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Home , Nephritic syndrome

Normal anatomy Hypersensitivity reactions Inflammatory glomerular Immune diseases Visceral epithelial cell (= ) injury Hypersensitivity reactions type II: directed against the intrinsic GBM antigens Hypersensitivity reactions type III: formation = immune complex Glomerular diseases Subepithelial deposits Subendothelial and mesangial deposits Type II or IV: Crescent formation and cell-mediated immunity Vascular diseases Systemic and antineutrophil cytoplasmatic antibodies Thrombotic microangiopathies Metabolic and toxic Collagen IV hereditary defect Chronic

Fig. 2 A podocyte surrounding a glomerular Normal anatomy All three layers (endothelium, glomerular basement Fig. 1 Anatomy of the and the juxtaglomerular membrane, slit pores between ) are negatively apparatus charged Mesangium is contractable → regulation of flow and filtration rate

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Hypersensitivity reactions Mast cells covered with IgE antibodies bind parasitic antigens → inflammatory response, attraction of eosinophils → killing worms Type II: cytotoxic Cell-mediated cytotoxicity requires prior binding of Type I: Immediate hypersensitivity (anaphylaxis) antibodies to target cells 1st exposure to antigen → production of specific AB → An epitope is present on a cell their binding to mast cells (sensitization). Next exposure - a self-molecule in autoimmune diseases (errant or → allergen degranulates mast cells → release of uncontrolled plasma cells produce antibodies against histamine (immediate response) →↑vascular self-antigens) permeability, ↓airways, hives, conjunctivitis, rhinitis. - a drug or microbial product passively adsorbed onto a Later: → leukotriens, prostaglandins, PAF, proteases cell surface (late phase) → localized anaphylaxis = atopy (asthma, hay fever, eczema, hives) systemic anaphylaxis – circulatory shock, dyspnea, laryngospasm ↓ Ts activity AB binds to the epitope and can stimulate cell damage by a epitope number of effector mechanisms: → → - AB + complement opsonization phagocytosis, anchor and activate K-cells → ADCC extracellular release of toxic molecules → - dependent cell-mediated cytotoxicity (ADCC) AB attach to the - Activation of complement → membrane attack surface of cells, bind (via Fc receptors) and activate complex GBM etc. neutrophils and - Activation of complement → C5b67 → bystander macrophages lysis („innocent bystanders“) - Anchoring and activation of killer cells → ADCC activate complement cascade K(iller) cells: Lymphocyte-like cells (not B or T) that kill a variety of tumor cells and virus-infected cells but damage of the cells, GBM etc. → inflammatory response only after previous immunization (some authors: = natural killer cells, NK) Examples: mismatched blood transfusions, autoimmune diseases (Hashimoto, Goodpasture, myasthenia gravis...)

Type III: Immune-complex-mediated-hypersensitivity Dysbalance between the antigen and AB quantities Fig. 3 Immunologic reactions after an injection of (e.g., antibody in excess) → small complexes → they heterologous deposit in walls → endothelial damage and inflammatory process Deposition of complexes may reflect hemodynamic factors (glomeruli)

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Type IV: Cell-mediated immune injury = delayed-type hypersensitivity Slowly evolving (1-2 days). No circulating antibody but sensitized lymphoid cells Resistant (intracellular) bacterium, herpes simplex and measles virus, foreign tissue, metals, chemicals etc. First exposure → origin of antigen-specific memory T- Inflammatory glomerular diseases lymphocytes; second exposure → their stimulation → Three typical : nephritic, nephrotic and chronic lymfokines → activation of TH cells →↑TC, ↑„angry“ glomerulonephritis (Fig. 4) macrophages, ↑Kcells, ↑N(atural) K(iller) cells (= perhaps, do not require prior immunization) → indiscriminate phagocytosis, exudation. Macrophages → epitheloid cells → giant cells → ganulomas If exaggerated (= type IV) → granulomatous , contact dermatitis, transplant rejection. Where cell-mediated reactions do not eliminate the → tissue destruction Immune diseases Visceral epithelial cell (= podocyte) injury = lipoid Fig. 5: some mesangial proliferation, edematous podocytes, fusion („loss“) of their foot processes

