GLOMERULAR DISEASES

GLOMERULAR NEPHRITIS diseases that primarily involve renal glomeruli Types/classification of GN 1. PRIMARY GN (kidney the only affected organ) 2. SECONDARY GN - secondary to systemic diseases as DM, SLE, bilharziasis, amylodoisis) Pathogenesis of GN IMMUNOLOGIC MECHANISM ANTIBODY-mediated injury Antigen-Antibody (immune) complexes - circulating complexes - in situ complexes Cytotoxic antibodies CELL-mediated injury NON-IMMUNOLOGIC MECHANISM

antibodies have direct toxicity, as: - antibodies to visceral epithelial antigen autoantibodies to epithelial antigen loss their foot process & detachment from GBM - anti-endothelial cell antibodies (AECA) autoantibodies against endothelial antigen vasculitis & GN

- NO Ab, NO deposits - sensitized (defective) T-cells produce cytokines cell injury

1. METABOLIC glomerular injury -as in diabetic glomerulosclerosis 2. HEMODYNAMIC glomerular injury - as in systemic hypertension & intraglomerular hypertension (FSGS) 3. glomerular ABLATION - any renal disease (glomerular/non-glomerular) reduces GFR to about 30-50% of the normal lead tp progressive glomerulosclerosis of the remaining glomeruli 4. DEPOSITION disease - as in renal amyloidosis

[ Antigen-antibody (immune) complex ]

-the main cause of primary glomerular injury in >70% of the cases - the antigen is either foreign (extrinsic/exogenous) or, from normal tissue constituent (intrinsic/endogenous) such as DNA - antigen stimulates antibody production leading to formation of immune complexes *immune complexes

Fate of immune deposits: -once immune complexes are deposited, they become degraded by infiltrating monocytes & mesangial cells with subside inflammation * this occurs if exposure to the inciting antigen is short-lived & limited as in acute GN (most cases of post-streptococcal GN) * but if there is repeated exposure of antigen, there are repeated cycles of immune complex formation with continuous progressive glomerular injury

- are formed in the circulation then become trapped and deposited inside the glomeruli (circulating immune complex) -might also form primarily in the glomeruli (in situ immune complex) - immune complexes should be detected by fluorescence microscope (FM) and electron microscope (EM) - 2 forms of injury asscociated with immune complexes = 1. circulating immune complex nephritis (type III hypersensitivity) - non-glomerular(foreign) antigen, may be endogenous or exogenous 2. in-situ immune complex nephritis - antibody reacts directly with : 1. Fixed antigen 2. Planted antigen = foreign antigen = normal glomerular antigen deposited within the glomerulus leading to anti-glomerular leading to in-situ immune basement membrane (anti-GBM) complex nephritis disease

antigen-antibody complexes are formed in the circulation and trapped in the glomeruli they activate complement induce glomerular injury -glomerular injury is may be in the form of : 1. proliferation of endothelial, mesangial and parietal cells 2. leukocytic infiltration anti-glomerular basement membrane (anti-GBM) disease - an autoimmune disease, where antibodies bind along glomerular basement membrane (GBM) collagen - many cases are characterized by: Severe glomerular damage Development of acute renal failure * sometimes GBM-antibodies cross react with basement of the lung alveoli resulting in simultaneous lung & kidney lesion (Goodpasture syndrome) in which hemoptysis will be associated with acute renal failure

in situ immune complex nephritis -antibodies react with previously planted non-glomerular antigens that may localize in the kidney - they interact with various intrinsic glomerular components - planted antigens include cationic molecules that bind to glomerular capillary anionic sites eg : DNA which has affinity to GBM components and bacterial products

Morphologic changes Light microscope 1. Pattern of involvement by the diseases: Diffuse - all the glomeruli are affected Focal - <50% of glomeruli are affected, the others looked normal Global - entire glomerulus is affected Segmental - the lesion involves one segment within the affected glomerulus 2. Absence & presence of disease/types of lesions - Normal glomeruli - Glomerular hypercellularity (proliferative GN), may be due to Increase in mesangial cells Proliferation of parietal cells leading to crescent formation Infiltration of the glomeruli by inflammatory cells (neutrophils) - Thickening of GBM (membranous GN) - Increase glomerular cellularity with thickening of GBM (membrano-proliferative GN) - Glomerular sclerosis - Deposition of foreign material, as in amyloidosis Electron microscope -useful to Detect changes not seen by LM Determine the site of deposition of immune complex - mesangial area - subendothelium site (between endothelial cells & GBM) - subepithelial site (between outer surface of GBM & podocytes) - intramembranous

Factors determining localization of immune complex 1. Size of immune complexes formed - Very large molecules are not nephrogenic because they are cleared by the reticuloendthelial system and do not reach the kidney 2. Molecular charge of these reactants - Highly cationic immunogens tends to cross the GBM and the immune complexes tend to be deposited in the subepithelial location -Highly anionic molecules are excluded from the GBM , either trapped subendothelily or not nephrogenic at all -Molecules with neutral charges tend to be deposited in the mesangium 3. Phagocyte function 4. Hemodynamic factors, mesangial function.

