What is the recommended treatment for glomerulonephritis, including supportive care and etiology-specific immunosuppressive therapy?

Treatment for Glomerulonephritis

Treatment of glomerulonephritis requires immediate identification of the underlying etiology and disease severity, with therapy ranging from supportive care alone for indolent disease to aggressive immunosuppression with cyclophosphamide or rituximab plus high-dose corticosteroids for rapidly progressive or crescentic disease. 1, 2

Initial Diagnostic Workup to Guide Treatment

Before initiating any immunosuppressive therapy, you must:

• Screen for infections including hepatitis B, hepatitis C, HIV, and syphilis, as these may be causative and require specific treatment 1, 3
• Obtain autoimmune serologies including ANCA, anti-GBM antibodies, ANA, and complement levels (C3, C4) to determine the etiology 2
• Perform kidney biopsy to confirm diagnosis, assess disease activity versus chronicity, and identify the specific pattern (immune complex, pauci-immune, or anti-GBM) 2
• Consider prophylactic trimethoprim-sulfamethoxazole before starting high-dose prednisone or other immunosuppression to prevent Pneumocystis infection 1

Universal Supportive Care (All Patients)

Regardless of etiology, all patients require:

• RAS blockade with ACE inhibitors or ARBs to reduce proteinuria and control blood pressure, even without hypertension 1, 4
• Blood pressure target <130/80 mmHg 4
• Sodium restriction to <2.0 g/day (<90 mmol/day) to reduce edema and control blood pressure 1, 4
• Protein restriction to 0.8-1 g/kg/day for nephrotic-range proteinuria, with plant-based sources preferred 1
• Statin therapy for dyslipidemia to reduce cardiovascular risk 4
• Anticoagulation prophylaxis if serum albumin <2.5 g/dL due to high thromboembolic risk 4

Treatment Based on Disease Severity and Etiology

Rapidly Progressive or Crescentic Glomerulonephritis (Medical Emergency)

For ANCA-associated vasculitis with severe disease (dialysis-requiring or rapidly increasing creatinine):

• Induction therapy: Rituximab OR cyclophosphamide PLUS high-dose corticosteroids 1, 2
  • Pulse IV methylprednisolone 500-1000 mg/day for 3 days, followed by oral prednisone 1 mg/kg/day (max 80 mg/day) with gradual taper 1
  • Cyclophosphamide: 15 mg/kg IV every 2-4 weeks OR 2 mg/kg/day orally for 3 months 1
• Add plasmapheresis for diffuse pulmonary hemorrhage or dialysis-dependent patients 1
• Maintenance therapy after remission: Azathioprine 1-2 mg/kg/day for at least 18 months, OR mycophenolate mofetil up to 1 g twice daily if azathioprine intolerant 1
• Discontinue cyclophosphamide after 3 months if dialysis-dependent without extrarenal manifestations 1

For anti-GBM disease:

• Immediate triple therapy: Cyclophosphamide PLUS corticosteroids PLUS plasmapheresis without delay once diagnosis confirmed 1
• Start treatment even before confirmation if highly suspected 1
• Exception: Do NOT treat if dialysis-dependent with 100% crescents on biopsy and no pulmonary hemorrhage (8% renal recovery rate) 1
• No maintenance immunosuppression required for anti-GBM disease 1
• Defer transplantation until anti-GBM antibodies undetectable for minimum 6 months 1

For immune complex-mediated crescentic GN:

• Treat with cyclophosphamide and high-dose corticosteroids similar to ANCA vasculitis regimen 1, 3
• Add plasmapheresis for severe presentations 3
• If HCV-associated with cryoglobulinemic flare: combine direct-acting antivirals with immunosuppression and consider plasma exchange 3

Nephrotic Syndrome with Progressive Decline

For membranous nephropathy with persistent proteinuria >4 g/day or ≥30% creatinine increase:

• Modified Ponticelli protocol (first-line): Alternate monthly cycles of IV methylprednisolone 1 g/day × 3 days followed by oral prednisone 0.5 mg/kg/day × 27 days, alternating with oral cyclophosphamide 2.5 mg/kg/day (adjusted for renal function) 4
• This reduces death/ESRD risk (RR 0.44) and increases remission rates (RR 1.46) 4
• Alternative: Calcineurin inhibitors (cyclosporine or tacrolimus) if cyclophosphamide contraindicated 4

For idiopathic immune complex GN with nephrotic syndrome and normal/near-normal creatinine:

• Trial of glucocorticoids as initial immunosuppression 1
• Consider mycophenolate mofetil, rituximab, or cyclophosphamide if glucocorticoid contraindicated or inadequate response 1
• Avoid long-term calcineurin inhibitors due to risk of immune complex-negative angiopathy 1

Active Nephritic Syndrome Without Crescents

For idiopathic immune complex GN with abnormal kidney function, active sediment, with/without nephrotic proteinuria:

• Add glucocorticoids and immunosuppressive therapy to supportive care 1
• Treat underlying infection first if identified as causative; add immunosuppression only if disease progresses despite infection control 1

Indolent Disease

For stable kidney function with non-nephrotic proteinuria:

• Supportive care with RAS inhibition alone is sufficient 1, 3
• No immunosuppression indicated 3

Critical Thresholds for Withholding Immunosuppression

Do NOT use immunosuppression if:

• eGFR <30 mL/min/1.73 m² with chronic changes (high interstitial fibrosis/tubular atrophy, glomerular sclerosis) on biopsy 1, 2
• Exception: Still treat if active necrotizing/crescentic GN, preserved parenchyma with acute tubular necrosis, or no significant fibrosis 1, 2

Common Pitfalls to Avoid

• Do not delay treatment while waiting for biopsy if clinical presentation compatible with small-vessel vasculitis and ANCA-positive 2
• Do not change immunosuppression based on ANCA titer changes alone 1
• Do not use etanercept as adjunctive therapy in ANCA vasculitis (ineffective) 1
• Do not delay transplantation for ANCA patients in complete remission who remain ANCA-positive 1
• Screen for Strongyloides in patients from endemic areas before immunosuppression if eosinophilia or elevated IgE present 1

Monitoring Treatment Response

• Complete remission: Proteinuria <0.3 g/day with stable renal function 4
• Partial remission: Proteinuria <3.5 g/day with ≥50% reduction from baseline and stable/improved renal function 4
• Surrogate endpoint: ≥40% decline in eGFR over 2-3 years predicts kidney failure 1
• Monitor anti-PLA2R antibodies in membranous nephropathy as they predict treatment response 4