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