What is the management of Anti-Glomerular Basement Membrane (Anti-GBM) disease?

Anti-GBM Disease: Comprehensive Overview

Pathophysiology

Anti-GBM disease is caused by autoantibodies directed against the noncollagenous (NC1) domain of the α3 chain of type IV collagen, which is present in both glomerular and alveolar basement membranes. 1, 2

• The antibodies bind to basement membranes causing necrotizing and crescentic glomerulonephritis with characteristic linear IgG deposition on immunofluorescence 2
• When both kidneys and lungs are affected, this is termed Goodpasture syndrome; renal-limited disease is called anti-GBM nephritis 1
• Untreated disease has a mortality rate up to 96% 1

Microbiology/Immunology

• Approximately 10% of cases may have falsely negative anti-GBM antibodies on serologic testing 1, 3, 2
• Some patients (10-40%) have dual positivity for both anti-GBM and ANCA antibodies, which significantly affects management and prognosis 3
• Relapse rate is very low (<5%) in isolated anti-GBM disease 3

Biochemistry/Laboratory Investigations

Send serologies for anti-GBM, ANA, and ANCA immediately, but do not delay treatment while awaiting results. 3

• Anti-GBM antibody levels should be monitored during treatment 3
• Serum creatinine at presentation is the most critical prognostic indicator 4
• CMV antigen testing should be considered during immunosuppressive therapy 5

Histopathology

Kidney biopsy is crucial when safe and feasible, as anti-GBM antibodies can be falsely negative in approximately 10% of cases. 1, 3

• Light microscopy shows necrotizing and crescentic glomerulonephritis 2
• Immunofluorescence demonstrates linear IgG staining along the glomerular basement membrane (pathognomonic finding) 2, 6
• Prognostic features include: percentage of crescents, degree of global glomerulosclerosis, and extent of tubular atrophy/interstitial fibrosis 3
• Patients with 100% crescents or >50% global glomerulosclerosis have extremely poor renal recovery rates 1, 4

Management

Immediate Treatment Protocol

Initiate triple therapy immediately with plasmapheresis, high-dose glucocorticoids, and cyclophosphamide in all patients except those who are dialysis-dependent at presentation with 100% crescents or >50% global glomerulosclerosis on biopsy and no pulmonary hemorrhage. 1, 3

Plasmapheresis

• Start immediately upon clinical suspicion 3
• Continue daily until anti-GBM antibodies are undetectable on two consecutive tests 3
• Do not stop when antibodies are merely reduced—continue until completely undetectable 3

Glucocorticoids

• Begin with high-dose intravenous methylprednisolone (pulse therapy) 3, 6
• Transition to oral prednisone and taper over approximately 6 months 3

Cyclophosphamide

• Oral cyclophosphamide 2-3 mg/kg daily for 2-3 months 3
• Adjust dose for reduced GFR or older age 3
• Monitor for leukopenia and other complications 7, 5

Prognostic Stratification and Treatment Decisions

Patients presenting with creatinine <500 μmol/L (5.7 mg/dL) have excellent outcomes with 95% renal survival at 1 year. 4

• Creatinine 500 μmol/L or higher but not requiring dialysis: 82% renal survival at 1 year with aggressive treatment 4
• Dialysis-dependent at presentation: only 8% renal survival at 1 year and 5% at long-term follow-up 4
• Dialysis-dependent patients should only receive aggressive immunosuppression if presentation is acute, non-oliguric, or biopsy shows features of acuity (not 100% crescents) 1, 3
• All patients requiring immediate dialysis with 100% crescents on biopsy remained dialysis-dependent in long-term studies 4

Special Populations

Dual Anti-GBM/ANCA Positive Patients

Patients with both anti-GBM and ANCA antibodies require maintenance immunosuppression as for ANCA-associated vasculitis due to significantly higher relapse rates. 3

Patients with Complications

• If thrombotic thrombocytopenic purpura (TTP) develops on cyclophosphamide, rituximab can be substituted successfully 7
• CMV enteritis is a serious complication requiring ganciclovir and potentially reduced immunosuppression 5

Maintenance Therapy

No maintenance immunosuppression is necessary for isolated anti-GBM disease after initial treatment due to the low relapse rate (<5%). 3

• Exception: dual anti-GBM/ANCA positive patients require maintenance therapy as for ANCA vasculitis 3
• Monitor for relapse for at least the first 2 years 2

Novel Therapies

• Imlifidase (IgG-degrading enzyme) shows promise with 67% dialysis-free survival at 6 months in phase 2 studies, with rapid antibody decline within 6 hours 3

Kidney Transplantation

Defer kidney transplantation until anti-GBM antibodies remain undetectable for at least 6 months. 3, 2

• Patients with Alport syndrome may develop anti-GBM antibodies to the foreign collagen chain in approximately 2-3% of transplant cases 3

Critical Pitfalls to Avoid

• Never delay treatment while awaiting serologic confirmation—begin therapy immediately based on clinical suspicion 3
• Do not stop plasmapheresis when antibodies are merely reduced; continue until completely undetectable 3
• Do not provide aggressive immunosuppression to dialysis-dependent patients with 100% crescents and no pulmonary hemorrhage, as they will not recover renal function 1, 4
• Remember that anti-GBM antibodies can be falsely negative in 10% of cases—kidney biopsy is essential when clinically suspected 1, 3
• Consider dual ANCA/anti-GBM positivity and adjust maintenance therapy accordingly 3
• Monitor closely for infectious complications, particularly CMV, during immunosuppressive therapy 5