1. Nephrotic & Nephritic Syndromes By:Dawit Ayele MD,Internist

2. objectives Understand the difference between nephrotic and nephritic syndrome Understand the biology of the glomerular filtration barrier Differentiate primary from secondary nephrotic syndromes Approach to management of nephrotic syndromes

3. WHAT MAKES THESE DISORDERS DIFFERENT?

4. Normal glomerular BM  Arteriolar lumen contains- Albumin –negatively charged,small Immunoglobulins - positively charged,large *Endothelial fenestrae – Negatively charged *Basement membrane – Negatively charged *podocyte- - -Bowman’s space- - - -

5. How do we make a diagnosis? Clinically, at the bed side? Investigations?

6. Nephrotic syndrome Proteinuria > 3g/day (adult) Proteinuria >40mg/h/m2 (child) Hypoalbuminemia Edema Hyperlipidemia Lipiduria

7. Nephrotic syndrome Diagnose type by renal biopsy Histologic hallmark of proteinuric states – simplification/ effacement of visceral podocyte foot processes Classically non-inflammatory Lack of inflammation is consistent with: – Absence of “active” urine (casts and cells) – Creatinine may not be very elevated

8. Proteinuria Depends on charge and size of molecules Small negatively charged molecules e.g.. albumin are repelled by negatively charged capillary wall Loss of charge but no overt structural injury can cause→ albuminuria (minimal change disease) Immunoglobulins are positively charged but too big to get through unless structural injury

9. Urine Protein A normal person has 7200g (180Lx 40g/L albumin) pass through the glomerulus every day (not filtered) Normal excretion of < 20mg/day = fractional excretion of 0.00028%!!!!!!!!!!!!!!!!!!!!!!!!! Even a nephrotic patient excreting 3g a day = 0.42%

10. Diagnosing Proteinuria Dipstick positive: – Likely > 150 – 300 mg/24h – Measure protein: creatinine ratio (PCR)  24h Urine Protein ≈PCR Dipstick negative: – Cannot exclude proteinuria, especially in DM and HT – Send albumin : creatinine ratio (ACR) if available (expensive)

11. Categories of nephrotic syndrome Primary renal: – Minimal change disease – Focal Segmental Glomerulosclerosis – Membranous Secondary – Diabetes – Amyloid – HIV – Drug associated: NSAIDS, gold, pamidronate – Etc…

12. Diagnoses made clinically and on biopsy

13. Age prevalences of nephrotic syndromes

14. Minimal change disease (MCD) 90% of nephrotic syndrome in children 20% of nephrotic syndrome in adults May not need biopsy Trial of steroids is part of diagnosis May be beginning of spectrum ranging to FSGS especially in black children Secondary forms may be associated with allergies, drugs (NSAIDS!!!), hematologic malignancies, viral infections

15. Minimal Change Disease Light microscopy normal Normal immunostaining Electron microscopy shows fusion of podocyte foot processes There is loss of negative charge

16. Specific treatment of 1° MCD 90% respond to steroids with 4-6 weeks – Taper over 6 weeks – Proteinuria resolves before albumin improves Implies not only decreased oncotic pressure driving edema… 25 % long term remission 25-30% infrequent relapses 20% chronically relapse – steroid dependent 5% don’t respond – steroid resistant

17. Membranous Nephropathy Most common cause of 1°nephrotic syndrome in adults (25%) Peak incidence in 4-5th decade (adult: child 26:1) 2-3:1 male predominance at ESRD Affects all races Differences in secondary causes may cause geographic differences in presentation

18. Membranous Thickening of capillary wall with “spikes” Positive immunoflourescence EM shows subepithelial deposits within newly laid basement membrane  Immune complexes are far from blood side – don’t incite inflammation

19. Clinical features Usually presents as nephrotic syndrome but 10- 20% have < 2g/d proteinuria HT from 13-55% Most have slightly decreased renal function Usually progresses slowly → must investigate abrupt change in renal function – Crescents 1/3 have anti GBM, some have ANCA – Renal vein thrombosis (4-52%) – Drug-induced injury: NSAIDS, diuretics, antibiotics

20. Clinical features Microscopic haematuria in 30-50% Impaired renal function at presentation <10% C3 and C4 typically normal Hyperfibrinogenaemia and decreased antithrombin 3 – Renal vein thrombosis in 5-63% – Deep vein thromboses 9-44% – Consider anticoagulation if albumin < 20g/L

21. Causes of Membranous Nephropathy 1° Idiopathic 2° Malignancy (colon, lung, gastrointestinal) Autoimmune diseases: SLE, rheumatoid arthritis, autoimmune thryroiditis Drugs: penicillamine, gold Infections: Hep B virus, Syphilis (congenital and secondary), Hep C, Hepatosplenic schistosomiasis Chronic transplant rejection Rarely sarcoid, captopril Other Glomerulonephritides

22. Treatment of membranous Determine whether idiopathic or 2° Decision should be based on an understanding of natural history: – Spontaneous remission in 5-30% – Partial remission (Proteinuria<2g/d) in 25-40% – Relapse rate 30-50% but only 5% → ESRD – Renal survival: 86% at 5 years 65% at 10 years

23. Treatment of membranous If poor prognositic factors or progressing – Hypertension – Male – Elevated creatinine Steroids  chlorambucil or other immunosuppression, ? Rituximab, ? mycophenolate

24. Nonimmunologic therapy of all nephrotic syndromes Treatment of hypertension esp. ACEI, ARB – Target < 120/75 Treatment of hypercholesterolemia – Target LDL < 2.0 Low sodium diet Calcium and vit D to reduce bone loss if steroid therapy is prolonged Bactrim for PCP prophyllaxis if steroids INH for TB prophyllaxis if immunosuppressed Anticoagulate if high risk Treat underlying cause if secondary

25. Nephritic syndrome e.g.. Post- infectious(streptococcal), lupus, IgA nephropathy Immune complexes and antibodies accumulate in subendothelial space → endothelial injury, recruitment of WBC →inflammation and injury. Serum complement = usually low

26. Nephritic Syndrome Hematuria – dysmorphic red blood cells, red blood cell casts Azotemia Oliguria Hypertension Variable proteinuria (usually < 3 g/day)

27. NephroticNephritic OnsetSlowe rRa p id Edema+ + a l l o v e r ++ BPNorma l/ lowi n c r e a s e d JVPNorma l/ lowi n c r e a s e d P r o t e i n u r i a> 3 g / d a y< 3 g / d a y H e m a t u r i aMay o c c u r+++ U r i n e s edimentHya l i n e c a s t s, l i p i d droplets R b c, wb c, r b c c a s t s, gr a n u l a r c a s t s Albumin↓ ↓ ↓No rma l /mi l d ↓ Cre a t i n i n eNorma l / i n c r e a s e dUs u a l l y i n c r e a s e d Ser u m sodiumMa y b e ↓ ↓Ma y b e ≈ ↓

28. Work up summary History and physical exam – Including meds!!! Quantitate urine protein Electrolytes, creatinine, albumin, lipids Urine dipstick + microscopy If necessary: – C3, C4, SPEP, UPEP, Hep B, ANA, DS DNA, LFTs, echo etc… Renal ultrasound ? biopsy

29. Thanks