PowerPoint Presentation: Etio -pathogenesis – of Glomerulonephritis PowerPoint Presentation: The glomerulus consists of an anastomosing network of capillaries invested by two layers of epithelium. The visceral epithelium ( podocytes ) is an intrinsic part of the capillary wall, whereas the parietal epithelium lines Bowman space (urinary space), the cavity in which plasma ultrafiltrate first collects. PowerPoint Presentation: The glomerular capillary wall is the filtration unit and consists of the following structures- A thin layer of fenestrated endothelial cells . A glomerular basement membrane (GBM), having 3 layers- lamina rara interna , lamina densa and lamina rara externa . The GBM consists of collagen (mostly type IV), laminin , polyanionic proteoglycans, fibronectin , and several other glycoproteins. 3. The visceral epithelial cells ( podocytes ), structurally complex cells that possess interdigitating processes embedded in and adherent to the lamina rara externa of the basement membrane. 4 . The entire glomerular tuft is supported by mesangial cells lying between the capillaries and scattered forming a meshwork of mesangial matrix. PowerPoint Presentation: Low-power electron micrograph of glomerulus. B, basement membrane; CL, capillary lumen; End, endothelium; Ep , visceral epithelial cells ( podocytes ) with foot processes; Mes , mesangium ; US, urinary space. PowerPoint Presentation: Scanning electron micrograph of the fenestrated endothelia lining the glomerular capillary. PowerPoint Presentation: Scanning electron micrograph of podocytes that line the outer surface of the glomerular capillaries (arrow shows foot process). PowerPoint Presentation: characteristics of glomerular filtration Most large proteins and all cells are excluded from filtration by a physicochemical barrier governed by pore size and negative electrostatic charge (called selective permeability or perm-selectivity .) This function is accounted for by the complex structure of the capillary wall, the integrity of the GBM, and many anionic molecules present within the wall. The podocytes are crucial to maintain this glomerular barrier function . PowerPoint Presentation: Glomerulo-pathies are the diseases of the glomerulus. And G lomerulo -nephritis i s the inflammation of the glomerular capillaries. There are many forms of glomerular disease with pathogenesis variably linked to the presence of genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, diabetes mellitus and idiopathic. PowerPoint Presentation: Pathogenesis of Glomerular Diseases The immune mechanisms underlie most types of primary glomerular diseases and many of the secondary glomerular diseases. Two forms of antibody-associated injury have been established: injury resulting from deposition of soluble circulating antigen-antibody complexes in the glomerulus, and injury by antibodies reacting in situ within the glomerulus, either with insoluble fixed (intrinsic) glomerular antigens or with molecules planted within the glomerulus. Cell-mediated immune mechanisms may also play a role in certain glomerular diseases. PowerPoint Presentation: A . Nephritis Caused by Circulating Immune Complexes With circulating immune complex-mediated disease, the glomerulus may be considered an "innocent bystander" because it does not incite the reaction. The antigen is not of glomerular origin. It may be endogenous , as in the GN associated with SLE, or it may be exogenous , as is probable in the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal ( Treponema pallidum ) infections. And often the inciting antigen is unknown, as in most cases of membranous nephropathy. PowerPoint Presentation: The antigen-antibody complexes are trapped in the glomeruli, and produce injury, through the activation of complement pathway and by recruitment of leukocytes. Regardless of the mechanism, the glomerular lesions usually consist of leukocytic infiltration (exudation) into glomeruli and variable proliferation of endothelial, mesangial , and parietal epithelial cells. Electron microscopy and immunofluorescence microscopy reveals immune complexes as electron-dense deposits or clumps that may lie : in the mesangium , between the endothelium and GBM ( subendothelial deposits), or between the outer surface of the GBM and the podocytes ( subepithelial deposits). PowerPoint Presentation: By immunofluorescence, the immune complexes are seen as granular deposits in the glomerulus. Once deposited in the kidney, immune complexes may eventually be degraded or phagocytosed , mostly by infiltrating leukocytes and mesangial cells, and the inflammatory changes may then subside as in most cases of poststreptococcal or acute infection-related GN. However, if the shower of antigens is continuous, repeated cycles of immune complex formation, deposition, and injury may occur, leading to chronic GN such as in hepatitis B virus infection, SLE etc. PowerPoint Presentation: B. Nephritis Caused by In Situ Immune Complexes autoimmune diseases where antibodies react directly with fixed or planted antigens in the glomerulus. The best-characterized disease in this group is classic anti-GBM antibody GN; that results from the formation of autoantibodies directed against the non-collagenous domain of the α3 chain of collagen type IV of the GBM. Deposition of these antibodies creates a linear pattern of staining, visualized with immunofluorescence microscopy . Sometimes the anti-GBM antibodies cross-react with basement membranes of lung alveoli, resulting in simultaneous lung and kidney lesions ( Good-pasture syndrome ). PowerPoint Presentation: Planted antigens include bacterial products, such as endostreptosin , a protein of group A streptococci; large aggregated proteins and immune complexes as they have reactive sites for further interactions with free antibody, free antigen, or complement. Most of these planted antigens induce a granular pattern of immunoglobulin deposition as seen by immunofluorescence microscopy. PowerPoint Presentation: Antibody-mediated glomerular injury. A, Deposition of circulating immune complexes gives a granular immunofluorescence pattern. B, Anti-GBM antibody GN is characterized by a linear immunofluorescence pattern. C, Antibodies against some glomerular components deposit in a granular pattern . PowerPoint Presentation: Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy . A , Granular, characteristic of circulating and in situ immune complex deposition. B , Linear, characteristic of classic anti-GBM antibody GN. PowerPoint Presentation: Cell-Mediated Immune Glomerulonephritis T cell-mediated injury may account for the instances of GN in which either there are no deposits of antibodies or immune complexes or the deposits do not correlate with the severity of damage; (though not proved in human models). e.g. MCD , FSGS PowerPoint Presentation: Mediators of Immune Injury A major pathway of antibody-initiated injury is complement-leukocyte-mediated. Local activation of Toll-like receptors on glomerular cells, or complement activation induces mononuclear cell infiltration, which subsequently leads to an adaptive immune response by local release of chemokines . Neutrophils, macrophages, and T cells are drawn by chemokines into the glomerular tuft, where they react with antigens and epitopes, producing more cytokines and proteases that damage the mesangium , capillaries, and/or the GBM. The membrane attack complex up-regulates TGF-β receptors on podocytes that stimulates synthesis of extracellular matrix , giving rise to altered GBM composition and thickening. PowerPoint Presentation: Amplification mediators such as locally derived oxidants and proteases expand glomerular inflammation, and, depending on the location of the target antigen, basement membranes are damaged with either endocapillary or extracapillary proliferation. PowerPoint Presentation: Other Mechanisms of Glomerular Injury Podocyte Injury Induced by antibodies to visceral epithelial cell antigens; or by toxins. Injury is reflected by morphologic changes in the podocytes , which include effacement of foot processes and detachment of cells from the GBM, and functionally by proteinuria. Functional abnormalities of the slit diaphragm may also result from mutations in its components, such as nephrin and podocin , causes hereditary forms of nephrotic syndrome. PowerPoint Presentation: Nephron Loss Once any renal disease, glomerular or otherwise, destroys sufficient functioning nephrons to reduce the GFR to 30% to 50% of normal, progression to end-stage renal failure often proceeds inexorably, and their kidneys show