Fluorescent microscope

- Using fluorescin-labelled antibodies against different antibodies and complement component - Useful in determining the pathogenesis of disease (immune complex mediated or not) - Deposits are either: Granular pattern in case of circulating immune complex nephritis & in situ immune complex nephritis against planted antigen Linear pattern only in case of in situ immune complex nephritis against glomerular antigen

Clinical manifestations of GN 1. Acute nephritic syndrome 2. Nephrotic syndrome 3. Asymptomatic hematuria & proteinuria 4. Rapidly progressive glomerulonephritis 5. Acute renal failure 6. Chronic renal failure * Azotemia = elevation of blood urea nitrogen & serum creatinine levels - largely related to decrease in GFR * Uremia = clinically manifested azotemia (azotemia with clinical signs and symptoms) - characterized by failure of renal excretory function metabolic & endocrinal alteration of the host secondary uremic gastroenteritis peripheral neuropathy uremic fibrinous pericarditis

ACUTE NEPHROTIC SYNDROME PATHOGENESIS acute glomerular injury. Lesions have proliferation of endocapillary cellularity(mesangial & endothelial cell) and leukocytic infiltration. -inflammatory reaction injures capillary wall, permit escape of RBC & protein in urine - mesangial cellularity compress capillary lumina induce haemodynamic changes leading to reduced GFR. Manifested by oliguria with fluid retention & azotemia -hypertension result from fluid retention & renin release from ischemic kidney. CAUSES OF NEPHROTIC SYNDROME 1. 1ry glomerular disease -infection: Post-streptococcal GN Non-streptococcal GN (certain pneumococcal & stapylococcal infections, some viral infections as HCV and HBV) 2. 2ry to systemic disease

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS Definition: a clinicopathological syndrome, clinically by rapid & progressive loss of renal function associated with severe oliguria leading to acute renal failure. histologically, by presence of crescents in more than 50% of glomeruli. PATHOGENESIS Injury of capillary wall escape of plasma protein, fibrin, & inflammatory cell to Bowmans capsule. This causes proliferation of parietal cell of glomerular capsule together with infiltration of interstitium by macrophages & interstitial fibroblast cresent formation. Cresents eventually obliterate Bowmans space & compress glomeruli. In some cases, Injury of glomerular capillary wall + injury of pulmonary alveolar basement membrane wall(due to formation of anti-GBM Ab that cross react with alveolar basement membrane) Clinical picture: Pulmonary haemorrhage with haemoptysis and acute renal failure (Goodpasture syndrome) IF: deposits of Ig G/Ig M and complement along capillary wall of kidney and alveoli wall(Linear pattern)

ACUTE NEPHRITIC SYNDROME Clinically, presented as: # Hematuria # Proteinuria # Oliguria & azotemia # Hypertension # Mild edema

NEPHROTIC SYNDROME Clinically: # Heavy proteinuria capillary permeability # Hypoproteinemia 2ry to loss of protein # Generalized edema plasma osmotic pressurecompensatory secretion of aldosteronesalt and water retention # Hyperlipidemia synthesis of lipoprotein # Lipiduria GBM permeability to lipoprotein. Causes: # some are directly targeting the glomeruli(1ry glomerular disease) # some are due to systemic disease that affect glomeruli & other tissue(2ry) Primary glomerular disease: According to morphology, -minimal change disease -focal segmented glomerularsclerosis -membronaous glomerulonephritis -membranoproliferative glomerulonephritis -Ig A nephropathy Secondary systemic cause: -diabetes mellitus -amyloidosis -SLE -infections(HBV, malaria, schistosomiasis) -drugs, maignancies, hereditary

POST STREPTOCOCCAL (ACUTE DIFFUSE PROLIFERATIVE GN) Common disorder among children that follow infection of skin or URT by nephritogenic strain of B-haem. streptococci.

MINIMAL CHANGES

FOCAL SEGMENTED GLOMERULOSCLEROSIS

MEMBRANOUS GLOMERULONEPHRITIS INCIDENCE Most frequent cause of NS among adults in western countries

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

IG A NEPHROPATHY

Main cause of NS among children < 15 years

NS in 15% of adults and children

5-10% of cases of primary NS in children and adults

Most common glomerular disease worldwide Peak: children and young adults

Normal looking glomeruli with LM & diffuse loss of epithelial foot processes by EM.

