No - Not All Nephritic Diseases with AKI Qualify as RPGN

Definition of RPGN - The Key Criteria

"A clinical syndrome characterized by a rapid loss of kidney function, often accompanied by oliguria or anuria and features of glomerulonephritis, including dysmorphic erythrocyturia, erythrocyte cylindruria (RBC casts), and glomerular proteinuria."

Why Not All Nephritic AKI = RPGN

"The term rapidly progressive GN is therefore often used to describe acute deterioration in kidney function in association with crescentic nephritis. Unfortunately, not all patients with a nephritic urine sediment and AKI will fit this syndrome. For example, AKI may also occur in milder glomerular disease if it is complicated by:

• Accelerated hypertension
• Renal vein thrombosis
• Acute tubular necrosis (superimposed)

This emphasizes the need to obtain histologic confirmation of the clinical diagnosis."

"Kidney diseases other than crescentic glomerulonephritis can cause the signs and symptoms of RPGN. Two examples are acute thrombotic microangiopathy and atheroembolic kidney disease. Although acute tubular necrosis and acute tubulointerstitial nephritis may cause rapid loss of kidney function and oliguria, these processes typically do not cause dysmorphic erythrocyturia, RBC casts, or substantial proteinuria."

The Critical Distinguishing Feature: Crescents on Biopsy

"RPGN is characterized by the presence of crescents in most of the glomeruli - hence the name crescentic glomerulonephritis... The onset of RPGN resembles other causes of nephritic syndrome, but oliguria and azotemia are more pronounced."

"A clinicopathologic syndrome defined by the rapid loss of kidney function over days to weeks in the context of nephritic syndrome."

Conditions That Cause RPGN (The Three Immunopathologic Types)

Practical Summary: How to Distinguish

Nephritic Syndrome + AKI
        |
        ├─ Gradual (weeks to months) → Chronic GN with AKI, NOT RPGN
        |
        ├─ AKI secondary to complication (hypertension, RVT, ATN) → NOT RPGN
        |
        └─ Rapid decline (days to weeks) + Marked oliguria/azotemia
                 |
                 └─ BIOPSY showing crescents in majority of glomeruli
                          |
                          └─ TRUE RPGN (= Crescentic GN)

1. Tempo matters - the loss must be over days to weeks, not months
2. Severity matters - oliguria and azotemia must be pronounced, not mild
3. Biopsy is mandatory - crescentic GN must be confirmed histologically; AKI from hypertension, ATN, or renal vein thrombosis complicating milder GN does not qualify
4. A small minority of all GN patients develop RPGN (Brenner & Rector estimates ~7 cases/million/year), except in anti-GBM and ANCA disease where crescents are frequent
5. Poststreptococcal GN - a common nephritic disease - typically does NOT cause RPGN; it is usually self-limiting, and AKI in that context is generally milder and reversible

• Brenner and Rector's The Kidney, 2-Volume Set, Chapter 31 (Crescentic and Rapidly Progressive GN)
• Comprehensive Clinical Nephrology, 7th Edition, Chapter 16-17
• Robbins Pathologic Basis of Disease and Robbins Basic Pathology, Glomerular Diseases chapter
• NKF Primer on Kidney Diseases, 8th Edition, Chapter on RPGN

Recent Guidelines on RPGN: Diagnosis and Treatment (2022-2025)

KEY GUIDELINE SOURCES

DIAGNOSIS

• KDIGO 2021 and KDIGO 2025 both state: biopsy is required for any patient with RPGN, proteinuria >1 g/day, or impaired kidney function
• KDOQI (2026 commentary on KDIGO 2024) explicitly states: start immunosuppression without delay in rapidly progressive disease even while awaiting biopsy results - the urgency of disease control overrides the wait
• Serologic workup must run in parallel with biopsy:

• Note: "double-positive" serology (both ANCA and anti-GBM positive) occurs in ~30% of anti-GBM cases - maintenance therapy in this case follows ANCA vasculitis protocols (CARI/KDIGO 2021)

TREATMENT BY TYPE

TYPE III - Pauci-Immune / ANCA-Associated (Most Common in Adults)

