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Rapidly progressive glomerulonephritis in children
- 1. Rapidly Progressive Glomerulonephritis In Children PRESENTED BY DR. NISHAT TASNIM FCPS PART 2 TRAINEE DEPT. OF PAEDIATRICS CUMILLA MEDICAL COLLEGE HOSPITAL
- 2. Case scenario A 7yr old boy was admitted with worsening generalized edema ,oliguria & hematuria for 4 days. There was no h/o sore throat, skin rash, joint pain or fever in recent past. His family history is non- contributory. On examination his BP was 140/100 mmhg, bedside urine for albumin was 4+. Urine analysis shows plenty of RBCs & RBC casts & few WBC. S. creatinine was 2.1 mg/dl. Two days later, his creatinine had risen to 3.4 mg/dl.
- 3. Introduction Glomerulonephritis is a histopathologic term defining inflammation of glomerular capillaries, characterized by edema, hematuria, oliguria & hypertension. RPGN is an unusual form of acute glomerulonephritis, which progresses to renal failure, in contrast to typical course of rapid resolution. Hence it must be considered a medical emergency.
- 4. Definition RPGN or crescentic glomerulonephritis is a clinico- pathological condition characterized by: Features of glomerulonephritis Rapid deterioration of renal function within a few days to weeks Crescents affecting at least 50% of glomeruli
- 5. Epidemiology True incidence is unknown due to varied definitions and multiple pathologies. Estimation : 7 cases per million in USA. Crescentic GN comprises approx. 5% of unselected renal biopsies in children. No population-based studies in children.
- 6. Etiology Based on histopathology & characteristics of immune deposits on IF staining, divided into 3 major categories: 1. Type I or anti-glomerular basement membrane antibody disease 2. Type II or immune complex mediated glomerulonephritis 3. Type III or pauci-immune crescentic glomerulonephritis
- 7. Type I Linear Ig G deposits in IF 1. Anti-GBM nephritis 2. Goodpasture syndrome 3. Post renal transplantation in Alport’s syndrome
- 8. Type II 1. Post infectious GN: Post streptococcal GN Infective endocarditis Shunt nephritis Visceral abscess Staph aureus sepsis Others: HIV, Hepatitis B & C, TB, Leprosy
- 9. Type II cont. 2. Systemic disorders: SLE nephritis HSP nephritis JIA Dermatomyositis Mixed connective tissue disorder 3. Primary GN: Ig A nephropathy Membrano-proliferative GN C1q nephropathy
- 10. Type III Mostly ANCA + vasculitis: 1. Microscopic polyangitis 2. Granulomatous polyangitis (Wegener’s) 3. Eosinophilic granulomatosis with polyangitis 4. Renal limited vasculitis 5. Idiopathic crescentic glomerulonephritis Medications: Penicillamine, hydralazine, propylthiouracil
- 11. Differentials RPGN-like clinical picture but without crescents: 1. Hemolytic uremic syndrome 2. Acute interstitial nephritis 3. Diffuse proliferative glomerulonephritis
- 12. Pathogenesis Crescent formation- Proliferation of parietal cells & migration of monocytes & macrophage into bowman’s space. Crescents eventually obliterate Bowman’s space & compress glomerular tuft. Fig: Normal glomeruli Fig: Crescent in glomeruli
- 13. Pathogenesis cont. 1. Nonspecific response to glomerular injury causes gaps in GBM by macrophages & T cells, movement of plasma proteins (fibrinogen) & inflammatory cells that release IL1, TNF-a & procoagulant factors into bowman’s space. 2. Proinflamatory cytokines causes epithelial proliferation & cellular crescent formation. 3. Fibroblast growth factor & transforming growth factor beta induce collagen deposition, forming fibrocellular & fibrous crescents.
- 15. Anti-GBM GN Circulating IgG against alpha-3 chain of type IV collagen in GBM &/or alveolar basement membrane. 10-15% of all diffuse cGN but very rare in children. Goodpasture syndrome= RPGN+ Pul hemorrhage+ AntiGBM Ab May also present as ANCA associated dual antibody disease.
- 16. Immune-complex GN Multiple stimuli, such as infection, systemic disease leads to crescent formation. It is the most common cause of cGN, accounting for 50-70% cases. Also the most severe form, particularly in children with IgA nephropathy, HSP & lupus nephritis.
- 17. Pauci-immune GN Few or no immune deposits & generally associated with systemic vasculitis. ANCA associated vasculitis caused by Ab against MPO & proteinase-3, causing destruction of small & medium sized vessels by releasing cytokines & inflammatory mediators.
- 18. Clinical features Most children presents with features of nephritic syndrome- Hematuria: 68-83% Proteinuria: 60-72% Hypertension Renal dysfunction: oliguria & renal failure Features of complications: Hypertensive emergencies, pulmonary edema, cardiac failure.
