kidney lecture 2. glomerular diseases. glomerular structure arterioles capillaries mesangium...
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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*
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
• 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
• 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
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