Glomerular disease pathophysiology Flashcards
Filtration unit
- basement membrane
- podocyte foot process -joined by tight junctions allow passage of molecules up to 4 nm
Charge on capillary wall
Net negative charge because albumin
Charge on podocytes
Negative charge -repels albumin
Mesangial cells + role
Capillaries supported by mesangium jellow like substance, contractlie cell
Help regulate flow of blood through glomerular capillaries (fine changes in bp/flow)
Size of capillary pore
4 nanometers
What happens if glomeruli are injured - clinically?
1) Proteinuria
2) Hematuria
3) Decreased GFR
Creatinine
Created by muscle metabolism. Filtered out of blood by glomeruli (none reabsorbed)
Categories mechanisms of glomerular disease
1) Immune mechanisms
2) Hemodynamic
3) Podocyte injury
4) POlyanion loss
5) Metabolic/genetic
Types of immune mechanisms
1) Antibody- mediated (IC, AGBM)
2) Cell-mediated
Hemodynamic mechanism of glomerular disease
1) Hyperperfusion/hyperfiltration
2) Ischemic
Types of metabolic/genetic
1) Familial
2) Acquired
Immune complex mediated glomerular disease -origin of complexes (2)
- may be circulating and deposit in glomeruli
- may form in glomeruli
How can identify immune complexes in the glomeruli
- fluorescence?? (around 20 min)
- get lumpy/bumpt
How can identify immune complexes in glomeruli formed by circulating Ab complexes
- circulating antibodies stick to antigen in collagen IV
- when do direct immunofluorscence get linear/smooth stain outlining capillary walls of glomerulus
Antibody-mediated mechanism??
1) Subendothelial/mesangial deposits
2) i) C’ activation -C5a
ii) Cell activation chemokines, adhesion
3) Both cause increase inflamatory cell migration to glomeruli (MO, PMN, T Cells)
4) Cytokines, procoagulan, growth factors, ROS proteolytic enzymes
Cytokines = leukocyte recruitment Procoagulant = fibrin Growth factors (PDGF, TGF)= cell proliferation increased EDC
What happens if immune complexes form on epithelial side of basement membrane
1) Subepithelial deposits
2) C’ activation
3) MAC (C5-9)
4) Podocyte injury (get proteinuria but no proliferation so glomerulus look normal –> only through fluorescence can detect immune complexes)
Hemodynamic moa of glomerula
- increased perfusion
- increased glomerular pressure
- glomeruli enlarged –> stretching leading to podocyte injury
- low perfusion through glomeruli
- glomeruli become ischemically contracted –> leading to podocyte injury
Podocyte injury - mechanisms
1) mechanically injured
- i.e. stretch
2) by infection
- HIV
- Paro virus
3) Chemical injury
- drugs (clamitrin A –> for bones??)
4) Metabolic injury
- familial
- acquired
MOA minimal change disease
-capillary charge lost
Familial metabolic injury
- deficiency in enzyme responsible for metaablism of complex lipids –> build up in podocyte and cause injury
- another deficiency that leads to build up of cysteine
Acquired metabolic injury
Complication high blood sugar in diabetes = glomerulo sclerosis
- get glycosylation of tissues that leads to advanced glycosylation end products
- have receptors in mesangial cells for these and stimulates meangial cell to reduce matrix + end products stick to structual proteins in glomerular basement membrane/proteins in mesangium and makes resistant to catabolism
- normally constant turnover of mesangium basement membrane - when glycosylation end product stick reduce catabolism= increase matrix and thickening of basement membranes