widespread glomerulosclerosis . These remaining glomeruli undergo hypertrophy and mal-adaptive changes to maintain renal function which causes ultimately further loss of nephron and decreased GFR viciously. PowerPoint Presentation: Patterns of Clinical Glomerulonephritis Glomerular Syndromes - Acute Nephritic Syndromes Poststreptococcal glomerulonephritis Subacute bacterial endocarditis Lupus nephritis Antiglomerular basement membrane disease IgA nephropathy ANCA small-vessel vasculitis - Granulomatosis with polyangiitis (Wegener's) -Microscopic polyangiitis - Churg -Strauss syndrome Henoch-Schönlein purpura Cryoglobulinemia Membranoproliferative glomerulonephritis M esangioproliferative glomerulonephritis PowerPoint Presentation: Pulmonary-Renal Syndromes Goodpasture's syndrome ANCA small-vessel vasculitis - Granulomatosis with polyangiitis (Wegener's ) -Microscopic polyangiitis - Churg -Strauss syndrome Henoch-Schönlein purpura Cryoglobulinemia PowerPoint Presentation: Basement Membrane Syndromes Anti-GBM disease Alport's syndrome Thin basement membrane disease Nail-patella syndrome Glomerular Vascular Syndromes Atherosclerotic nephropathy Hypertensive nephropathy Cholesterol emboli Sickle cell disease Thrombotic microangiopathies Antiphospholipid syndrome ANCA small-vessel vasculitis - Granulomatosis with polyangiitis (Wegener's) -Microscopic polyangiitis - Churg -Strauss syndrome Henoch-Schönlein purpura Cryoglobulinemia AL and AA amyloidosis PowerPoint Presentation: Infectious Disease–Associated Syndromes Poststreptococcal glomerulonephritis Subacute bacterial endocarditis HIV Hepatitis B and C Syphilis Leprosy Malaria Schistosomiasis PowerPoint Presentation: Poststreptococcal Glomerulonephritis Skin and throat infections with particular M types of streptococci ( nephritogenic strains) antedate glomerular disease; M types 47, 49, 55, 2, 60, and 57 are seen following impetigo and M types 1, 2, 4, 3, 25, 49, and 12 with pharyngitis. The nephritogenic antigen, streptococcal pyrogenic exotoxin B (SPEB), has been demonstrated inside the subepithelial "humps" on renal biopsy. PowerPoint Presentation: IgA Nephropathy an antibody-mediated glomerular disease in which the immune deposits localize to the mesangium . It is not certain whether the deposits form in situ or from circulating immune complexes . - Patients with IgA nephropathy usually present with one of three syndromes . 1. Macroscopic hematuria concurrent with an upper respiratory infection; so-called synpharyngitic hematuria . 2. Asypmtomatic microscopic hematuria and variable proteinuria . 3. Henoch-Schonlein purpura is the systemic form of the disease process causing IgA nephropathy, and occurs more frequently in children than adults. Patients with Henoch-Schonlein purpura manifest skin, joint and intestinal involvement . PowerPoint Presentation: Morphologic Features - mesangial hypercellularity . Segmental proliferation, sclerosis, and necrosis with crescent formation may also be seen. The diagnosis of IgA nephropathy resets on the demonstration of mesangial deposits of IgA by direct immunofluorescence microscopy; IgG and C3 are variably present . - The mesangial deposits, often have a “ paramesangial ” location beneath the basement membrane. PowerPoint Presentation: Focal Segmental Glomerulosclerosis Primary focal segmental glomerulosclerosis Secondary focal segmental glomerulosclerosis Viruses: HIV/Hepatitis B/Parvovirus Hypertensive nephropathy Reflux nephropathy Cholesterol emboli Drugs: Heroin/analgesics/ pamidronate Alport's syndrome, Sickle cell disease Lymphoma, Radiation nephritis Familial podocytopathies NPHS1 mutation/ nephrin NPHS2 mutation/ podocin ACTN4 mutation/ actinin Galactosidase A deficiency/ Fabry's disease nephrosialidosis PowerPoint Presentation: Lupus Nephritis Lupus nephritis results from the deposition of circulating immune complexes, which activate the complement cascade leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of various cytokines. In situ immune complex formation following glomerular binding of nuclear antigens, particularly necrotic nucleosomes, also plays a role in renal injury. The presence of antiphospholipid antibodies may also trigger a thrombotic microangiopathy in a minority of patients . PowerPoint Presentation: WHO Classification