Immune complex-mediated glomerular damage is seen in all except -

Glomerular Disease Histologic alterations: Various types of glomerulonephritis are characterized by one or more of four basic tissue reactions. Q Hypercellularity. Some inflammatory disease of the glomerulus are characterized by an increase in the number of cells in th glomerular tufts. This hypercellularity is characterized by one or more combinations of the following. Cellular proliferation of mesangial or endothelial cells Leukocytic infiltration, consisting of neutrophils, monocytes, and in some disease, lymphocytes. Formation of crescents. The epithelial cell proliferation that characterizes crescent formation occurs following an immune/inflammatory injury. Fibrin, which leaks into the urinary space, often through ruptured basement membranes, has been long thought to be the molecule that elicits the crescentic response. Other molecules that have been implicated in crescent formation include procoagulants such as tissue factor and cytokines such as interleukin-1, tumor necrosis factor, and interferon-g. Glomerular Diseases a. Primary Glomerulopathies Acute diffuse proliferative glomerulonephritis Poststreptococcal Non-poststreptococcal Rapidly progressive (crescentic) glomerulonephritis Membranous glomerulopathy Minimal change disease Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis IgA nephropathy Chronic glomerulonephritis b. Systemic Diseases with Glomerular Involvement Q Systemic lupus erythematosus Diabetes mellitus Amyloidosis Goodpasture syndrome Microscopic polyarteritis/polyangiitis Wegener granulomatosis Henoch-Schonlein purpura Bacterial endocarditis c. Hereditary Disorders Q Alport syndrome Thin basement membrane disease Fabry disease The Glomerular Syndromes 1. Acute nephritic syndrome - Hematuria, azotemia, variable proteinuria, oliguria, edema, Hypertension 2. Rapidly progressive glomerulonephritis - Acute nephritis, proteinuria, and acute renal failure 3. Nephrotic syndrome - >3.5 gm proteinuria, hypoalbuminemia, hyperlipidemia, Lipiduria 4. Chronic renal failure - Azotemia a uremia progressing for years 5. Asymptomatic hematuria / proteinuria a Glomerular hematuria; sub nephrotic proteinuria Immune Mechanisms of Glomerular Injury Antibody-Mediated Injury In Situ Immune Complex Deposition Fixed intrinsic tissue antigens NC1 domain of collagen type IV antigen (anti-GBM nephritis) Heymann antigen (membranous glomerulopathy) Mesangial antigens Others Planted antigens Exogenous (infectious agents, drugs) Endogenous (DNA, nuclear proteins, immunoglobulins, immune complexes, IgA) Circulating Immune Complex Deposition Endogenous antigens (e.g., DNA, tumor antigens) Exogenous antigens (e.g., infectious products) Cytotoxic Antibodies Cell-Mediated Immune Injury Activation of Alternative Complement Pathway Figure : Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes (A) or, more commonly, from in situ formation of complexes exemplified by anti-GBM disease (B) or Heymann nephritis (C). Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy: granular, characteristic of circulating and in situ immune complex nephritis and linear, characteristic of classic anti-GBM disease. Q FIGURE : Localization of immune complexes in the glomerulus: (1) subepithelial humps, as in acute glomerulonephritis; (2) epimembranous deposits, as in membranous and Heymann glomerulonephritis; (3) subendothelial deposits, as in systemic lupus erythematosus and membranoproliferative glomerulonephritis; (4) mesangial deposits, as in IgA nephropathy; (S1 basement membrane. LRE, lamina rara externa; LRI, lamina rara interna; LD, lamina densa; EP, epithelium; EN, endothelium; MC, mesangial cell; MM, mesangial matrix. Q TABLE -- Summary of Major Primary Glomerulonephritides Glomerular Pathology Disease Most Frequent Clinical Presentation Pathogenesis Light Microscopy Fluorescence Microscopy Electron Microscopy Poststreptococcal glomerulonephritis Acute nephritis Antibody mediated; circulating or planted antigen Diffuse proliferation; leukocytic infiltration Granular IgG and C3 in GBM and mesangium Subepithelial humps Goodpasture Syndrome Rapidly progressive glomerulonephritis Anti-GBM COL4- A3 antigen Proliferation; crescents Linear IgG and C3; fibrin in crescents No deposits; GBM disruptions; fibrin Idiopathic RPGN Rapidly progressive glomerulonephritis Anti-GBM antibody Immune complex ANCA-associated Proliferation; focal necrosis; crescents Linear IgG and C3 Granular IgG or IgA or IgM Negative or equivocal No deposits Deposits may be present No deposits Membranous glomerulopathy Nephrotic syndrome In situ antibody-mediated; antigen unknown Diffuse capillary wall thickening Granular IgG and C3; diffuse Subepithelial deposits Minimal change Disease Nephrotic syndrome Unknown, loss of glomerular polyanion; podocyte injury Normal; lipid in tubules Negative Loss of foot processes; no deposits Focal segmental glomerulosclerosis Nephrotic syndrome; non-nephrotic proteinuria Unknown, Ablation nephropathy Plasma factor(?); podocyte injury Focal and segmental sclerosis and hyalinosis Focal; IgM and C3 Loss of foot processes; epithelial denudation Membranoproliferative glomerulonephritis (MPGN) Type I Nephrotic syndrome (I) Immune complex Mesangial proliferation; basement membrane thickening; splitting (I) IgG + C3; C1q + C4 (I) Subendothelial deposits Dense deposit disease (MPGN Type II) Hematuria Chronic renal failure (II) Autoantibody: alternative complement pathway (II) C3 +- IgG; no C1q or C4 (II) Dense deposits IgA nephropathy Recurrent hematuria or proteinuria Unknown Focal proliferative glomerulonephritis; mesangial widening IgA +/- IgG, IgM, and C3 in mesangium Mesangial and paramesangial dense deposits Chronic glomerulonephritis Chronic renal failure Variable Hyalinized glomeruli Granular or negative Rapidly Progressive Glomerulonephritis (RPGN) 1. Type I RPGN (Anti-GBM Antibody) Idiopathic Goodpasture syndrome 2. Type II RPGN (Immune Complex) Idiopathic Postinfectious Systemic lupus erythematosus Henoch-Schonlein purpura (IgA) 3. Type III RPGN (Pauci-Immune) ANCA associated Idiopathic Wegener granulomatosis Microscopic polyarteritis nodosa/microscopic polyangiitis Pathophysiology The manifestations of the nephrotic syndrome include: Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children) Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL Generalized edema Hyperlipidemia and lipiduria. Membranous glomerulopathy (Membranous nephropathy) Membranous glomerulopathy is the most common cause of the nephrotic syndrome in adults. It is characterized by diffuse thickening of the glomerular capillary wall and the accumulation of electron-dense, immunoglobulin-containing deposits along the subepithelial side of the basement membrane. The most notable such associations are as follows: Drugs (penicillamine, captopril, gold, nonsteroidal anti-inflammatory drugs ) Underlying malignant tumors, particularly carcinoma of the lung and colon and melanoma. SLE. Infections (chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria) Other autoimmune disorders, such as thyroiditis Minimal change disease (Lipoid nephrosis) This relatively benign disorder is the most frequent cause of nephrotic syndrome in children. It is characterized by diffuse effacement of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy. Its most characteristic feature is its usually dramatic response to corticosteroid therapy. Fig: ABS showing effacement of foot process. Ref: Weber S, Gribouval O, Esquivel EL et al. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 2004; 66: 571-579 Focal segmental Glomerulosclerosis This lesion is characterized by sclerosis of some, but not all, glomeruli (Thus, it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus, it is segmental). In association with other known conditions, such as HIV infection (HIV nephropathy), heroin addiction (heroin nephropathy), sickle cell disease and massive obesity. Reflux nephropathy, hypertensive nephropathy, or with unilateral renal agenesis. As a primary disease (idiopathic focal segmental glomerulosclerosis) HIV-associated nephropathy Most commonly, a severe form of the collapsing variant of focal segmental glomerulosclerosis. Membranoproliferative glomerulonephritis Primary MPGN is divided into two major types on the basis of distinct ultrastructural, immunofluorescent, and pathologic findings: type I and type II MPGN (dense-deposit disease). Type I & II MPGN differ in their ultrastructural and immunofluorescent features. Type I MPGN (the great majority of cases) is characterized by the presence of subendothelial electron-dense deposits.) In dense-deposit disease (type II MPGN) a relatively rare entity, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure because of the deposition of dense material of unknown composition. Pathogenesis: In most cases of type I MPGN there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways. Q Secondary MPGN: Secondary MPGN (invariably type I) is more common in adults and arises in the following settings. Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis. Alpha1-Antitrypsin deficiency Malignant disease (chronic lymphocytic leukemia and lymphoma) Hereditary deficiencies of complement regulatory proteins. IgA nephropathy (Berger disease) This form of glomerulonephritis is characterized by the presence of prominent IgA deposits in the mesangial regions, detected by immunofluorescence microscopy. Figure : The alternative complement pathway. Note that C3NeF, present in the serum of patients with membranoproliferative glomerulonephritis, acts at the same step as properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 breakdown and causing hypocomplementemia. Q Hereditary syndromes of isolated hematuria: Hereditary nephritis refers to a group of heterogeneous familial renal disease associated primary with glomerular injury. Alport syndrome: Alport syndrome, when fully developed, is manifest by nephritis progressing o chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy. In the mos common X-linked form, males express the full syndrome, and females are carriers in whom manifestations of disease are typically limited to hematuria. Q Rare autosomal-recessive and autosomal-dominant pedigrees also exist, in which males and females are equally susceptible to the full syndrome.Q Morphology: The characteristic findings of fully developed disease are seen with the electron microscope and are found in most patients with hereditary nephritis. The GBM shows irregular foci of thickening alternating with attenuation (thinning), with pronounced splitting and lamination of the lamina densa, often with a distinctive basket-weave appearance.. Q Immunohistochemistry can be helpful in cases with absent or borderline basement membrane lesions, because antibodies to alpha3, alpha4, and alpha5 collagen fail to stain both glomerular and tubular basement membranes in the classic X-linked form. Q There is also absence of alpha5 staining in skin biopsy specimens. Pathogenesis. Defective GBM synthesis because of the production of abnormal collagen type IV underlies the renal lesions. In patients with X-linked disease, the defect is caused by mutations in the gene encoding the alpha5-chain of collagen type IV (COL4A5), a component of the GBM. Thin Basement membrane disease (Benign Familial Hematuria) This is a fairly common entity manifested clinically by familial asymptomatic hematuria - usually uncovered on routine urinalysis. Morphologically by diffuse thinning of the GBM to between 150 and 250 nm (compared with 300 to 400 nm in normal adult individuals) although mild or moderate proteinuria may also be present, renal function is normal and prognosis is excellent. Q