrophil activation) have been used successfully[27&28] and were used in our patient's case. He responded well to this treatment, and although remaining dialysis dependent, his respiratory symptoms settled.

In conclusion, this it is the first report of IgM C-ANCA in association with anti-GBM disease. Consideration should be given to the presence, not only of IgG ANCA, but also of IgM ANCA in anti-GBM disease where pulmonary hemorrhage remains refractory. This case also highlights the successful therapeutic use of anti-CD52 in this condition.

Acknowledgment

The authors want to acknowledge the contribution made by Dr. C. M. Lockwood (deceased), Addenbrooke's Hospital, Cambridge, UK.