KIDNEY LECTURE 2. Glomerular diseases

Glomerular structure

• Arterioles• Capillaries• Mesangium (“between

capillaries”)• Urinary space

surrounds glomerulus within Bowman’s capsule

Glomerular structure - Mesangium

• Between capillaries• Mesangial cells & matrix• Supporting framework• Cell proliferation, produce

matrix• Contractile - directs local

capillary blood flow• Phagocytosis• Cytokines - IL-1

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

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

RBCEN

EPI

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)

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

Immune complexes

• Immune complexes are granular deposits (immunofluorescence)

• Electron dense deposits* (EM)

• GBM or mesangial*

Anti-GBM antibodies

• Linear fluorescence continuously along GBM

• Not seen on EM

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

Nephrotic syndrome, nephrotic-range proteinuria

Caused by excessive glomerular permeability to protein - no protein in normal urine

Nephrotic syndromeProteinuria >3.5gm / 24 hrsHypoalbuminemiaOedema - ankles, peiorbital, etcHyperlipidemia (low albumin -> incr liver synthesis of LDL, VLDL, and less breakdown of lipoproteins)

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

IgA nephropathy• Mesangial cell

proliferation• IgA immune complex

deposits in mesangium, EM deposits

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

Minimal Change Disease

• Glomeruli normal on LM

• EM loss of foot processes

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

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

Membranous GN

Membranous GN

• EM deposits outer GBM– Deposits dark, spikes pale

• FM Granular GBM deposits IgG; also C’3

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