Vasculitides AND ANTI-GBM


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Vasculitides AND ANTI-GBM

  1. 1. RENAL VAscuLitis DR. ANAss AhmED QAsEm
  2. 2. DefinitionClassificationEtiology and AssociationsPathogenesisClinical PresentationTreatment
  3. 3. VASCULITISGeneral definitionDefined by the presence of inflammatory leukocytes in vesselwalls with reactive damage to mural structures.●Loss of vessel integrity may lead to bleeding.●Compromise of the lumen leads to tissue ischemia and necrosis.RENAL VASCULITIS●The kidneys are targets for a variety of systemic vasculitides.●Renal vasculitis is a collective term for a heterogenous group of disorders characterized by inflammation of arteries, arterioles, and venules with or without GN.
  4. 4. DefinitionClassificationEtiology and AssociationsPathogenesisClinical PresentationTreatment
  5. 5. Chapel Hill ClassificationLarge vessel vasculitis Giant cell arteritisRefers to the aorta and Takayasu’s arteritisits major tributariesMedium vessel vasculitisClassical polyarteritis nodosaMedium and small sizedarteries and arterioles. Kawasaki’s disease ANCA }Small vessel vasculitis Microscopic polyangiitisSmall arteries, arterioles, Wegener’s granulomatosisVenules, capillaries and Churg–Strauss syndromeGlomerulus. Henoch-Schönlein purpura Hypersensitivity vasculitis Essential cryoglobulinaemia
  6. 6. DefinitionClassificationEtiology and AssociationsPathogenesisClinical PresentationTreatment
  7. 7. Vasculitis SyndromesPrimary Vasculitis Secondary VasculitisWegeners granulomatosis Serum sicknessChurg-Strauss syndrome  InfectionPolyarteritis nodosa  MalignancyMicroscopic polyangiitis  Rheumatic diseaseGiant cell arteritis Drug-induced vasculitisTakayasus arteritis *Antithyroid medicationHenoch-Schönlein purpura *HydralazineIdiopathic cutaneous vasculitisEssential mixed cryoglobulinemia *MinocyclineBehçets syndrome *AllopurinolKawasaki disease *Phenytoin *Penicillamine
  8. 8. DefinitionClassificationEtiology and AssociationsPathogenesisClinical PresentationTreatment
  9. 9. Mechanisms of Vessel DamagePathogenic immune complex formation and or deposition Henoch-Schönlein purpura Vasculitis associated with collagen vascular diseases Serum sickness and cutaneous vasculitis syndromes Hepatitis C–associated essential mixed cryoglobulinemia Hepatitis B–associated polyarteritis nodosaProduction of antineutrophilic cytoplasmic antibo diesWegeners granulomatosis Microscopic polyangiitisRenal limited vasculitisChurg-Strauss syndromPathogenic T lymphocyte and granuloma formation Giant cell arteritis Takayasus arteritis Wegeners granulomatosis Churg-Strauss syndrome
  10. 10. ANCA●ANCAs are directed against antigens that reside within the primary granules of neutrophils and monocytes.Two types of ANCA are relevant to vasculitis PR3-ANCA♠Proteinase 3 (PR3) PR3-ANCA♠Myeloperoxidase (MPO) MPO-ANCA. MPO-ANCAStaining on ethanolANCA titres are generally measured using ELISA and indirect immunofluorescence
  11. 11. ANCA Pauci-immune small PR3-ANCA MPO-ANCA vessel vasculitisWegeners 90% 20%granulomatosisMicroscopic polyangiitis 40% 60%Renal limited vasculitis 30%–10 70%–30Churg-Strauss syndrom 10% 70%–30
  12. 12. Role of ANCAsStriking and unexplained feature of ANCA-associated vasculitis is that patients virtually never have antibodies to both PR3 and MPOPatients with PR-3 ANCA are more than one and a half times as likely to relapse when compared to those with MPO -ANCAANCA may sometimes be positive with other inflammatory conditions *Inflammatory bowel disease *Rheumatoid disease *Bacterial endocarditis *Cystic fibrosis. *Chronic inflammatory liver diseaseIn this setting, specificity of the ANCA may not be against PR3 or MPO but against other neutrophil antigens, including lactoferrin, cathepsin G, and anti–bactericidal/permeability- increasing protein.
  13. 13. Role of ANCAs IL-1 TNF IL-1 IL-8 LeuB4 ExpressPr3 or MPO
  14. 14. LAMP-2 Recently, autoantibodies to lysosomal membrane protein 2 (LAMP-2) were reportedly identified in the circulation of most patients with either MPO-ANCA or PR3-ANCA. LAMP-2 has homology to the bacterial adhesin FimH, and thus autoantibodies to LAMP-2 may arise by molecular mimicry secondary to infection. Rats injected with anti–LAMP-2 or immunized with FimH develop pauci-immune focal necrotizing and crescentic GN. If these exciting observations are confirmed, anti–LAMP-2 antibodies will be a useful marker for pauci-immune small- vessel vasculitis but also may prove to be critically important in the pathogenesis of pauci-immune vasculitis and GN.
