What is the recommended management of rapidly progressive renal failure, including anti‑GBM disease, ANCA‑associated vasculitis, immune‑complex glomerulonephritis, infection‑related cases, drug‑induced acute interstitial nephritis, and thrombotic microangiopathy?

Management of Rapidly Progressive Renal Failure by Etiology

Initial Diagnostic Workup (All Types)

Before initiating any immunosuppression, obtain urinalysis with microscopy for glomerular hematuria and RBC casts, autoimmune serologies (ANCA, anti-GBM, ANA, anti-dsDNA, complement), hepatitis B/C screening, and kidney biopsy when feasible. 1, 2

• Urine dipstick positive for protein and blood with sediment showing dysmorphic RBCs, RBC casts, and/or pyuria without infection confirms glomerular disease 1, 2
• Draw all serologies before starting immunosuppression to avoid false-negative results 2, 3
• Exclude prerenal azotemia, acute tubular necrosis from nephrotoxins (NSAIDs, aminoglycosides, contrast), and urinary obstruction via renal ultrasound 2
• Do not delay treatment while awaiting biopsy if MPO/PR3-ANCA is positive with compatible vasculitis presentation, or if anti-GBM disease with pulmonary-renal syndrome is suspected 1, 4

---

ANCA-Associated Vasculitis (Most Common Cause, 50-60% of RPRF)

Initiate IV methylprednisolone 500-1000 mg daily for 3 days, then oral prednisone, combined with either rituximab or cyclophosphamide for induction. 1, 2, 3

• Both rituximab and cyclophosphamide are evidence-based first-line options with equivalent efficacy 1
• Cyclophosphamide remains preferred when serum creatinine >4 mg/dL (>354 μmol/L) due to limited rituximab data in severe renal impairment 1
• Limit cumulative cyclophosphamide to ≤25 g to reduce malignancy risk 2, 3
• Recent trials demonstrate safe glucocorticoid dose reduction from traditional high-dose regimens 1, 3
• ~90% of pauci-immune RPGN patients are ANCA-positive (MPO or PR3), though ANCA negativity does not exclude diagnosis 4

---

Anti-GBM Antibody Disease (Goodpasture's Syndrome, ~20% of RPRF)

Use the identical immunosuppressive regimen as ANCA vasculitis (high-dose glucocorticoids plus cyclophosphamide or rituximab) but add urgent therapeutic plasma exchange to rapidly remove pathogenic antibodies. 2, 3

• Plasma exchange is critical in pulmonary-renal syndrome to prevent life-threatening alveolar hemorrhage 2
• All patients require testing for both anti-GBM and ANCA antibodies, as 10-30% have dual positivity with higher relapse risk 5, 6, 7, 8
• Double-positive patients (anti-GBM + ANCA) should be treated as anti-GBM disease with plasma exchange but require long-term monitoring for ANCA-vasculitis relapse 6, 7, 8

---

Immune-Complex Glomerulonephritis with Crescents

IgA Nephropathy with Rapidly Progressive Course

Treat crescentic IgAN (usually >50% crescents) with cyclophosphamide and glucocorticoids using the same protocol as ANCA-associated vasculitis. 1

• True rapidly progressive IgAN requires both extensive crescent formation and concomitant rapid GFR decline; crescents alone without GFR deterioration do not constitute RPGN 1, 4
• AKI from severe visible hematuria requires only supportive care; consider repeat biopsy if no improvement within 2 weeks after hematuria cessation 1

Lupus Nephritis with Rapid Progression

Administer IV methylprednisolone pulses followed by oral prednisone combined with cyclophosphamide or rituximab for induction. 2, 3

• Monitor anti-dsDNA antibody titers serially as they correlate with disease activity 2, 3
• Assess serum creatinine, proteinuria, urinary sediment, albumin, and complement levels at baseline and regularly during treatment 3

Hepatitis C-Associated Cryoglobulinemic Vasculitis

Prioritize direct-acting antiviral therapy combined with immunosuppression (glucocorticoids ± cyclophosphamide/rituximab), adding plasma exchange for severe renal involvement. 2, 4, 3