• Glucocorticoids + Rituximab (RTX) OR Cyclophosphamide (CYC) - both are first-line for organ/life-threatening disease
  • Rituximab is now preferred in many settings, especially PR3-ANCA, relapsing disease, and post-RTX induction
  • Cyclophosphamide preferred in severe kidney involvement or when RTX is contraindicated
• Glucocorticoid dose reduction is a major theme in KDIGO 2024: the PEXIVAS trial established a reduced-dose GC regimen (vs standard high-dose) that is now the standard, with similar efficacy but lower infection rates
• Avacopan (C5a receptor blocker): KDIGO 2024 includes avacopan as an alternative to standard GC in GPA/MPA - the ADVOCATE trial showed avacopan + RTX/CYC achieves superior sustained remission at 1 year and is nephroprotective (significantly improves eGFR, especially in those with worse baseline function). This represents a major shift from steroid-heavy regimens
  • EULAR 2022: "Avacopan may be considered as part of a strategy to reduce GC exposure in GPA or MPA"
• Start therapy without delay, even before biopsy results, if RPGN is suspected clinically (KDOQI 2026 emphasis)

• No longer routine - the PEXIVAS trial (n=704) showed no benefit on composite endpoint of ESKD or death
• However, KDIGO 2024 retains a conditional recommendation for PLEX based on meta-analysis data in:
  • Creatinine >300 µmol/L (3.4 mg/dL)
  • Patients on dialysis at presentation
  • Rapidly rising creatinine
  • Hypoxemic patients with diffuse alveolar hemorrhage (DAH)
  • Risk: increased severe infection - must weigh benefit vs harm

• Rituximab is preferred over azathioprine for maintenance, especially in PR3-ANCA and relapsing disease (KDIGO 2024, EULAR 2022)
• Azathioprine or methotrexate remain alternatives
• Duration: typically 18-24+ months; individualized based on relapse risk
• ANCA subtype guides choice: PR3-ANCA has higher relapse risk than MPO-ANCA

TYPE I - Anti-GBM Disease / Goodpasture Syndrome

• Key prognostic indicators: degree of crescents on biopsy + presence of oliguria
• Creatinine at presentation predicts renal recovery (>5.7 mg/dL or dialysis-dependent at presentation = very poor renal recovery)

• Plasmapheresis (PLEX) + high-dose glucocorticoids + cyclophosphamide - standard triple therapy
• PLEX is a strong recommendation here (unlike in ANCA), as it removes circulating anti-GBM antibodies
• Exception: patients with 100% crescents, advanced renal failure, AND no pulmonary hemorrhage - immunosuppression may be withheld as renal recovery is unlikely; dialysis support instead
• For double-positive (anti-GBM + ANCA) patients: maintenance therapy follows ANCA vasculitis protocol

TYPE II - Immune Complex-Mediated RPGN

• KDIGO 2025 (September 2025): For rapidly progressive IgAN - treat with cyclophosphamide + systemic glucocorticoids following the KDIGO 2024 ANCA-AAV protocol
• Kidney biopsy mandatory; exclude ANCA-associated vasculitis and anti-GBM disease first
• Insufficient evidence for rituximab in rapidly progressive IgAN (KDIGO 2025 explicitly states this)
• For IgAV (HSP) with RPGN: PLEX evidence is insufficient; immunosuppression as per ANCA-AAV protocol

• Crescentic lupus (Class III/IV with crescents): high-dose corticosteroids + mycophenolate mofetil (MMF) or low-dose CYC (Euro-Lupus regimen)
• Belimumab or voclosporin may be added per KDIGO 2024

• CARI/KDIGO 2021: High-dose corticosteroids + cyclophosphamide for crescentic/RPGN presentation
• Treat underlying infection; GN is often self-limiting in postinfectious GN, but with crescents, aggressive immunosuppression is warranted

SUMMARY TABLE

KEY TRIALS INFORMING CURRENT GUIDELINES

• PEXIVAS (2020): Reduced-dose GC is non-inferior; PLEX showed no benefit on ESKD/death - PMID 32053298
• ADVOCATE (2021): Avacopan non-inferior at 26 weeks, superior sustained remission at 52 weeks; nephroprotective - underpins KDIGO 2024 avacopan recommendation
• RITUXVAS / RAVE trials: Established RTX equivalence/superiority to CYC for induction
• EULAR 2022 AAV Recommendations (Hellmich B et al., Ann Rheum Dis 2024, PMID 36927642) - 4 overarching principles, 17 recommendations; strongly endorses GC-sparing strategies
• KDIGO 2024 ANCA-AAV Guideline published in Kidney International 2024 (105:3s, S71-S116)
• KDIGO 2025 IgAN/IgAV Guideline published September 2025, Kidney International