KIDNEY LECTURE 2. Glomerular diseases

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KIDNEY LECTURE 2. Glomerular diseases
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Glomerular structure

• Arterioles
• Capillaries
• Mesangium (between capillaries)
• Urinary space surrounds glomerulus within
  Bowmans capsule

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Glomerular structure - Mesangium

• Between capillaries
• Mesangial cells matrix
• Supporting framework
• Cell proliferation, produce matrix
• Contractile - directs local capillary blood flow
• Phagocytosis
• Cytokines - IL-1

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Flow and filtration in glomerulus

• Blood enters by afferent arteriole -gt capillary
  loops and exits by efferent arteriole
• From blood in capillaries water small solutes
  (lt70,000 kD) are freely filtered into urinary
  space
• This early urine -gt PCT and to rest of nephron

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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
EPI
GBM
Nephrin
RBC
EN
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Normal glomerular filtration

• Filtration is relatively selective
• Size - water, small solutes lt 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 -gt plasma
  proteins leak through GBM and proteinuria. But
  many other FP proteins also.
• (Protein conformation)

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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) -gt
  lysis
• Cytotoxic antibodies, cytokines, O2 species, AA
  metabs, N Oxide from glomerular or inflammatory
  cells fibrin PDGF, TGFb

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Immune complexes

• Immune complexes are granular deposits
  (immunofluorescence)
• Electron dense deposits (EM)
• GBM or mesangial

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Anti-GBM antibodies

• Linear fluorescence continuously along GBM
• Not seen on EM

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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 -gt 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

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Nephrotic syndrome, nephrotic-range proteinuria
Caused by excessive glomerular permeability to
protein - no protein in normal urine Nephrotic
syndrome Proteinuria gt3.5gm / 24
hrs Hypoalbuminemia Oedema - ankles, peiorbital,
etc Hyperlipidemia (low albumin -gt incr liver
synthesis of LDL, VLDL, and less breakdown of
lipoproteins)
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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

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IgA nephropathy

• Mesangial cell proliferation
• IgA immune complex deposits in mesangium, EM
  deposits

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IgA nephropathy

• Commonest glomerular disease worldwide
• Children, young adults MF 31
• 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

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Minimal Change Disease

• Glomeruli normal on LM
• EM loss of foot processes

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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

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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

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Membranous GN
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Membranous GN

• EM deposits outer GBM
• Deposits dark, spikes pale
• FM Granular GBM deposits IgG also C3

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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 -gt O2 species -gt
  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