  15. 15. DefinitionClassificationEtiology and AssociationsPathogenesisClinical PresentationTreatment
  16. 16. Clinical PresentationVasculitis should be considered in patients who present withsystemic symptoms as fever, malaise ,myalgias, and weight loss,with evidence of single and or multiorgan dysfunction.The presence of certain signs is strongly suggestive.●Mononeuritis multiplex●Palpable purpura●Pulmonary-renal involvementRenal presentation of systemic vasculitis●Hematuria ●Proteinuria ●Hypertension●Rapidly progressive glomerulonephritis
  17. 17. Renal manifestations of individual vasculitis Takayasu’s ArteritisLarge Vessel Vasculitis: Giant cell arteritis●Renovascular hypertension. Polyarteritis NodosaMedium-Sized Vessel Vasculitis: Kawasaki’s Disease●The major targets are the interlobar and arcuate arteries●Necrotizing arteritis with transmural inflammation that can lead to the formation of pseudoaneurysms.●Pseudoaneurysms may rupture causes severe, even fatal, retroperitoneal, and intraperitoneal hemorrhage.●Glomerulonephritis not a feature, but they can cause hematuria, proteinuria (usually less than 2 g/24 hours), and renal insufficiency as a result of renal infarction
  18. 18. Renal manifestations of systemic vasculitisSmall Vessel Vasculitis●Hematuria with dysmorphic red blood cells and RBC casts.●Proteinuria is usually moderate (2–3 g/day) but may be 20 g/day.●Asymptomatic hematuria with minimal amounts of proteinuriaPauci-immune small vessel vasculitis●Pauci-immune is the most common type of crescentic GN.●Necrotizing and crescentic glomerulonephritis,●Either alone “renal-limited ANCA” or as a component of a systemic disease.‫٭‬Have little or no vascular wall localization of immunoglobulins
  19. 19. CryoglobulinemiaPolyarteritis nodosa Giant Henoch-Schönleindisease Lupus cell arteritis Kawasakis Wegeners disease purpura Thick-walledTakayasus right upper lobe Saddle-nose Palatal ulcer cavity arteritis
  20. 20. Glomerulonephritis in Small vessel vasculitisWegener’s granulomatosis 80%Churg–Strauss syndrome 45%Microscopic polyangiitis 90%Henoch-Schönlein purpura 50%Cryoglobulinaemic vasculitis 55%SLE 50%PAN No
  21. 21. WHY IS THE DISEASE SOMETI LIMITED TO THE KIDNEYS ?No definite answer .Two types of reasoning exist .FirstThe disease process itself might specifically target a particular,organ-specific vasculature.SecondVasculature became immunogenic●Previously unrecognized antigen by the immune system e.g. IV collagen●Deposition of antigen e.g., in situ formation of immune complexes in poststreptococcal glomerulonephritis.●Change of a preexisting antigen (formation of neoepitopes)●Change in endothelial function.
  22. 22. Renal biopsy findingsLesions MPA RLV WGNormal glomeruli 21% 27% 40%Fibrinoid necrosis 21% 21% %23 Crescents 47% 49% 42%Glomerulosclerosis 30% 23% 16%Periglomerular granulomas 2% 4%Interstitial infiltrate ++ ++ -/+Interstitial fibrosis ++ ++ -/+Tubular atrophy ++ ++ -/+Tubular necrosis ++ ++ -/+Arteriosclerosis ++ ++ -/+
  23. 23. RENAL TRANSPLANTATION INPAUCI-IMMUNE RENAL DISEASE♠20% to 40% of patients with ANCA-associated renal vasculitis develop ESRD.♠Allograft survival is comparable with other inflammatory renal diseases♠Recurrent vasculitis occurs in about 17% of patients with ANCA vasculitis following renal transplantation.♠The mean time to recurrence is roughly 31 months, although recurrence has been reported within days and up to 13 years after transplantation
  24. 24. DefinitionClassificationEtiology and AssociationsPathogenesisClinical PresentationTreatment
  25. 25. Large-vessel vasculitisGiant cell arteritis 2 w. 4 w. ↓Every®Prednisone Rapid improve 60 mg/d ↓to 50 40 ↓10% 1 - 2 w.☺Acute visual loss 1 g/d methylprednisolone for 3 to 5 daysTakayasu arteritis Relieve 25% to 100%®Prednisone 1 mg/kg 1-3 M Persistent disease®Cytotoxic therapy MTX 15 to 25 mg/wk + Prednisone ↑Remission and ↓ side effect CYC Severe disease . Unresponsive . Intolerant®Surgery Stents Angioplasty By pass
  26. 26. Medium-Sized Vessel VasculitisKawasaki’s disease®Intravenous 2 g/kg Prevent coronary aneurysm ↓ myocardial inflammation immunoglobulin + mg/kg Lessen fever® Aspirin 80 -100 Multiple aneurysms®Long-term anticoagulation Giant aneurysms Coronary obstruction®Corticosteroid contraindicatedPolyarteritis nodosa®High-dose corticosteroids 6 m-12 m. Beneficial +® Cyclophosphamide 2 mg/kg Improves®Antiviral agents Hepatitis B virus-associated PAN outcomes.