CHARACTERISTICS HISTOLOGICAL FEATURES Focal & segmental Accumulation of immune obliteration of capillary complexes in loop by deposition of subepithelial zone of collagen(sclerosis)+accu glomerular capillaries. mulation of lipid & proteinaceous material

Glomerular hypercellularity with thickening of GBM.

Deposition of immune complex formed predominantly of Ig A

-immune complex deposited within the glomeruli initiate inflammation by activation of complement system

-might be 1ry epithelial injury(no immune complex deposition) -disorder in Tlymphocytes leading to elaboration of cytokines that affect synthesis of nephrin. Consequently, there is loss of podocyte. In NS, there is neither hypertension nor hematuria

PATHOGENESIS -injury to epithelial cell Immune complex lead to focal mediated disease: hyperpermeable foci -1ry: due to in situ entrapment of plasma deposition of immune protein & lipid complexes against renal -result in mesangial cell autoantigen reaction with mesangial -2ry: due to circulating matrix immune complexes against exogenous antigen

-Type I caused by circulating immune complexes -Type II: autoimmune disease. The patients serum has factor called C3 nephritic factor that activate alternate complement pathway with elaboration of biologically active complement pathway.

-genetic or aquired abnormality of immune regulation leading to mucosal Ig A synthesis in response to resp of GIT exposure to environmental agents. Ig A and Ig A complex then get trapped within mesangium, activate alternate complement pathway & initiate glomerular injury. 1.gross hematuria that occur within 1-2 days of nonspecific URT/GIT infection. Hematuria lasts several days then subsides. Its recurs every few months & associated with loin pain. 2.less 10% with NS Has remitting & relapsing course. Rarely resolves but many patients maintain normal renal functions for decades. 50% slowly progress to chronic renal failure within 20 years.

1.nephritic syndrome 2.low serum complement level 3.high titre of antistreptolysin O(ASO) in serum

CLINICAL PICTURES 1.non selective NS, sometimes nonproteinuria nephrotic range non2.may progress to NS selective proteinuria 3.may develop hypertension & hematuria

Both types present mainly by NS, sometimes with nonnephrotic range proteinuria

Depend on pts age 7 causative agents -good prognosis with streptococcal infection & among children. -children: usually recover (90%) after sveral weeks - few cases developed rapidly progressive Gn or chronic renal disease. -in adult: 15-50% develop chronic Gn within few years

Good prognosis with excellent response to corticosteroid therapy in > 90% of affected children & less figures in adult.

PROGNOSIS AND FATE Poor response to Proteinuria usually does corticosteroids with not respond to progression to renal corticosteroids. However failures within 10 years in it has an indolent course about 50% of cases. & only about 40% of pts Lesion tend to recur in progress to renal failure renal allograft.

Both types have poor prognosis, more than 50% of them progress to chronic Gn after 10 years. Type II has tendency to recur in renal allograft.

-Diffuse in mesangial cells with infiltration by neutrophils leading to compression of capillary lumina (bloodless glomeruli) -cresent formation(proliferation of parietal cells)
Granular deposits of Ig G and C3 along capillary wall

Normal looking glomeruli

MICROSCOPIC PICTURES LIGHT MICROSCOPE Some show segmental Diffuse thickening of obliteration of capillary GBM, normal loop with mesangial glomerular cellularity. matrix, collapsed GBM & accumulation of lipid & proteinaceous material.

Both types have similar LM. Glomeruli are diffusely enlarged, hypercellular(mesangial proliferation) & leukocytes with diffuse thickening of GBM that displayed double contour(tram-track appearance) by silver stain.
Type I: granular deposits of Ig & complement along capillary wall & mesangium Type II: granular deposits of C3 allong capillary with absence of Ig deposition. Type I: marked mesangial hypercellularity + mesangial interposition between capillary wall splllitting associat with subendothelial & mesangial electron dense deposits Type II: ribbon-like dense deposits in the centre of thickened GBM.

Not specific. The glomeruli commonly show mesangial proliferation

No deposits

FLUOROSCENCE MICROSCOPE Usually negative Typical granular deposits of Ig & complement along GBM

Intense mesangial staining for Ig A

Scattered subepithelial deposits shaped like humps

Diffuse loss of epithelial foot processes

ELECTRON MICROSCOPE Focal segmental in Subepithelial deposits mesangial matrix with nestle against GBM & prominent injury of separated from each overlying podocyte other by small spike-like protrusion of GBM matrix

Electron dense deposits within the mesangium.