An Exceptional Case of Crohn-Associated IgA-Mediated Goodpasture Disease

Abstract

Anti-glomerular basement membrane (anti-GBM) disease is typically mediated by IgG autoantibodies and presents with pulmonary hemorrhage and rapidly progressive glomerulonephritis, classically referred to as Goodpasture disease. We describe a novel IgA-mediated variant in a 53-year-old man with Crohn colitis, who presented with oligo-anuric acute kidney injury and hemoptysis. Despite having negative serology for anti-GBM antibodies, kidney biopsy revealed necrotizing crescentic glomerulonephritis with linear IgA deposition along the glomerular basement membrane. We suspect that a Crohn colitis flare may have incited a novel IgA-driven anti-GBM process which, remarkably, resolved in the absence of conventional immunosuppressive therapy, sharply deviating from previously reported IgA-mediated disease requiring aggressive intervention. Such a case suggests a possible link between abnormal IgA glycosylation in inflammatory bowel disease and the development of a unique IgA-mediated anti-GBM process. Recognition of this entity may broaden the diagnostic approach to seronegative pulmonary-renal syndromes and also highlight the potential for nonimmunosuppressive management.

Goodpasture disease is a well-recognized pulmonary-renal syndrome characterized by rapidly progressive crescentic glomerulonephritis and alveolar hemorrhage, primarily driven by IgG autoantibodies against the NC1 domain of the α3 chain of type IV collagen.¹ Diagnosis typically relies on detecting circulating IgG anti-GBM antibodies using an enzyme-linked immunosorbent assay (ELISA), crescentic glomerulonephritis under light microscopy, and identifying linear IgG deposits along the glomerular basement membrane via immunofluorescence.² However, rare variants involving IgA challenge this archetype and may present as seronegative Goodpasture disease, in which the classic IgG anti-GBM ELISA is negative.³ Recognition of such atypical variants is crucial, as they demand alternative diagnostic consideration.

Patients with inflammatory bowel disease, including Crohn disease, may be predisposed to aberrant IgA-mediated immunopathology, leading to unusual renal disease.4, 5, 6, 7 This case report documents the first known instance of IgA-mediated Goodpasture disease achieving spontaneous remission without the use of immunosuppression beyond glucocorticoids, defying conventional expectations and highlighting uncertainty regarding the presumed necessity of aggressive therapies in such cases.

Case Report

We present a case of a 53-year-old male with a history of hypertension and Crohn colitis, diagnosed in 2016, who underwent a proctectomy with end colostomy formation in 2019. He had been treated with multiple biologic therapies, most recently infliximab, until 2019. In May 2023, he presented with a Crohn disease flare, complicated by acute kidney injury, increased stoma output, peripheral edema, and severe anemia (hemoglobin 4.6 g/dL). His serum creatinine was 270 μmol/L, risen from a baseline of 70 μmol/L, and his urinary protein-to-creatinine ratio was 200 mg/mmol. A flexible sigmoidoscopy confirmed moderate-to-severe active Crohn disease, and the patient was started on intravenous hydrocortisone, followed by a weaning course of oral prednisolone.

Despite treatment, his kidney function continued to deteriorate, peaking at a serum creatinine of 509 μmol/L, with oligo-anuria. He soon then developed hemoptysis, severe hypertension (>200/100 mm Hg), and metabolic acidosis with a lactate of 4 mmol/L. Imaging with chest X-ray and computed tomography pulmonary angiography was suggestive of pulmonary edema, and the patient was subsequently managed with continuous veno-venous hemofiltration, a labetalol infusion for blood pressure control, and noninvasive ventilation in the high dependency unit. An intrinsic renal screen, including serologic testing for anti-GBM antibodies, was negative. This included negativity (<1 IU/mL) for antineutrophil cytoplasmic antibody to myeloperoxidase and proteinase 3, normal IgA levels (2.01 g/L; normal range: 0.8-4.0 g/L), normal C4 (0.33g/L; normal range: 0.1-0.4 g/L), and a C3 level just within the normal range (0.87 g/L; normal range: 0.9-1.8 g/L). Antistreptolysin O titers were not measured given that there was no history or clinical suspicion of infection preceding the patient’s presentation.