  27. 27. Small-vessel vasculitisWegener’s granulomatosis ®MTX. 20 to 25 mg/wk Or ®AZA.2 mg/kg/day OrActive WG life-threatening ®Mycophenolate mofetil Remission maintenance® Cyclophosphamide 2 mg/kg Stopped 3-6m. 4 weeks + improvement Tapered®Prednisone 1 mg/kg per day Prednisone is tape 6-12 m.Active but nonsevere disease Discontinued®Prednisone Effective And + inducing Maintaining remission®MTX.20-25 mg/wk For 2 y.
  28. 28. Small-vessel vasculitisWegener’s granulomatosisFulminant disease immediately threatening to life®Methylprednisolone 1 g/d 3 days Prednisone.1mg/kg/day®CYC 3-4 mg/kg/day ↓2 mg/kg per day 7 sets within 14 days®Plasmapheresis benefit in patients Replaced by 5% albumin with RPGN 60 mg/kg. Patients with®Rituximab 375 mg/m2 IV weekly active severe WG“anti-CD20” 4 weeksBefore the development of treatment, mean survival time 5 monthsWith treatment 5-year survival rate was 74%
  29. 29. Henoch-Schönlein purpura●Typically self-limited condition often does not require treatment Improve •Tissue edema®Glucocorticoids. •Arthritis •Abdominal discomfort •↓rate of intussusception®Glucocorticoids Beneficial + Active glomerulonephritis and®Cytotoxic agent progressive renal insufficiencyCryoglobulinemic vasculitis®IFN-a + HCV-associated®Ribavirin Cryoglobulinemic vasculiti ↑viremia®Immunosuppressive drugs Transiently improve not practical®Plasmapheresis Brief responses®Rituximab Favorable results
  30. 30. Churg–Strauss syndrome CSS Asthma often persists®Prednisone. 1 mg/kg / day Effective ↓Steroid discontinuation®Glucocorticoids + Life-threatening disease®CYC.2 mg/kg / dayCutaneous vasculitis®Glucocorticoids®Nonsteroidal anti-inflammatoryagents®Antihistamines®Dapsone®Hydroxychloroquine.®Colchicine Severe disease that is®Cytotoxic agents unresponsive to other measures
  31. 31. ANtigLomERuLAR BAsEmENt mEmBRANE DisEAsE ANDgooDpAstuRE’s DisEAsE
  32. 32. ETIOLOGY AND PATHOGENESIS1-Autoimmunity to a Component of the Glomerular Basement Membrane• autoimmunity to the carboxyl terminal, noncollagenous (NC1) domain of a type IV collagen chain, α3(IV)NC1, also known as the Goodpasture antigen2- Predisposing Factors:• HLA class II alleles, including DRB1*1501 and DR4 alleles• DR1 and DR7 confer strong and dominant protection
  33. 33. ETIOLOGY AND PATHOGENESIS3- Precipitating Factors
  34. 34. CLINICAL MANIFESTATIONSLung Hemorrhage :• alone or in association with renal affection• Cough , dyspnea , hemoptysis , consolidation• The most sensitive indicator of recent lung hemorrhage is an increased uptake of inhaled carbon monoxide (Dlco).• Patients with lung hemorrhage are usually current cigarette smokers.
  35. 35. CLINICAL MANIFESTATIONSGlomerulonephritis:• Hematuria , oliguria , loin pain• Dysmorphic RBCs , red cell cast , proteinuria• Normal kidney or enlarged on U/S
  36. 36. PATHOLOGYLight Microscopy :• Diffuse proliferative GN with variable degrees of necrosis, crescent formation, glomerulosclerosis, and tubular loss• The degree of crescent formation and tubular loss correlates with renal prognosis
  37. 37. PATHOLOGYImmunohistology :• linear deposition of immunoglobulin along the GBM is pathognomonic.• The immunoglobulin is usually IgG, sometimes with IgA or IgM, but very rarely IgA alone is detected.• Linear deposition of C3 is detectable in about 75% of biopsies.
  38. 38. Anti–Glomerular Basement Membrane Antibodies• Circulating IgG anti-GBM antibodies are almost invariably present, even in the rare instances in which only IgM or IgA is demonstrated on the GBM.• They may be detected and quantified by use of immobilized Goodpasture antigen in an immunoassay.• The titer of anti-GBM antibody at presentation correlates with the severity of nephritis.• Treatment and relapse are often mirrored by changes in titer.
  39. 39. TREATMENT
  40. 40. TREATMENT
  41. 41. Monitoring Effect of Treatment on Disease Activity• The effect of treatment on the renal disease is monitored by following serum creatinine values.• Indicators of recent lung hemorrhage include hemoptysis, decreases in hemoglobin concentration, chest radiograph changes, and increases in the Dlco,• Monitoring of anti-GBM titers during and particularly 24 hours after the last planned plasma exchange treatment is useful for confirming effective suppression of autoantibodies. They should be undetectable within 8 weeks
  42. 42. Thank you