of Lupus Nephritis Class I Minimal mesangial - Normal histology with mesangial deposits Class II Mesangial proliferation - Mesangial hypercellularity with expansion of the mesangial matrix Class III Focal nephritis - Focal endocapillary ± extracapillary proliferation with focal subendothelial immune deposits and mild mesangial expansion Class IV Diffuse nephritis - Diffuse endocapillary ± extracapillary proliferation with diffuse subendothelial immune deposits and mesangial alterations Class V Membranous nephritis - Thickened basement membranes with diffuse subepithelial immune deposits; may occur with class III or IV lesions and is sometimes called mixed membranous and proliferative nephritis Class VI Sclerotic nephritis (ESRD) - Global sclerosis of nearly all glomerular capillaries PowerPoint Presentation: Antiglomerular Basement Membrane Disease The target epitopes for this autoimmune disease lie in the quaternary structure of 3 NC1 domain of collagen IV. When associeted with lung hemorrhage , called Goodpasture's syndrome. Renal biopsies typically show focal or segmental necrosis that later, with aggressive destruction of the capillaries by cellular proliferation, leads to crescent formation in Bowman's space. The presence of anti-GBM antibodies and complement is recognized on biopsy by linear immunofluorescent staining for IgG (rarely IgA ). PowerPoint Presentation: ANCA Small-Vessel Vasculitis Granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis , and Churg -Strauss syndrome belong to this group because they are ANCA-positive and have a pauci -immune glomerulonephritis with few immune complexes in small vessels and glomerular capillaries. ANCA’s are produced with the help of T cells and activate leukocytes and monocytes, which together damage the walls of small vessels. Granulomatosis with Polyangiitis (Wegener's) Renal biopsies demonstrate segmental necrotizing glomerulonephritis without immune deposits. The cause of is unknown, exposure to silica dust and patients with 1-antitrypsin deficiency may implicate. PowerPoint Presentation: Microscopic Polyangiitis The distinction is made on biopsy, where the vasculitis is without granulomas . Churg -Strauss Syndrome Small-vessel vasculitis and focal segmental necrotizing glomerulonephritis can be seen on renal biopsy, usually absent eosinophils or granulomas. The cause is autoimmune, but the inciting factors are unknown. Interestingly, some asthma patients treated with leukotriene receptor antagonists develop this vasculitis . PowerPoint Presentation: Post-infectious GN Infection is a common cause of GN and can be seen with a variety of bacterial and viral infection. Post-streptococcal GN is the most common and classic form. Other common causes are hepatitis B, hepatitis C, malaria, syphilis, infective endocarditis, HIV, schistosomiasis etc. PowerPoint Presentation: Endocarditis-associated glomerulonephritis Due to renal deposition of circulating immune complexes with complement activation; Particularly in patients who remain untreated for a long time, have negative blood cultures, or have right-sided endocarditis. Grossly , the kidney shows subcapsular hemorrhages with a "flea-bitten" appearance, and Microscopy reveals focal proliferation around foci of necrosis associated with abundant mesangial , subendothelial , and subepithelial immune deposits of IgG , IgM , and C3 and sometimes cresents . PowerPoint Presentation: Hepatitis B related GN mainly membranous nephropathy and less commonly MPGN Hepatitis C related GN Typically related with cryoglobulinemia and hypocomplimentimia MPGN most commonly t he pathogenesis is unknown, but the glomerular damage may be due to deposition of immune complexes of HCV, IgG , and IgM rheumatoid factors. PowerPoint Presentation: Diabetic Nephropathy Risk factors - hyperglycemia , hypertension, dyslipidemia , smoking, family history. 2 forms- a . Diffuse glomeruloslerosis thickening of the GBM and diffuse proliferation of mesangial matrix. Various exudative lesions such as capsular hyaline drops and fibrin caps may also be present. b . Nodular glomeruloslerosis Also called Kimmelstiel -Wilson (KW) lesions or intercapillary glomeruloscerosis . The pathologic changes are consist of PAS-positive nodules in glomeruli surrounded by glomerular capillary loops.