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

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

*immune complexes - 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) 2. in-situ immune complex nephritis - non-glomerular(foreign) antigen, may be endogenous or exogenous - antibody reacts directly with : 1. Fixed antigen 2. Planted antigen = foreign antigen = normal glomerular antigen deposited within the glomerulus antigen-antibody complexes are formed in the circulation and trapped in leading to anti-glomerular leading to in-situ immune the glomeruli they activate complement induce glomerular injury basement membrane (anti-GBM) complex nephritis -glomerular injury is may be in the form of : disease 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 -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

Electron microscope

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 NEPHRITIC SYNDROME PATHOGENESIS - acute glomerular injury - lesions have proliferation of endocapillary cellularity (mesangial & endothelial cell) + 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 leads toescape 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) resulting in CLINICAL PICTURES 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 cap. permeability # Hypoproteinemia 2ry to loss of protein # Generalized edema plasma osmotic pressurecompensatory secretion of aldosterone salt and water retention # Hyperlipidemia synthesis of lipoprotein # Lipiduria GBM permeability to lipoprotein. MINIMAL CHANGES Main cause of NS among children < 15 years - Less frequent encountered among adults FOCAL SEGMENTED GLOMERULOSCLEROSIS (FSGS) NS in 15% of adults and children Causes: # some are directly targeting 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 segmentd glomerularsclerosis - membronaous GN - membranoproliferative GN - Ig A nephropathy MEMBRANOUS GN (MGN) Secondary systemic cause: -diabetes mellitus -amyloidosis -SLE -infections(HBV, malaria, schistosomiasis) -drugs, maignancies, hereditary IG A NEPHROPATHY CHRONIC GN

POST STREP. (ACUTE DIFFUSE PROLIFERATIVE GN) Common disorder among children, that follow infection of skin or URT by nephritegenic strain of B-haemolytic streptococci

MEMBRANOPROLIFERATIVE GN (MPGN)

INCIDENCE Most frequent 5-10% of cases of primary cause of NS among NS in children and adults adults in western countries

Most common glomerular disease worldwide Peak: children and young adults

30 50% of end-stage renal disease - require chronic dialysis or renal transplantation

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

CHARACTERISTICS HISTOLOGICAL FEATURES Focal & segmental Accumulation of Glomerular hypercellularity obliteration of immune complexes with thickening of GBM. capillary loop by in subepithelial zone deposition of of glomerular collagen(sclerosis) + capillaries accumulation of lipid & proteinaceous material

Deposition of immune complex formed predominantly of Ig A

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

1. might be 1ry epithelial injury (no immune complex deposition) 2. disorder in Tlymphocytes leading to elaboration of cytokines that affect synthesis of nephrin 3. Consequently, loss of podocyte & glom. polyanions

-injury to epithelial cell lead to focal hyperpermeable foci causing entrapment of pl. protein & lipid -result in mesangial cell reaction with mesangial matrix

PATHOGENESIS Immune complex -Type I caused by circulating mediated disease: immune complexes -Type II: autoimmune -1ry: due to disease. in situ deposition of The patients serum has immune complexes factor called C3 nephritic against renal autoAg factor that activate -2ry: due to alternate complement circulating immune pathway with elaboration of complexes against biologically active exogenous antigen complement pathway

-genetic or aquired abnormality of immune regulation leading to mucosal Ig A synthesis in response to resp or GIT exposure to environmntl agents. Ig A & 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 & ass. with loin pain 2.less 10% with NS - has remitting & relapsing course. rarely resolves but many patients maintain normal renal functions for decade - 50% slowly progress to chronic renal failure within 20 years

glomerular nephritis which are commonly progressed to chr. GN: 1. RPGN (90%) 2. Membranous GN (40%) 3. MPGN (50%) 4. FSGS (50%) 5. IgA nephropathy (50%) *20% of chronic GN are idiopathic may occur at any age, esp young and middleaged adults - characterized by hypertension & ureamia

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

In NS, there is neither hypertension nor hematuria

1.non selective proteinuria 2.may progress to NS 3.may develop hypertension & hematuria

CLINICAL PICTURES NS, sometimes non- Both types present mainly nephrotic range by NS, sometimes with nonnon-selective nephrotic range proteinuria proteinuria

Depend on pts age & causative agents: -good prognosis with strep. infection & among children - children: usually recover (90%) after several weeks - few cases develop RPGN or chronic renal disease - in adult: 15-50% chr. GN in few years

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

Poor response to c/steroids with progression to renal failures within 10 years in about 50% of cases. Lesion tend to recur in renal allograft.

PROGNOSIS AND FATE Proteinuria usually Both types : poor prognosis does not respond to - more than 50% of them c/steroids. progress to chronic Gn after However it has an 10 years indolent course & - Type II has tendency to only about 40% of recur in renal allograft. pts progress to RF

death will occur from ureamia *unless the pt undergoes chronic dialysis or renal transplantation

-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

Some show segmental obliteration of capillary loop with mesangial matrix, collapsed GBM & accumulation of lipid & proteinaceous material.

MICROSCOPIC PICTURES LIGHT MICROSCOPE - diffuse thickening Both types have similar LM of GBM -normal glomerular - glomeruli are diffusely cellularity. enlarged, hypercellular (mesangial proliferation) & leukocytes - 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

Not specific. - the glomeruli commonly show mesangial proliferation

glomeruli : in number, most are completely hyalinised or sclerozed tubules : atrophic, intersititum is fibrozed 2ry to glomerular damage small and medium BV: arteriolar sclerosis 2ry to hypertension GROSS

No deposits

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

Intense mesangial staining for Ig A

kidney: - small, symmetrically contracted with, - red brown, diffusely granular external surface C/S: - cortex is narrow & atrophic with - multiple small cysts - cortex indistinguishable from the medulla

Scattered subepithelial deposits shaped like humps

Diffuse loss of epithelial foot processes

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

Type I: -marked mesangial hypercellularity + mesangial interposition between capillary wall its splitting -subendothelial & mesangial electron dense deposits Type II: ribbon-like dense deposits in the centre of thickened GBM

Electron dense deposits within the mesangium.