Pathophysiology of Glomerulonephritis Raj Maganti Anatomic Pathology Resident March 29, 2012.

Pathophysiology of Glomerulonephritis

Raj MagantiAnatomic Pathology Resident

March 29, 2012

Glomerular diseases Glomerulonephritis - Immune mediated/Infectious/Chemical induced

Clinically manifest as nephrotic syndrome

– Proteinuria (lose more than 3.5 g protein/day)

– Hypoalbuminemia and generalized edema

– Hypercholesterolemia and hyperlipoproteinemia: compensatory hepatic change to restore colloid osmotic pressure

Glomerulopathy

– lacks the cellular inflammatory component.

– Similar clinical manifestations

Glomerulitis: Bacterial (embolic) and viral

Glomerular Amyloidosis

Glomerular Vasculopathy

Glomerular Lipidosis: incidental in dogs; inherited hyperlipoproteinemia

in cats

Anatomy of the Glomerulus

Mesangial Cells

Glomerular Capillary Lumina

Urinary Space

Parietal Epithelial Cells

(Bowman’s Capsule)

2 types of mesangial cells Myofibroblastic type: structural & contractile Phagocytic/inflammatory type

Mesangial cells

Podocytes & filtration slit

Podocytes & filtration slit

Composed of proteins such as Nephrin, CD2- associated protein and podocin

In humans, mutations in the genes that encode these diaphragm proteins give rise to nephrotic syndrome.

Type IV Collagen

Laminin(glycoprotein)

Heparin Sulfate(negative-charged polyanion)

Lamina rara externa

Lamina densa

Lamina rara interna

capillary lumen

Podocyte foot processes

Endothelial cell

urinary space

Glomerular Basement Membrane (GBM)

Glomerular and Epithelial Cell Injury

Antibodies to epithelial cell antigens, with subsequent toxins, cytokines, or other factors causing injury and detachment of epithelial cells, resulting in protein leakage

Mediators of Glomerular injury

Combination of immune complex with C3 results in solubilization and subsequent removal of the immune complex. Finnish-Landrace lambs: inherited C3 deficiency - severe glomerular disease

Excess antigens stimulate complement fixation. Leukocyte-dependent:Complement fragments (C3a, C5a, C567) - chemotactic for neutrophils.

Leukocyte-independent:C5b-9- terminal membrane attack complex of complement

Stimulate mesangial cells and glomerular epithelial cells to produce chemical mediators (proteases, oxidants, IL-1, PG).

Additional membrane damage through neutrophil release of proteinases, arachidonic metabolites (e.g. thromboxane), and oxidants (esp oxygen derived free radicals and H2O2).

Mediators of Glomerular injury

Neutrophils Infiltrate glomerulus due to immune complex activation & complement

Release C5a and Fc-mediated immune adherance

Release lysosomal enzymes: collagenases, elastases, chymotrypsin like protease, arachidonic acid metabolites, oxygen derived free rads, vasodilator peptides and chemotactic substances for macrophages

Activated macrophages Infiltrate glomerulus due to immune complex activation & complement &

chemotatic substances produced by neutrophils

Release proteases, complement components, chemotactic factors for neutrophils, reactive oxygen metabolites, IL-1, and platelet activating factor.

Monocytes produce a procoagulant factor that activates the extrinsic coagulation pathway.

Mediators of Glomerular injury

Platelets Platelets release arachidonic acid metabolites and growth factors

Interaction of platelets with complement fragments and/or damaged endothelial cells can initiate coagulation, thrombosis, and fibrinolysis.

Antiplatelet agents have beneficial effects in both human and experimental glomerulonephritis

Fibrinogen Leak into Bowman's space and in this region are relatively inaccessible to

fibrinolytic mechanisms.

Consequently fibrin in this location may stimulate epithelial cell proliferation and infiltration of macrophages.

Mediators of Glomerular injury

Immune mediated: Ab-Ag complex & Complement

Infectious: Bacteria and Viruses

Chemicals: Chemotherapeutic agents

Types of glomerulonephritis

2 mechanisms in dogs and cats:Preformed circulating Ag-Ab complexes:

Heymann’s model – anti-rat antibodies were harvested from rabbits and injected into rats

Antigen is trapped in glomerular capillary wall and circulating antibodies form complexes with them (FIP, FeLV, Dirofilaria immitis, SLE, neoplasia)

The 3rd mechanism: Formation of anti-GBM Ab Goodpasture’s syndrome (Humans and NHP) Abs against NC1 (Non-Collagen domain 1) of α3 of collagen

type 4

Immune mediated Glomerulonephritis

Lumpy-Bumpy pattern (Preformed complexes/Trapped antigen

Smooth linear pattern (Anti-GBM antibodies)

Immunflorescence microscopy

Sub-endothelial Along GBM Sub-epithelial

Immune complexes deposition

Direct injury to glomerular endothelial and epithelial cells

Altered Renal Blood Flow (e.g. cyclosporin A)