Nephrotic in general – a tetrad: - heavy (more than 3 g/day) - Focal segmental glomerulosclerosis (more serious degree - of lipoid n.) - Focal = <50% of glomeruli are affected by light microscopy Diffuse = >50% affected Pathogenesis: Segmental = only a part of the glomerular tuft is involved - Epithelial cell damage → distortion of slit diaphragms → Glomerulosclerosis = obliteration (scarring) of capillary proteinuria lumens - Loss of fixed negative charges of GBM → loss of (negatively charged) Both diseases result from primary injury of podocytes. Unclear - Physicochemical changes in serum (lipoid podocyte damaging – some lymphokine? React to nephrosis, diabetes) → proteinuria glucocorticoids - Proteins between 50 000 – 200 000 daltons are lost (albumin, some IgG)

Pathogenesis of symptoms (Fig. 7)

Fig. 6 Porosity versus permeability Hypersensitivity reactions type II: Hypersensitivity reactions type III: Immune complex formation = immune complex disease

Antibodies directed against the intrinsic GBM antigens Glomerulus is highly susceptible to the entrapment or formation of immune complexes Antiglomerular basement membrane = „idiopathic“ Detection: electron , immunofluorescence (granular crescentic GN appearance) The nature of the antigen → whether subepithelial or Antigen: noncollagenous portion of the α3 chain of subendothelial deposition type IV collagen Location of the complexes → type of injury and clinical Complement and mediators → focal glomerular manifestations. However, histopathology does not correlate well necrosis, crescent formation → end-stage renal with clinical syndroms failure Anti-GBM antibodies bind in a linear pattern to the Subepithelial deposits GBM (without electronoptically dense deposits)

Goodpasture´s syndrome: antigens in GBM and alveolar basement membrane in the → focal proliferative GN and hemorrhagic pneumonitis. Crescents,

Fig. 8 (left side): Circulating complexes cannot pass through Postinfectious GN GBM → in situ immune complex formation. Experimental circulating cationic antigen (A, β-hemolytic streptococci) model: circulating cationic antigen, later penetrate the Fig. 9: „humps“ formed by immunocomplexes corresponding antibodies (A, β-hemolytic streptococci); typical „humps“

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Membranous nephropathy - idiopathic form (=unknown antigens) – ? Experimental model: filtered ; antigen present in situ (glycoprotein on podocyte cell membrane). Common, variable course, treatment - ? - in systemic disease - systemic erythematosus – (AB against DNA) - hepatitis B - tumor antigens Fig. 11 (Membranous GN): Precipitation of Fig. 12 (idiopathic membranous nephropathy) immunoglobulins on the outer surface of the GBM („spikes“ → complete incorporation of Ig into the membrane)

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Table 1

CATIONIC ANTIGEN

„ HUMPS“ POSTINFECTIOUS GN (FIG. 9,10) (MOSTLY A, β-HEMOLY- TIC STREPTOCOCCI) Clinical manifestations: typically nephrotic Distortion of slit diaphragms → proteinuria AMORPHOUS DEPO- SYSTEMIC DISEASES IDIOPATHIC Activated complement is not in contact with circulating SITS ↔ MEMBRANOUS LUPUS NEPHRITIS (against podocyte inflammatory cells → lack of inflammatory cell NEPHROPATHY. „SPIKES“ HEPATITIS B membrane antigens) infiltration → proteinuria lasts for a long time, but (FIG. 11,12) little damage

Subepithelial deposits ⇔ injury to the podocytes: membrane attack complex C5b-9 → fusion of the foot processes Subendothelial and mesangial deposits

Rather rarely: entrapped anionic antigens (e.g., DNA in lupus) and circulating antibodies → in situ immune complex formation More often Fig. 8 (right side): entrapment of preformed circulating immune complexes •Lupus autoantigens •Tumor neoantigens •Postinfectious GN: - Streptococci – nephritogenic strains, bacterial endocarditis, pneumonitis, meningitis, abscesses etc. Acute diffuse proliferative GN , mostly mild, rarely crescents - hepatitis B, malaria

8 Inflammatory response Sometimes no known source of antigenic stimulation: - Complexes generate C3a and C5a in contact with - Berger´s disease = IgA nephropathy circulation → chemotaxis Upper respiratory . Circulating IgA → deposition - Activation of Hageman factor →↑coagulation in mesangium → mesangial proliferation, no cellular cascade infiltrates. Focal proliferative GN. Mostly benign - Damaged endothelium → cytokines and autocoids course (local hormones) →↑adhesion molecules → - Schönlein-Henoch purpura activation of endothelial and inflammatory cells Skin IgA deposits → purpura; , hemorrhagic , nephritis (mostly benign). Focal Local glomerular inflammation → breaking filtration membrane proliferative GN →↑porosity, , - Membranoproliferative GN proteinuria C3 nephritic factor activates complement → blocking of glomerular ↓complement → Circulating immune complexes → mostly end stage ↓permeability → renal failure , uremia ()

