Anti-Glomerular Basement Membrane Glomerulonephritis with Subsequent Pulmonary Hemorrhage in the Course of Pulmonary Tuberculosis

Abstract

A 66-year-old man with uremia and on hemodialysis was referred to our hospital because of hemoptysis. A chest radiograph showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure accompanied by hematuria and proteinuria. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgG along the glomerular basement membrane (GBM). Circulating IgG anti-GBM antibody was not detected. Because the findings of renal biopsy suggested anti-GBM disease, the patient was treated with plasmapheresis and pulse steroid therapy, which resulted in a rapid resolution of his pulmonary symptoms and chest radiograph abnormalities. However, sputum culture submitted on admission yielded Mycobacterium tuberculosis 3 weeks later. Therefore, immunosuppressive agents were discontinued and antituberculous agents were administrated. No relapse of pulmonary hemorrhage occurred during the next 1-year period of follow-up, but the patient did not regain renal function and remained on hemodialysis.

• anti-glomerular basement membrane disease
• Goodpasture’s disease
• pulmonary hemorrhage
• pulmonary tuberculosis

INTRODUCTION

Anti-glomerular basement membrane (GBM) disease is often used synonymously to refer to Goodpasture’s disease in which circulating autoantibodies are directed against an antigen intrinsic to the GBM, typically presenting with rapidly progressive glomerulonephritis and pulmonary hemorrhage. The principal target for the anti-GBM antibodies is the noncollagenous domain of the α3 chain of type IV collagen of GBM.¹ This disorder is most often idiopathic. However, it can occasionally follow pulmonary infections or be associated with pulmonary injury. Here, we report an unusual case of anti-GBM disease presenting with crescentic glomerulonephritis and subsequent pulmonary hemorrhage in the course of pulmonary tuberculosis. To the best of our knowledge, such a case has never been previously reported in the literature.

CASE REPORT

A 66-year-old man with uremia and on hemodialysis for 3 months was referred to our hospital because of hemoptysis. He had a previous history of hypertension, was a lifelong nonsmoker, and drank alcohol only occasionally. He had no family history of any renal disease. Renal dysfunction was first detected at a local hospital in January 2010, with a serum creatinine level of 2.8 mg/dL. Urinalysis at the time showed hematuria and proteinuria. The second report of renal function test was recorded at the same hospital in August 2010, with a serum creatinine level of 4.0 mg/dL and urine protein-to-creatinine ratio of 2283 mg/g. No follow-up was done on the patient until he presented to another hospital in January 2011 because of uremia and requiring renal replacement therapy. Later he was admitted into a hemodialysis program, and was then referred to our hospital in April 2011 with a 1-week history of hemoptysis. A chest radiograph showed diffuse infiltration in the right lung field (Figure 1A). He had no fever, arthralgia, or skin lesion, and had clear consciousness. Crackles were heard in the right basal lung field. Laboratory studies revealed the following: white blood cell count 5600/μL, hemoglobin 8.4 g/dL, platelet count 102,000/μL, creatinine 9.99 mg/dL, total protein 5.1 g/dL, and albumin 2.7 g/dL. Prothrombin time and partial thromboplastin time were normal. Urinalysis showed protein of 300 mg/dL and red blood cell >100/high-power field. Serum complements were normal. Serology was negative for anti-nuclear antibody, anti-neutrophil cytoplasmic antibody (ANCA), and IgG anti-GBM antibody (using indirect immunofluorescence).

Figure 1. Chest radiograph on admission showing diffuse infiltration in the right lung field (A); follow-up chest radiograph on day 14 showing resolution of the infiltration after plasmapheresis and pulse methylprednisolone therapy (B).

With a presumed diagnosis of pulmonary renal syndrome, a kidney biopsy was performed on the seventh day of admission. The specimen contained 23 glomeruli, of which 18 were globally sclerotic. Of the remaining five viable glomeruli, three had fibrocellular crescents and two had fibrous crescents. Immunofluorescence studies revealed staining of IgG (2+) in a linear pattern along the glomerular capillary loops (Figure 2). Electron microscopy was not performed as no viable glomeruli were visible. Because the findings of renal biopsy suggested that the patient had anti-GBM disease, he was treated with two sessions of plasmapheresis and pulse methylprednisolone (500 mg/day × 3 days), followed by oral prednisone (1 mg/kg/day) and oral cyclophosphamide (1 mg/kg/day), which resulted in a rapid resolution of his pulmonary symptoms and chest radiograph abnormalities (Figure 1B). However, microbiological studies of sputum specimens collected on the day of admission yielded Mycobacterium tuberculosis 3 weeks later. Therefore, immunosuppressive agents were discontinued and antituberculous therapy was started with rifampicin, isoniazid, ethambutol, and pyrazinamide. No relapse of pulmonary hemorrhage was noted during the next 1-year period of follow-up, but the patient did not regain renal function and remained on hemodialysis.