Induction of Immune complex formation and inflammation

Some examples: Puromycin aminonucleosideAdriamycinCyclosporine AHistamine receptor antagonistsd-penicillamine andProcainamide

Chemical Induced Glomerular Injury

Morphology of Glomerulonephritis

Glomerulonephritis Chronic Pyelonephritis

Chronic Renal Failure (Interstitial Fibrosis)

Common types of renal disease: gross appearance

The small, white, round foci in the cortex are enlarged glomeruli

Subacute Glomerulonephritis

Membranous GN: characterized by thickened GBM Most common form of immune-complex GN in cats Predominantly subepithelial deposits Bacterial kidney disease of salmonids: Rainbow trouts with

Renibacterium salmoninarum

Proliferative GN: characterized by hypercellularity Proliferation of mesangial cells + influx of WBCs Budgerigar fledging disease (polyomavirus)

Membranoproliferative GN: Combination of thickened GBM and proliferation of mesangial cells Most common form of immune-complex GN in dogs Predominently subendothelial deposits

Histological patterns of Glomerulonephritis

Types of Membranoproliferative Glomerulonephritis

Type I: Subendothelial deposits

type II: Intramembranous dense deposits (dense deposit disease).

Proliferative GN – Hypercellularity Membranous GN – Thickened GBM

Membranoproliferative GN – Both Features Present Glomerular Sclerosis – End Stage

• Glomerulosclerosis: Fibrosis, hyalinization or scarring of glomeruli resulting in a shrunken, hypocellular and nonfunctional structure.

• Glomerular synechia (synechiae): Adhesion of glomerular tufts to the Bowman's capsule

• Sclerosis/Hyalinization of Bowman’s capsule

• Global GN: Lesion affects the entire glomerulus

• Segmental GN: Lesion involves only a portion of the glomerulus.

Histological changes in Glomerulonephritis

Synechia

(Segmental)

(Global)

Glomerulosclerosis Glomerular hypertrophy -> glomerular hypertension -> injury to

podocyte and endothelial cells -> glomerulosclerosis

Tubulointerstitial fibrosis Injured podocytes cannot proliferate -> gaps in GBM -> proteinuria ->

damaging to tubular epithelium -> tubulointerstitial fibrosis

Additional tubular injury from : Sclerotic glomeruli -> downstream tubular ischemia Close association with glomerular inflammation

Downstream changes of Glomerulonephritis

Embolic (bacterial) Glomerulitis

Hematogenous spread common in neonates and animals with immunosuppression Puppies: Streptococcus sp., E. coli Foals: Actinobacillus equuli Neonatal pigs: Erysipelothrix rhusiopathiae Sheep and Goat: Corynebacterium pseudotuberculosis Calves: Archanobacterium pyogenes; Mannheimia hemolytica

Dogs: Infectious Canine Hepatitis

Horses: Equine Viral Arteritis

Swine: Hog Cholera & Porcine Cytomegalovirus

Avian: Newcastle disease

Direct viral damage to glomerular endothelial cells secondary to viral replication in endothelium

ICH - Intranuclear Viral Inclusions

Viral Glomerulitis

Greyhound: Idiopathic Glomerular & Cutaneous Vasculopathy

The fine white dots in the cortex (both on the capsular and cut surfaces) are glomeruli with extensive glomerular capillary thrombosis.

Necrotic glomerular endothelial cells and glomerular capillary

thrombosis

Renal amyloidosis

Diffusely tan, waxy (firm), and slightly enlarged

Amyloid- Beta-pleated sheet

confirmation Resistant to normal

degradation Serum protein AA most

common (reactive product)

Initial trigger is unknown

Treated w/Lugol’s Iodine followed by dilute sulphuric acid

Glomerular amyloidosis

Congo red

Dog - Glomerular Amyloidosis

Glomerular amyloid most common in dogs and cattle. Deposits in mesangium and subendothelial sites.

Medullary deposits in Shar-peis and cats, especially Abyssinian. Therefore, may not see proteinuria.

“The Abyssinian and Shar-pei got married at the pink amyloid wedding. Medussa attended the wedding.”

Cat – Interstitial Amyloidosis

Renal amyloidosis

• Dogs: Membranoproliferative GNSamoyed hereditary glomerulopathy – X-linked trait; mutation in COL4A5 (α5 of type 4 collagen)Other breeds: Bull Terrier (autosomal dominant); English Cocker Spaniel (autosomal recessive); Bernese Mountain; Dobermann; Norwegian ElkhoundBorrelia; dirofilaria; ICH (adenovirus)

• Cats: Membranous GN; FeLV; FIP; FIV

• Horse: Membranoproliferative GN; Equine infectious anemia; streptococcus equi; Herpes virus infections

• Pig: Membranoproliferative GN ; PCV-2

• Ruminants: Membranoproliferative GN; Finnish Landrace sheep – deficiency of complement component C3 – causes impairedComplement-mediated stabilization of immune complexes

Prevalence of Glomerulonephritis

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