Transcript Kidney-lect-2010-2-Glomer

KIDNEY LECTURE 2010.2
Glomerular diseases
Glomerular structure
• Arterioles
• Capillaries
• Mesangium (“between
capillaries”)
• Urinary space
surrounds glomerulus
within Bowman’s
capsule
Glomerular structure - Mesangium
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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
FP
EPI
GBM
Nephrin
EN
RBC
• Blood in capillary lumen
• Part of endothelial cell with
fenestrae (E N)
• Glomerular Basement
Membrane (GBM)
• Epithelial cell foot processes
(FP)
– Filtration slits, slit diaphragms &
nephrin between FP
• Urinary space
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, TGF b
Immune complexes
• Immune complexes
are granular deposits
(immunofluorescence)
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• 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
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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 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)
Glomerular diseases
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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
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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
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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
IgG
• FM Granular GBM
deposits of 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 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