The patient was transferred to our nephrology unit for ongoing intermittent hemodialysis but despite significant ultrafiltration volumes, he remained oxygen-dependent. High-resolution computed tomography revealed multi-segmental collapse and consolidation with inflammatory nodules, but no features suggestive of interstitial lung disease. Bronchoscopy confirmed the presence of old/coagulated blood. Based on these findings, we concluded that his initial presentation was due to an acute pulmonary hemorrhage rather than pulmonary edema. Consequently, a kidney biopsy was performed, revealing necrotizing crescentic glomerulonephritis, with crescents in 6 of 19 glomeruli (4 cellular and 2 fibrocellular) (Fig 1A and B). The crescents were associated with endocapillary proliferation, which was not observed in the noncrescentic glomeruli. Several of the noncrescentic glomeruli exhibited widespread ischaemic wrinkling of the capillary walls, and one glomerulus demonstrated mesangiolysis. Immunofluorescence demonstrated strong IgA staining in a linear distribution along the glomerular basement membrane, resembling the classic IgG pattern seen in anti-GBM disease (Fig 2A and B). Additional staining showed 1+ granular mesangial staining for both κ and λ light chains, 1+ granular C3 deposition within the mesangium and focally along the glomerular basement membranes, segmental 1+ IgM deposition, and negative C1q staining. Electron microscopy revealed wrinkling of the glomerular basement membranes with subendothelial lucencies, focal foot process effacement, and no definitive electron-dense deposits.

Figure 1.

Light microscopy PAS original magnification, ×35. (A) Glomerulus with cellular crescent; B. Methylene silver stain of the same glomerulus with a cellular crescent original magnification, ×35.

Figure 2.

Immunofluorescence staining. (A) IgA staining with linear deposition along the glomerular basement membrane. (B) IgG staining with no uptake.

The multidisciplinary team agreed on a treatment plan consisting of a colectomy to control Crohn disease, followed by cyclophosphamide for the anti-GBM disease. However, before the colectomy could be performed, the patient’s kidney function began improving spontaneously. He was discharged 8 weeks after presentation with a serum creatinine of 293 μmol/L. Three weeks later, the patient underwent an uncomplicated total colectomy, with a serum creatinine of 218 μmol/L at the time of surgery.

At follow-up 5 months later, his serum creatinine had further improved to 163 μmol/L, and his urine protein-to-creatinine ratio had decreased to 54 mg/mmol. Given this sustained improvement, immunosuppressive therapy was deemed unnecessary.

Discussion

This case represents a very rare instance of IgA-mediated Goodpasture disease. Standard anti-GBM ELISA assays detect only IgG anti-GBM antibodies, explaining the negative serologic result in our patient. However, the linear IgA deposition along the glomerular basement membrane, coupled with focal necrotizing crescentic glomerulonephritis and an acute pulmonary-renal syndrome, aligns with the classical features of Goodpasture disease, albeit through an IgA-driven mechanism.

The relationship between inflammatory bowel disease and IgA nephropathy is well-documented, with gut-associated lymphoid tissue playing a key role in IgA dysregulation.^8,9 In IgA nephropathy, aberrantly glycosylated IgA1 forms immune complexes that deposit in the glomerular mesangium. However, this case of IgA-mediated Goodpasture disease differs in both localization and mechanism. Instead of mesangial deposition, we observed linear IgA deposits along the glomerular basement membrane. This supports the possibility that Crohn disease-induced immune dysregulation may trigger an IgA variant of anti-GBM disease, an entity that remains poorly understood.

Although IgA-mediated anti-GBM disease has been described previously,^3,10, 11, 12, 13 this case is unique since remission occurred without the use of immunosuppression, aside from glucocorticoids. In nearly all reported cases, aggressive immunosuppression, including cyclophosphamide and plasma exchange, has been required, yet renal outcomes have been poor, often culminating in dialysis dependence. Furthermore, in a prior case of Crohn-associated IgA-mediated anti-GBM disease, outcomes were catastrophic.¹³

This case expands the spectrum of anti-GBM disease to include an IgA-driven, Crohn-associated variant with an unexpectedly favorable conclusion. We propose that the flare of Crohn disease served as an immune priming event, triggering the formation of abnormal IgA complexes that cross-reacted with the glomerular basement membrane. The spontaneous remission without conventional immunosuppressive therapy raises the possibility of distinct immunopathologic mechanisms in IgA-driven variants and suggests that, in select cases, nonimmunosuppressive management may be a viable approach, challenging current therapeutic assumptions. This case hence highlights the complexity of immune dysregulation in Crohn disease and its potential to precipitate rare autoimmune phenomena such as IgA-mediated anti-GBM disease. Further research is needed to delineate the precise triggers and pathogenic pathways underlying IgA-mediated glomerular basement membrane injury, particularly in the context of inflammatory bowel disease. Identifying key immunologic differences between IgA- and IgG-mediated anti-GBM disease may not only refine diagnostic approaches but also open avenues for more targeted therapeutic strategies.