Clinical manifestations: typically nephritic syndrome: - active sediment: red cells, white cells, cellular and granular casts - mild to moderate proteinuria - ↓GFR Fig. 13: Mechanisms causing reduction of GFR in the nephritic syndrome Recovery more rapid, but severe inflammation → irreversible cell injury → glomerulosclerosis

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Type II or IV: Crescent formation and cell-mediated immunity Fig. 14. Severe damage of capillary wall → leaks (rents) in GBM → fibrinogen and other plasma components („whole blood“) Crescents = accumulation and proliferation of extracapillary enter Bowman´s space → proliferation of all components (of cells aggressive white cells, endo- and epithelia, mesangium, → compression of the glomerular tuft → rapid renal failure epitheloid and giant cells), leakage of fibrin. Hypersensitivity Crescentic glomerulonephritis (>50% glom.) ⇔ rapidly reaction type II or IV progressive GN Etiology: - any severe nephritic condition – 50% of patients - antiglomerular basement membrane nephritis = idiopathic crescentic GN (if no antibodies are detectable), see above -ANCA-positive disorders

14 Systemic vasculitis and antineutrophil cytoplasmatic antibodies Acute systemic process of arteries. - Large vessel arteritides, e.g. classic form of polyarteritis nodosa → distal glomerular ischemia (no inflammation) → ↓GFR Vascular diseases - Glomerular tuft is directly involved, e.g. microscopic form of polyarteritis nodosa or Wegener´s granulomatosis (i.e., with no A variety of systemic diseases → injury of the renal arteries evident extrarenal involvement). They were summarized under (e.g., → nephrosclerosis) the pauci-immune necrotizing GN characterized specifically by Two acute disorders: novel circulating autoantibody – antineutrophil cytoplasmic antibody = ANCA ANCA → respiratory burst of phagocytic cells → release of free radicals → degranulation → injury to endothelial cells → focal (= < 50% glomeruli affected) proliferative GN, glomerular necrosis, crescents, active urine sediment. Malign course - hypersensitive vasculitis diseases connected with drugs (penicillin, sulfonamides etc.)

Thrombotic microangiopathies Metabolic and toxic Injured endothelial cell loses its natural thromboresistance → Amyloidosis →↑ → platelet activation → thrombi in the lumen → possibly fibrinoid Plasma cell disorder immunoglobulin in serum primary necrosis and fibrin deposition into media amyloidosis, e.g., in multiple myeloma → Include: Hemolytic-uremic syndrome: thrombocytopenia, Chronic inflammatory diseases secondary amyloidosis → microangiopathic hemolytic anemia, of Infiltration of GBM etc. with amyloid fibrills nephrotic glomerular capillaries →↓renal function syndroma Pathogenesis of thrombotic microangiopathies: - verotoxin-producing → damage to Diabetes endothelia (infantile diarrhea); also immunosuppresives Increased synthesis of extracellular substances → thickness and chemotherapeutics of the GBM and masangial matrix and glomerulosclerosis (= - ↑Willebrand factor →↑platelet aggregation; hyaline deposits or scarring within glomeruli) autoantibody against inhibitors of platelet aggregation Fig. 15: Proliferative sclerotizing GN: advanced mesangial - antibody-mediated endothelial injury in hyperacute proliferation → narrowing and destruction of capillaries renal transplant rejection Nephrotic syndroma. Generalized microangiopathy → nephropathy, retinopathy and neuropathy

Collagen IV hereditary defect – Alport´s syndrome Congenital defect of collagen, X-linked (mild in females), GBM very thin or multilayered, sclerotic changes. Myopia and deafness. Nephritic syndrome

Chronic glomerulonephritis Not an anknown form of GN, but a common final pathway for many glomerular diseases Experimentally: 5/6 nephrectomy →↑single nephron GFR (= hyperfiltration) Loss of nephrons → hyperperfusion → hyperfiltration → sclerosis of glomeruli ↓ 15 Proteinuria, RBCs and casts, GFR, ocassionally nephrotic syndrome Drugs and Stable or goes on to the end stage renal disease Captopril, gold, antibiotics...