Glomerular diseases

1. Glomerular diseases • 1. Normal anatomy • 2. Pathogenesis 21 Hypersensitivity reactions 22 Pathogenetic mechanisms of glomerular diseases23 Mechanisms of vascular injury

2. 1 Normal anatomy Fig. 1 Anatomy of the glomerulus and thejuxtaglomerular apparatus 1

3. Fig. 2 A podocyte surrounding a glomerular capillary All three layers (endothelium, glomerular basement membrane, slit pores between podocytes) are negatively charged Mesangium is contractable  F 2

4. Fig. 3 Glomerular basement membrane (GBM) GBM 1 3

5. 2 Pathogenesis • 21 Hypersensitivity reactions: • Mast cells covered with IgE antibodies bind parasite antigens  inflammatory response, attraction of eosinophils  killing worms

6. Type I: Immediate hypersensitivity (anaphylaxis) • 1st exposure to antigen  production of specific AB  their binding • to mast cells (sensitization). Next exposure  allergen • degranulates mast cells  release of histamine (immediate • response) vascular permeability, airways, hives, • conjunctivitis, rhinitis. Later:  leukotriens, prostaglandins, PAF, • proteases (late phase) localizedanaphylaxis = atopy (asthma, • hay fever, eczema, hives) • systemic anaphylaxis – circulatory shock, • dyspnea, laryngospasm • Ts activity 

7. Type II: Antibody-dependent cellular cytotoxicity (ADCC) • Cell-mediated cytotoxicity that requires prior binding of antibodies to • target cells • K(iller) cells: Lymphocyte-like cells (not B or T) that kill a variety of tumor cells and virus-infected cells but only after previous immunization • Errant or uncontrolled plasma cells produce antibodies against selfantigens • Drugs combine with body antigens (e.g., on erythrocytes) • anchor and activate K-cells  ADCC • AB attach to the • surface of cells, bind (via Fc receptors) and activate • GBM etc. neutrophils and macrophages • activate complement cascade • damage of the cells, GBM etc.

8. Type III: Immune-complex-mediated-hypersensitivity Fig. 4 Immunologic reactions after injection of heterologous protein 4

9. ANTIGEN EXCESS  SMALL COMPLEXES (PERSISTENT INFECTION, AUTOIMMUNITY, REPEATED CONTACT WITH ENVIRON- MENTAL ANTIGEN) DEFECT IN SYSTEMS REMOVING IMMUNE COMPLEXES (PHAGOCY- TES & COMPLEMENT)   CLEARANCE OF COMPLEXES  THEIR DEPOSITION IN TISSUES  ACUTE INFLAMMATORY RESPONSE

10. Deposition of complexes may reflect hemodynamic factors (glomeruli) Type IV: Cell-mediated immune injury = delayed-type hypersensitivity Resistant (intracellular) bacterium, foreign tissue etc.  activation of TH cells  TC, “angry” macrophages, K cells, N(atural) K(iller) cells (=do not require prior immunization)  indiscriminate phagocytosis, exudation  granulomatous inflammation, contact dermatitis, transplant rejection 22 Pathogenetic mechanisms of glomerular diseases Three typical syndromes: nephritic, nephrotic and chronic glomerulonephritis

11. Fig. 5 Etiology of glomerular injury - survey 5

12. Histology • May not correlate with the • clinical presentation • Fig. 6, 7 Various histological • types of glomerulonephritis 6

13. 7

14. B: “Minimal changes” GN= lipoid nephrosis: some mesangial proliferation, edematous podocytes, fusion (“loss”) of their foot processes C: Intracapillary mesangial proliferative GN: proliferation of endothelia and mesangium, peeling off of enthelial cells from the GBM, duplication of GBM, “humps” formed by immunocomplexes D: Crescentic GN: proliferation of all components (aggressive white cells, endo- and epithelia, mesangium, epitheloid and giant cells), leakage of fibrin. Hypersensitivity reaction type II or IV E: Membranous GN: Precipitation of immunoglobulins on the outer surface of the GBM (“spikes”  complete incorporation of Ig into the membrane) F: Proliferative sclerotizing GN: advanced mesangial proliferation  narrowing and destruction of capillaries

15. 221 Visceral epithelial cell (= podocyte) injury Minimal change disease = lipoid nephrosis (Fig. 7 B) 7

16. Focal segmental glomerulosclerosis (FGS) Focal = 50% of glomeruli are affected by light microscopy Diffuse = 50% affected Segmental = only a part of the glomerular tuft is involved Glomerulosclerosis = obliteration of capillary lumens Nephrotic syndrome. Edematous podocytes, fusion (“loss”) of their foot processes. Unclear podocyte damaging toxin – some lymphokine? React on glucocorticoids

17. 222 Immune complex formation = immune complex disease Glomerulus is highly susceptible to the entrapment or formation of immune complexes Detection: electron microscopy, immunofluorescence (granular appearance) Location of the complexes  type of injury and clinical manifestations Fig. 8 Porosity versus permeability 8

