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 GBM Nephrin RBC EN EPI

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, O 2 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. 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