---

Multiple Myeloma-Associated Rapid Renal Failure

Combine plasma exchange with corticosteroids and maintain aggressive IV saline hydration to achieve urine output >3 L/day. 2

• Early plasma exchange markedly reduces dialysis requirement 2
• Kidney biopsy is unnecessary and carries high bleeding risk in suspected myeloma 2
• Avoid all nephrotoxic drugs and iodinated contrast unless adequate hydration is ensured 2
• Aggressive hydration is especially critical with Bence-Jones proteinuria or hypercalcemia 2

---

Drug-Induced Acute Interstitial Nephritis

Discontinue the offending agent immediately; consider glucocorticoids if no improvement after 5-7 days or if severe renal impairment persists. 2, 9

• Common culprits include NSAIDs, proton pump inhibitors, antibiotics (beta-lactams, quinolones), and 5-ASA compounds 2, 9
• Urinalysis typically shows sterile pyuria with white blood cell casts and eosinophiluria 9
• Biopsy shows interstitial inflammation with tubulitis; immunosuppression beyond glucocorticoids is rarely needed 9

---

Thrombotic Microangiopathy (TMA)

Initiate urgent therapeutic plasma exchange for thrombotic thrombocytopenic purpura (TTP); avoid plasma exchange in Shiga toxin-associated hemolytic uremic syndrome (HUS) and use supportive care only. 9

• TTP requires daily plasma exchange until platelet count normalizes and LDH declines; add rituximab for refractory cases or severe ADAMTS13 deficiency 9
• Atypical HUS may respond to eculizumab (C5 inhibitor) when complement dysregulation is documented 1
• Distinguish from ANCA vasculitis and anti-GBM disease via serologies and absence of glomerular hematuria/RBC casts 1, 9

---

Critical Safety Considerations

Actively exclude tuberculosis, hepatitis B, and other opportunistic infections before initiating cyclophosphamide or rituximab. 2, 3

• Obtain baseline hepatitis B surface antigen, hepatitis C antibody, and chest imaging 2, 3
• Withhold aggressive immunosuppression when eGFR <30 mL/min/1.73 m² is accompanied by extensive interstitial fibrosis, tubular atrophy, or glomerular sclerosis on biopsy, unless active necrotizing/crescentic lesions are present 2, 4, 3
• Kidney recovery can occur despite advanced histologic damage; do not withhold induction therapy based solely on unfavorable biopsy findings if active inflammation is present 1

---

Monitoring Treatment Response

Track serum creatinine, proteinuria, and urinary sediment weekly initially, then monthly; stable or falling creatinine defines remission even if hematuria persists. 1, 2, 3

• Persistent hematuria occurs in 50% of patients and does not necessarily indicate active disease if creatinine is stable 1
• Histologic activity is unlikely in the absence of hematuria 1
• For lupus nephritis, monitor anti-dsDNA titers as adjunctive markers of activity 2, 3

---

Management of Refractory Disease

If no adequate response after 3-4 months, switch between mycophenolate and cyclophosphamide, add rituximab, or enroll in clinical trials. 2, 3

• Treatment-resistant disease is defined as persistence or new appearance of vasculitis manifestations while receiving induction-intensity therapy 1
• Consider repeat kidney biopsy to differentiate active inflammation from chronic scarring 1, 2

---

Common Pitfalls to Avoid

• Delaying therapy while awaiting biopsy in ANCA-positive patients leads to irreversible kidney injury 2, 4
• Initiating immunosuppression without infection screening can precipitate life-threatening sepsis 2, 3
• Attributing RPRF to contrast-induced nephropathy is erroneous; <1% of acute renal failure in myeloma is temporally linked to contrast when dehydration is avoided 2
• Excessive glucocorticoid dosing should be avoided; use evidence-based tapering protocols 1, 2, 3
• Aggressive immunosuppression in chronic histology (predominant fibrosis/sclerosis without active inflammation) provides no benefit and increases adverse events 2, 4, 3