What is the clinical significance of triple-positive Anti-Neutrophil Cytoplasmic Antibodies (ANCA) and Anti-Glomerular Basement Membrane (anti-GBM) and Immunoglobulin A (IgA) antibodies in glomerulonephritis (GN) case reports?

From the Guidelines

Triple-positive glomerulonephritis (GN) with ANCA, anti-GBM, and IgA antibodies requires aggressive immunosuppression with a combination of high-dose corticosteroids, cyclophosphamide, and plasma exchange, as well as maintenance therapy with immunosuppressants to prevent relapse and improve outcomes. This condition represents an overlap syndrome with features of ANCA-associated vasculitis, anti-GBM disease, and IgA nephropathy. The treatment approach is based on the most recent guideline recommendations, including the 2021 KDIGO clinical practice guideline for the management of glomerular diseases 1 and the 2023 KDOQI US commentary on the 2021 KDIGO guideline 1.

Key Considerations

• The pathophysiology of triple-positive GN involves complex immune dysregulation with multiple autoantibody production targeting different renal structures simultaneously.
• Early diagnosis through kidney biopsy and serological testing is crucial, as is close monitoring for treatment complications including infections, bone marrow suppression, and metabolic derangements.
• Maintenance therapy with immunosuppressants, such as azathioprine, mycophenolate mofetil, or continued low-dose rituximab infusions, is necessary to prevent relapse and improve outcomes, especially in patients with double-positive disease with positivity for both ANCA and anti-GBM antibodies 1.
• The prognosis of triple-positive GN is worse than single-antibody disease, with higher rates of end-stage renal disease and mortality, emphasizing the need for aggressive and prompt treatment.

Treatment Approach

• High-dose corticosteroids (methylprednisolone 500-1000mg IV daily for 3 days, followed by oral prednisone 1mg/kg/day with gradual taper) are recommended as initial treatment.
• Cyclophosphamide (either IV 15mg/kg every 2-3 weeks or oral 2mg/kg/day) and plasma exchange (PLEX, typically 7-14 sessions) are also recommended as part of the initial treatment regimen.
• Rituximab (375mg/m² weekly for 4 weeks) may be used as an alternative to cyclophosphamide in some cases.
• Maintenance therapy with immunosuppressants, such as azathioprine, mycophenolate mofetil, or continued low-dose rituximab infusions, is necessary to prevent relapse and improve outcomes.

From the Research

Clinical Significance of Triple-Positive ANCA and Anti-GBM and IgA Antibodies

• The presence of triple-positive Anti-Neutrophil Cytoplasmic Antibodies (ANCA) and Anti-Glomerular Basement Membrane (anti-GBM) and Immunoglobulin A (IgA) antibodies in glomerulonephritis (GN) case reports is a rare and complex condition [ 2 ].
• Studies have reported cases of patients with crescentic glomerulonephritis who were dual positive for proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA or ANCA and anti-GBM antibody [ 2 ].
• The coexistence of anti-GBM disease and other immune complex mediated glomerulonephritis, such as IgA nephropathy, is common [ 3 ].
• IgA-mediated anti-GBM disease is extremely rare and presents diagnostic difficulties as circulating IgA antibodies will not be detected by standard serological tests for anti-GBM disease [ 4 ].

Treatment and Outcomes

• Intensive therapy, including prednisolone, plasma exchange, and intravenous cyclophosphamide, has been effective in treating patients with triple-positive ANCA and anti-GBM antibodies [ 2 ].
• Plasma exchange using fresh frozen plasma combined with oral prednisolone has been shown to be effective in reducing autoantibody levels and achieving dialysis independence in patients with MPO-ANCA-positive anti-GBM antibody disease [ 5 ].
• Aggressive combination therapy, including avacopan, has been used to effectively manage necrotizing crescentic glomerulonephritis in patients double-seropositive for anti-GBM antibodies and ANCA [ 6 ].

Diagnostic Challenges

• The diagnosis of IgA-mediated anti-GBM disease can be challenging due to the lack of detection of circulating IgA antibodies by standard serological tests [ 4 ].
• Kidney biopsy and immunofluorescence staining are essential for diagnosing anti-GBM disease and detecting linear staining of IgA along the GBM [ 4 ].