What is the best treatment approach for a patient with rapid progressive renal failure and a history of kidney disease, hypertension, or autoimmune disorders?

Management of Rapidly Progressive Renal Failure

Immediate Action: Start Immunosuppression Before Biopsy

If clinical presentation suggests rapidly progressive glomerulonephritis (RPGN) with compatible urinalysis findings (glomerular hematuria, red cell casts, proteinuria) and positive or pending ANCA, anti-GBM, or lupus serologies, initiate aggressive immunosuppression immediately without waiting for kidney biopsy confirmation. 1, 2

The only absolute requirement before starting treatment is excluding active infection with as much certainty as possible—this includes screening for hepatitis B (HBsAg and anti-HBc), hepatitis C, and other infections. 1, 2, 3

Diagnostic Workup (Performed Simultaneously with Treatment Initiation)

Essential Immediate Tests

• Urinalysis with microscopy: Look specifically for glomerular hematuria (dysmorphic RBCs), red blood cell casts, and proteinuria 1, 4
• Autoimmune serologies: ANCA (MPO and PR3), anti-GBM antibodies, ANA, complement levels (C3, C4) 1, 4, 5
• Infection screening: Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis C antibodies 2, 3
• Kidney biopsy: Obtain when feasible for diagnosis confirmation and prognosis, but do not delay treatment 1, 2

Initial Immunosuppressive Regimen

Corticosteroids (All Patients)

• Pulse IV methylprednisolone 500-1000 mg daily for 3 consecutive days 2
• Followed by oral prednisone 1 mg/kg/day with gradual taper over at least 6 months 2

Choice Between Cyclophosphamide vs. Rituximab

Cyclophosphamide is preferred when: 1, 2

• Severe kidney dysfunction present (serum creatinine >4 mg/dL or >354 μmol/L)
• For severe cases, consider combination of two IV pulses of cyclophosphamide with rituximab 1

Rituximab is preferred when: 1, 2

• Less severe kidney dysfunction
• Concerns about cyclophosphamide toxicity (fertility preservation, hemorrhagic cystitis risk)
• PR3-ANCA positive disease 1

Critical Caveat on Rituximab

Limited data exist for rituximab induction when serum creatinine >4 mg/dL (>354 μmol/L); cyclophosphamide remains the preferred agent in this setting. 1

When NOT to Treat: Critical Contraindications

Withhold immunosuppression if ALL of the following are present: 2

• eGFR <30 mL/min/1.73 m²
• Kidney biopsy shows extensive chronic changes (high degree of interstitial fibrosis and tubular atrophy, extensive glomerulosclerosis)
• Absence of active necrotizing or crescentic glomerulonephritis on biopsy

However, DO treat even with low eGFR if: 2

• Active necrotizing or crescentic GN is present on biopsy
• Preserved renal parenchyma with acute tubular necrosis (potentially reversible)

This is a critical decision point: eGFR alone should never determine treatment—the biopsy findings of disease activity versus chronicity are paramount. 2

Plasma Exchange: When to Use

Do NOT use plasma exchange routinely for ANCA-associated vasculitis based on the PEXIVAS trial showing no benefit with reduced glucocorticoid dosing. 1, 2

DO use plasma exchange for: 1, 2

• Anti-GBM antibody disease (all patients except those with 100% crescents, >50% global glomerulosclerosis, or dialysis-dependent without pulmonary hemorrhage)
• ANCA vasculitis that overlaps with anti-GBM antibody disease

Disease-Specific Considerations

ANCA-Associated Vasculitis (Most Common Cause)

ANCA-associated vasculitis is the most common cause of rapidly progressive kidney failure. 1, 5 Treatment consists of cyclophosphamide or rituximab plus high-dose corticosteroids as outlined above. 1, 2

Anti-GBM Antibody Disease

Add plasmapheresis to cyclophosphamide and glucocorticoids for all patients except those with 100% crescents, >50% global glomerulosclerosis, or dialysis-dependent without pulmonary hemorrhage. 2 Patients presenting on dialysis have >90% chance of remaining dialysis-dependent, so treatment should be reserved for those with pulmonary hemorrhage or recent dialysis initiation. 2

Lupus Nephritis with RPGN

Treat with high-dose glucocorticoids and cyclophosphamide or rituximab, similar to ANCA-associated vasculitis regimen. 2, 5

Immune Complex-Mediated RPGN (IgA Nephropathy, MPGN)

Treat crescentic presentation with rapidly progressive disease using high-dose glucocorticoids and cyclophosphamide, with rituximab as alternative. 2, 5

Common Pitfalls to Avoid

• Delaying treatment while waiting for biopsy results: The combination of compatible clinical presentation and positive serology is sufficient to begin therapy 2
• Treating patients with advanced chronic kidney disease and extensive fibrosis on biopsy: These patients face only toxicity risk without benefit 2
• Using calcineurin inhibitors (tacrolimus, cyclosporine) for immune complex RPGN: These cause immune complex-negative angiopathy and thrombotic microangiopathy 2
• Assuming all patients with low eGFR should not be treated: Active crescentic disease warrants treatment regardless of eGFR if biopsy shows viable parenchyma 2
• Failing to screen for hepatitis B before immunosuppression: HBV reactivation can result in fulminant hepatitis, hepatic failure, and death in patients treated with rituximab or other immunosuppressants 3

Monitoring During Treatment

Infection Surveillance

Monitor for serious bacterial, fungal, and viral infections (including CMV, HSV, parvovirus B19, VZV, West Nile virus, hepatitis B and C reactivation) during and following rituximab-based therapy. 3 Patients with evidence of current or prior HBV infection require monitoring for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months (up to 24 months) following rituximab therapy. 3

Renal Function

Monitor serum creatinine closely; discontinue rituximab in patients with rising serum creatinine or oliguria. 3

Cardiac Monitoring

Perform cardiac monitoring during and after all infusions for patients who develop clinically significant arrhythmias or who have history of arrhythmia or angina. 3

Supportive Care

While immunosuppression addresses the underlying disease, maintain fluid and electrolyte balance, correct metabolic acidosis, and provide nutritional support. 1 Administer aggressive IV hydration and anti-hyperuricemic therapy in patients at high risk for tumor lysis syndrome (particularly those with high circulating malignant cell counts). 3

Referral and Multidisciplinary Care

Refer immediately to specialist nephrology services for patients with abrupt sustained fall in GFR, consistent finding of significant albuminuria, or urinary red cell casts with RBC >20 per high-power field sustained and not readily explained. 1 Management should occur in a multidisciplinary care setting with access to dietary counseling, education about RRT modalities, and transplant options. 1