18. 2221 Subepithelial deposits Fig. 9 left side 9

19. Circulating complexes cannost pass through GBM in situimmune complex formation: - circulating cationic antigen, afterwards enter the corresponding antibodies - filtered autoantibody; antigen present in situ (glycoprotein on podocyte cell membrane). CATIONIC ANTIGEN AUTOANTIBODIES POSTINFECTIOUS GN (MOSTLY A, -HEMOLY- TIC STREPTOCOCCI) „ HUMPS“ (FIG. 6C) AMORPHOUS DEPO- SITS  MEMBRANOUS NEPHROPATHY. „SPIKES“ (FIG. 6E) SYSTEMIC DISEASES LUPUS NEPHRITIS HEPATITIS B IDIOPATHIC

20. 6

21. Injury to the podocytes: membrane attack complex C5b-9 fusion of the foot processes Clinical manifestations of exclusively subepithelial deposits: typically nephrotic. Distortion of slit diaphragms  proteinuria Activated complement is not in contact with circulating inflammatory cells lack of inflammatory cell infiltration proteinuria lasts for a long time

22. Nephrotic syndrome Fig. 10 Pathogenesis of symptoms 10

23. 2222 Subendothelial and mesangial deposits Fig. 9 right side 9

24. Typically caused by passive entrapment of preformed circulating immune complexes. The nature of the antigen  whether subepithelial or subendothelial deposition Lupus nephritis Postinfectious GN: Streptococci, bacterial endocarditis, hepatitis B, malaria Berger Schönlein-Henoch Inflammatory response - Complexes in contact with circulation generate C3a and C5a - Activation of Hageman factor coagulation cascade - Damaged endothelium  cytokines and autocoids (local hormones) adhesion molecules  activation of endothelial and inflammatory cells

25. Clinical manifestations: inflammatory and proliferative response  typically nephritic syndrome: • active urine sediment: red cells, white cells, cellular and granular casts • GFR • Recovery more rapid, but severe inflammation  irreversible cell injury  glomerulosclerosis • Hypersensitivity reaction type III

26. Nephritic diseases (Survey, Fig. 11): 11

27. Fig. 12 Mechanisms causing reduction of GFR in the nephritic syndrome 12

28. 223 Antibodies directed against GBM antigens Antigen: noncollagenous portion of the 3 chain of type IV collagen Complement and mediators  focal glomerular necrosis, crescent formation  end-stage renal failure Anti-GBM antibodies bind in a linear pattern to the GBM (without electronoptically dense deposits) Hypersensitivity reaction type II Goodpasture syndrome

29. 224 Crescent formation and cell-mediated immunity Fig. 6D 6

30. Severe damage of capillary wall  leaks (rents) in GBM  fibrinogen and other plasma components enter Bowman´s space • Crescents= accumulation and proliferation of extracapillary cells •  compression of the glomerular tuft  rapid renal failure • Crescentic glomerulonephritis (50% glom.)  rapidly progressive GN • Etiology: • any severe GN • anti-GBM antibody disease • ANCA-positive disorders • Hypersensitivity reaction type II or IV (?) • 225 Alport syndrome • Congenital defect of collagen

31. 23 Mechanisms of vascular injury • 231 Systemic vasculitis and antineutrophil cytoplasmatic antibodies • Acute systemic process of arteries. • - Large vessel arteritides, e.g. polyarteritis nodosa distal • glomerular ischemia (no inflammation) GFR • - Glomerular tuft, e.g. polyarteritis nodosa, Wegener´s • granulomatosis  focal glomerular necrosis, crescents, • active urine sediment • Novel circulating autoantibody – antineutrophil cytoplasmic • antibody = ANCA • Highly specific for systemic necrotizing vasculitides • ANCA  respiratory burst of phagocytic cells  release of free radicals  degranulation  injury to endothelial cells

32. 232 Thrombotic microangiopathies Injured endothelial cell loses its natural thromboresistance  platelet activation  thrombi in the lumen  possibly fibrinoid necrosis and fibrin deposition into media Hemolytic-uremic syndrome:thrombocytopenia, microangiopathic hemolytic anemia, renal function Pathogenesis: - verotoxin-producing Escherichia coli  damage to endothelia (infantile diarrhea); also immunosuppresives and chemotheraputics - Willebrand factor platelet aggregation; autoantibody against inhibitors of platelet aggregation - antibody-mediated endothelial injury in hyperacute renal transplant rejection

33. Hematuria, azotemia, hypervolemia. Mild to moderate proteinuria Primary and secondary (=systemic with renal involvement) diseases The majority is of immunologic etiology – hypersensitivity reactions type II or III Local glomerular inflammation  breaking filtration membrane porosity, hematuria, proteinuria blocking of glomerular capillaries permeability  hypervolemia, uremia Membranous GN (type E)  proteinuria, rather slow Proliferating GN (type C and D)  hypertension, more acute