- 19. Clinical feature cont. Extrarenal involvement: Lungs: Cough, hemoptysis, pulmonary hemorrhage Skin: Vasculitic rash, pyoderma Others: Sore throat, joint pain, sinusitis, neurological manifestation (convulsion, altered consciousness) etc.
- 20. Diagnosis RPGN is a medical emergency requiring rapid dx & aggressive mx to prevent irreversible kidney damage. Definitive diagnosis by obtaining kidney biopsy. Delineation of underlying etiology made by- additional biopsy findings, extrarenal symptoms & signs, serological testing. If the biopsy has no immune or electron microscopic deposits, the diagnosis is idiopathic RPGN.
- 21. Investigations Complete blood counts: mild anemia, neutrophilia, thrombocytosis Urinalysis: microscopic hematuria with red cell casts, WBC, granular casts & variable degree of non selective proteinuria Renal function tests: S. Urea, creatinine, electrolytes Spot urinary PCR: maybe >3
- 22. Investigations cont. Serology: ASO titre, anti DNAaseB, HBsAg, anti HCV Ab Compliments: C3- ↓ in PIGN, LN, normal in Pauci-immune & anti GBM GN C4, CH50 ANA, Anti DsDNA Ab: for lupus nephritis
- 23. Investigations cont. For specific etiology: S. Ig A level Anti GBM Ab ANCA levels by IF & ELISA Radio-imaging: CXR, CT, USG of KUB Genetic study: For idiopathic/primary MPGN, atypical HUS.
- 24. Renal biopsy 1. To confirm etiology 2. To classify by immunofluorescence 3. To assess degree of renal damage 4. To predict reversibility of the damage.
- 25. Anti-GBM GN Immune complex RPGN Pauci-immune GN Light microscopy Focal glomerular capillary vasculitis, to diffuse, exudative & necrotizing GN Diffuse exudative glomerular proliferation (APIGN/LN) Duplication/splitting of glomerular basement membrane (MPGN/C3 GN) Mesangial proliferation (IgAN/HSP) Segmental fibrinoid necrosis, karyorrhexis & crescents Immuno- fluorescence (IF) Linear deposition of IgG along capillary walls C3/IgG (APIGN) C3 deposits (MPGN) Full-house IF (LN) IgA deposits (IgAN/HSP) No or scanty immune deposits Renal biopsy findings in RPGN
- 28. Management Supportive care: Maintaining fluid & nutrition Control of HTN, correction of electrolyte imbalance & anemia Treatment of infection Strict monitoring for complications of AKI, respiratory support & mx of systemic disease Prophylaxis for osteoporosis & gastric protection in long term management.
- 29. Specific Mx Induction phase: To control inflammation & associated immune response. 1. I/V pulses of Methyl prednisolone 10-30 mg/kg/day (maximum 1g/day) for 3-6 days, followed by 2. Oral prednisolone 1.5-2 mg/kg/day for 4-6 weeks, with gradual tapering to 0.5 mg/kg/day by 3 months. 3. I/V Cyclophosphamide 500 mg/m²/dose (maximum 750 mg/m²/dose) every 4 weeks for 3-6 doses, or P/O 2 mg/kg daily for 8-12 weeks.
- 30. Specific Mx cont. Maintenance phase: To prevent further damage & relapses. Initiated when disease remission is achieved, usually at 3-6 months. 1. Oral prednisolone 0.5-1 mg/kg on every alternative day with slow tapering for 12 months, plus 2. Azathioprine 1.5-2 mg/kg/day, or 3. Mycophenolate mofetil 800-1200 mg/m²/day for 12- 24 months
- 31. Specific Mx cont. Antibody mediated or refractory disease: 1. Plasmapheresis: Intensive plasma exchange (10-14 days) in Pauci-immune GN or Anti-GBM disease &/or diffuse pulmonary hemorrhage. 2. Rituximab: 375 mg/m² weekly for 4 weeks if cyclophosphamide is contraindicated, especially in ANCA associated vasculitis. 3. IV Ig, Anti-TNF alpha Ab (infliximab) for failed induction or refractory cases.
- 32. Prognosis Depends on underlying etiology, severity of disease & time of initiation of therapy. With adequate treatment, >50% patients show partial or complete recovery of renal function. RPGN from PIGN: >90% regain normal renal function at short-term f/u with a risk of CKD up to 31%. Worst prognosis: ESKD in IC mediated GN & LN is at 54% & 29% respectively. AAV has high relapse rate.
- 33. Poor prognostic factors RPGN with Nephrotic syndrome AKI requiring dialysis Large number of fibrous crescents in renal biopsy High chronicity index
- 34. Conclusion RPGN, although uncommon in children, is a management challenge & is limited to tertiary centers. Timely referral, diagnosis & urgent treatment is essential for optimal renal outcome. Long term follow up & monitoring for relapses, adverse effects, renal function, hypertension, infection & growth monitoring is recommended.