KIDNEY LECTURE 2. Glomerular diseases

1. KIDNEY LECTURE 2. Glomerular diseases

2. Glomerular structure • Arterioles • Capillaries • Mesangium (“between capillaries”) • Urinary space surrounds glomerulus within Bowman’s capsule

3. Glomerular structure - Mesangium • Between capillaries • Mesangial cells & matrix • Supporting framework • Cell proliferation, produce matrix • Contractile - directs local capillary blood flow • Phagocytosis • Cytokines - IL-1

4. Flow and filtration in glomerulus • Blood enters by afferent arteriole -> capillary loops and exits by efferent arteriole • From blood in capillaries water & small solutes (<70,000 kD) are freely filtered into urinary space • This early urine -> PCT and to rest of nephron

5. Glomerular capillary filter N.B. most blood in capillaries returns to the circulation • Blood in capillary lumen • Part of endothelial cell with fenestrae (EN) • Glomerular Basement Membrane (GBM) • Epithelial cell foot processes (FP) • Filtration slits, slit diaphragms & nephrin between FP • Urinary space FP EPI GBM Nephrin RBC EN

6. Normal glomerular filtration • Filtration is relatively selective: • Size - water, small solutes < 70,000kD • Charge - GBM region is anionic e.g. GBM heparan sulphate, epithel and endothel cell membrane glycoproteins - thus, cationic molecules are more easily filtered • Nephrin in slit diaphragms helps maintain integrity of filter. Nephrin mutation -> plasma proteins leak through GBM and proteinuria. But many other FP proteins also. • (Protein conformation)

7. Pathogenesis of glomerular disease • Immunologically mediated • A. Immune complex (commonest; antigen often unknown) • B. Anti-GBM (rare) • C. Other immune mechanisms: • Activated T cells • “pauci-immune” • Non-immune - metabolic, vascular, hereditary, other • Glomerular injury caused by • Complement + neutrophils, macrophages, O2 spec, etc • Complement + membrane attack complex (C5-C9) -> lysis • Cytotoxic antibodies, cytokines, O2 species, AA metabs, N Oxide from glomerular or inflammatory cells; fibrin; PDGF, TGFb

8. Immune complexes • Immune complexes are granular deposits (immunofluorescence) • Electron dense deposits* (EM) • GBM or mesangial *

9. Anti-GBM antibodies • Linear fluorescence continuously along GBM • Not seen on EM

10. Two signs of glomerular disease - haematuria & proteinuria • Haematuria • RBCs in urine - microscopic and / or macroscopic • (Normal GBM impermeable to RBCs, and no RBCs in urine) • In certain glomerular diseases, RBCs -> breaks in GBM • (Other causes e.g. bladder, renal carcinoma) • Proteinuria • GBM,epithelial cell injury, (nephrin mutation, altered FP proteins) • Loss of negative charge, loss of foot processes • (Dipstick); 24 hour urine collection

11. Nephrotic syndrome, nephrotic-range proteinuria • Caused by excessive glomerular permeability to protein - no protein in normal urine • Nephrotic syndrome • Proteinuria >3.5gm / 24 hrs • Hypoalbuminemia • Oedema - ankles, peiorbital, etc • Hyperlipidemia (low albumin -> incr liver synthesis of LDL, VLDL, and less breakdown of lipoproteins)

12. Glomerular diseases • Children usually primary - other organs unaffected • Adults - primary or secondary glomerular disease • Diagnosis: combines clinical, serology, and pathology • Renal biopsy • Light microscopy - LM • Immunofluorescence microscopy - FM • Electron microscopy - EM • Types of glomerular disease are descriptive: membranous, minimal change disease, IgA nephropathy

13. IgA nephropathy • Mesangial cell proliferation • IgA immune complex deposits in mesangium, EM deposits

14. IgA nephropathy • Commonest glomerular disease worldwide • Children, young adults M:F = 3:1 • Haematuria 1-2 days after (recurrent) respiratory infection • Proteinuria variable; serum IgA increased • IgA immune complex deposits in mesangium, mesangial cell proliferation • Inability to regulate mucosal IgA synthesis and clearance in response to viral, bacterial or food antigens • Alternate complement pathway - no C1q, C4 • Coeliac dis, dermatitis herpetiformis, liver disease • Chronic course overall - 40% need dialysis, transplant at 10 yrs

15. Minimal Change Disease • Glomeruli normal on LM • EM loss of foot processes

16. Minimal Change Disease • Young children; nephrotic syndrome • Highly selective proteinuria • Normal glomeruli by LM, FM • Loss of foot processes on EM • ? Factor secreted by T cells e.g. IL-8, TNF that reverses GBM anionic charge by inhibiting nephrin synthesis • Nephrin gene mutations in congenital nephrotic syndrome • Responds to steroids, good prognosis

17. Membranous Glomerulonephritis • Commonest primary glomerular cause of proteinuria / nephrotic syndrome in adults; 30-50 yrs • Classic chronic immune complex disease • Thick GBMembrane LM • IC dense deposits and “spikes” on EM • Fluorescent IC deposits on outer GBM

18. Membranous GN

19. Membranous GN • EM deposits outer GBM • Deposits dark, spikes pale • FM Granular GBM deposits IgG; also C’3

20. Membranous GN • Many known antigens • Drugs, SLE, tumours, hepatitis B, but usually idiopathic • Immune complexes deposited on GBM or form in situ to intrinsic antigen • C5 -C9 Membrane attack complex -> O2 species -> mesangial and endothelial cells, inhibiting nephrin synthesis • Chronic renal failure and dialysis in 40% at 20 yrs; also spontaneous remissions in 10-30%. • Rx is controversial