KIDNEY LECTURE 2010.2 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. 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 GBM 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

• In children, are usually primary - kidney only• 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

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 disease, 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

• Imm Complex 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 of IgG; also C’3IgG

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 activates mesangial and endothelial

cells -> O2 species -> protein leakage– *NEJMed July 2 2009: Phospholipase A(2) Receptor and PLA(2) R

Autoantibodies in 70% patients with idiopathic MGN – PLA(2) R found in normal podocytes and also in MGN immune

complexes; mostly IgG4 autoantibodies

• Chronic renal failure and dialysis in 40% at 20 yrs; also spontaneous remissions in 10-30%. – Rx is controversial because clinical course so variable