Figure 2. Immunofluorescence microscopy of renal biopsy showing characteristic linear deposition of IgG along the glomerular capillary loops.

DISCUSSION

Pulmonary renal syndrome is a potentially life-threatening combination of pulmonary hemorrhage and glomerulonephritis. Several pathological entities can cause this syndrome. Similar to the differential diagnosis of rapidly progressive glomerulonephritis, the immunopathology of pulmonary renal syndrome comprises of three major categories: anti-GBM antibodies-mediated disease, which has linear immunoglobulin deposits and serologic detection of anti-GBM antibodies; immune complex-mediated diseases, which have granular immune deposits; and ANCA-associated diseases, which have a paucity of immune deposits and serologic detection of ANCA. In the patient, the presence of significant IgG deposition in a linear pattern along the GBM suggested an anti-GBM antibodies-mediated mechanism.

Anti-GBM disease is also known as Goodpasture’s disease. Most patients present with the combination of rapidly progressive glomerulonephritis and pulmonary hemorrhage, although 30–40% present with isolated renal involvement.² The diagnosis can usually be established rapidly by the detection of anti-GBM antibodies in serum using either indirect immunofluorescence or direct enzyme-linked immunoassay. However, neither method is completely reliable. Furthermore, the circulating anti-GBM antibodies may be transitory such that the antibodies are not always detected. False-negative results may occur in those patients with low antibody titers and in some patients with Alport syndrome who develop post-transplant anti-GBM disease, with antibodies directed against the α5 chain of type IV collagen.^3,4 Therefore, a kidney biopsy should be performed to confirm the diagnosis. Light microscopy of renal biopsy usually shows crescentic glomerulonephritis, whereas immunofluorescence microscopy demonstrates the virtually pathognomonic finding of linear deposition of IgG along the GBM. In rare cases, the antibody may be IgA or IgM.⁵

There is increasing evidence to show that genetic factors may affect the susceptibility to this disorder. Although a strong association exists between Goodpasture’s disease and human leukocyte antigen DRB1*1501, this allele is present in as many as one-third of individuals in white populations and thus cannot solely explain the susceptibility to such a rare disease.⁶ It has, therefore, been proposed that additional factors are required for disease expression, which may be genetic or environmental. Pulmonary infections have long been linked to the disease. Goodpasture’s original paper emphasized the association with influenza infection.⁷ A recent study showed that Goodpasture’s disease could be incited by Pneumocystis carinii pneumonia.⁸ Exposure to hydrocarbons has been associated with the onset of symptoms, and case–control studies have shown higher levels of anti-GBM antibodies in individuals exposed to inhaled hydrocarbons.⁹ Cigarette smoking has frequently been reported in association with the development of disease, and disease relapses have been temporally linked with episodes of smoking.^10,11 One hypothesis is that damage to the lung from pulmonary infections, hydrocarbons, or cigarette smoking exposes a cryptic epitope within the alveolar basement membrane that triggers an autoimmune response to the α3 chain of type IV collagen with subsequent anti-GBM disease.¹²

In the present case, although histological confirmation was not obtained, resolution of the pulmonary symptoms and chest radiograph abnormalities immediately after plasmapheresis and pulse steroid therapy supported the diagnosis of pulmonary hemorrhage complicating anti-GBM disease. Since anti-GBM disease with isolated renal involvement had existed for more than 1 year before the development of pulmonary hemorrhage and there were no clinical symptoms or chest radiograph abnormalities suggestive of pulmonary tuberculosis during this period, it seems unlikely that the anti-GBM disease was originally incited by pulmonary tuberculosis. However, the subsequent pulmonary hemorrhage was supposed to be associated with an additional pulmonary insult caused by tuberculosis infection. The variable presence of pulmonary involvement in anti-GBM disease appears to reflect a general lack of access of the circulating anti-GBM antibodies to the α3 chain of type IV collagen within the alveolar basement membrane. Thus, it is possible that pulmonary injury through pulmonary tuberculosis infection resulted in exposure of the normally hidden antigen within the alveolar basement membrane and allowed access of already existing circulating anti-GBM antibodies to the antigen.^10,13 In the present case, even though the patient had discontinued immunosuppressive therapy, no relapse of pulmonary hemorrhage after treating tuberculosis suggested a causal relationship between the development of autoimmune-mediated pulmonary hemorrhage and pulmonary tuberculosis. One hypothesis is that there was short-live production of circulating autoantibodies in response to an inciting stimulus by pulmonary tuberculosis.

In conclusion, early diagnosis of anti-GBM disease responsible for pulmonary renal syndrome is crucial because of the danger of irreversible loss of renal function or mortality from culminant pulmonary hemorrhage. Because the accuracy of serologic assays for anti-GBM antibodies is variable, confirmation of the diagnosis necessitates renal biopsy. Furthermore, this study suggests that additional pulmonary insults such as infections should be considered in patients with subsequent pulmonary involvement.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.