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  • 1. Pulmonary-Renal Syndrome Alanna Beckman MSIV
  • 2. Pulmonary-Renal Syndrome
    • Potentially life-threatening disorder,
      • Diffuse alveolar hemorrhage
        • pulmonary capillaritis
      • In conjunction with
      • Rapidly progressive glomerulonephritis
    • AGN/RPGN +/- lung hemorrhage is and emergency  requires early diagnosis and treatment.
  • 3. Diffuse Alveolar Hemorrhage
    • Presentation of patients with DAH can range from cough with or without hemoptysis to severe respiratory distress.
    • Onset is usually abrupt.
    • Suspect DAH:
      • Hemoptysis (Absent in 1/3 of patients)
      • Radiographic Abnormalities (Alveolar opacities, Interstitial opacities, Fibrosis)
      • Unexplained drop in Hematocrit
    Capillaritis: neutrophile infiltrates and hemorrhage
  • 4. Rapidly Progressive Glomerulonephritis
    • Acute onset (days to weeks)
    • Acute renal failure and oliguria (400mL/day)
    • Renal Blood flow and GFR  fall
      • Obstruction of the glomerular capillary lumen
        • By infiltrating inflammatory cells
        • Proliferating resident glomerular cells.
      • Intrarenal vasoconstricion and mesangial cell contraction
        • Local imbalances of vasoconstrictors (leukotrienes, endothelins, thromboxanes, platelet-activating factor) and vasodilators ( NO, prostacyclin ) in the microcirculation of the kidney.
  • 5. Pulmonary-Renal Syndromes
    • ANCA-associated vasculitides account for approximately 60%
    • Goodpasture's Syndrome for approximately 20% of the cases.
    • Other causes 20%
  • 6.  
  • 7. Work-up for GN
    • ANCA
    • Anti-GBM
    • Complement levels (C3,C4)
    • Depending on history/clinical suspicion:
      • ANA
      • ASLO
      • BCx
      • Cryocrit
      • Hepatitis serologies
    • Renal Biopsy
      • Immunofluorescence
      • Electron microscopy
      • (Light microscopy)
    • Consider GN mimics: thrombotic microantiopathy, cholesterol emboli, AIN, myeloma
    • For Pulmonary-Renal Syndrome you will also want to bx other tissues.
  • 8. Goodpastures
    • Autoimmune
      • Autoantibodies directed against type IV collagen  RPGN and crecentic glomerulonephritis.
      • 50-80% have lung hemorrhage.
      • Bimodal distribution:
        • Typically young males (5-40years) Male:Female ratio = 6:1
        • Presentation in second peak, 6 th decade, generally do not have lung hemorrhage and have almost equal sex distribution.
  • 9. Goodpasture’s Syndrome
      • Common presentation:
        • Hematuria
        • Nephritic urinary sediment (dysmorphic RBC &/or RBC casts)
        • Subnephrotic proteinuria (<3.5 g/24 hours)
        • Rapidly progressive renal failure over weeks
        • With or without pulmonary hemorrhage
          • Pulmonary hemorrhage, when it does occur, usually predates nephritis by weeks or months.
          • Lung involvement can vary from fluffy pulmonary infiltrates on CXR with mild dyspnea on exertion to potentially fatal pulmonary hemorrhage
        • Usually not hypertensive.
  • 10. GP Diagnosis
    • Diagnostic serologic marker is anti-GBM antibodies with a specificity for NCI domain of the alpha3 chain of type IV collagen.
    • These antibodies are detected in >90% of patients with anti-GBM nephritis.
    • RENAL BIOPSY is the GOLD STANDARD for diagnosis of anti-GBM nephritis.
      • Light microscopy : diffuse proliferative GN with focal necrotizing lesions and crescents in >50% of glomeruli.
      • Immunofluorescence : linear ribbon-like deposits of IgG
      • Electron Microscopy : inflammatory change without immune deposits
  • 11. Normal Glomerulus RPGN/Crescentic GN
      • Immunofluoresence Microscopy:
      • “ Linear ribbon like” deposition of IgG along GBM
  • 12. GP Treatment
    • Emergency plasmapheresis is done daily or on alternate days until anti-GBM antibodies are not detected in circulation
    • Prednisone (1mg/kg per day) is started simultaneously along with cyclophosphamide (2 to 3 mg/kg per day) or azathioprine (1 to 2 mg/kg per day) to suppress new synthesis of anti-GBM antibodies.
  • 13. GP Prognosis
    • Without treatment, 80% get ESRD within 1 year
    • Early Treatment
      • If treatment is started early, before creatinine is over 5mg/dL, then 1 year survival is over 90%. It is 80% if renal failure is more advanced.
    • If patients require dialysis at time of presentation, they rarely recover renal function.
    • If crescents exist in >50% of glomeruli, then usually survival <2 yrs
    • Better response to treatment if ANCA +
  • 14. ANCA Vasculitis (pauci-immune)
        • Wegener’s Granulomatosis
        • Microscopic Polyangiitis
        • Churg-Strauss Arteritis
  • 15. ANCA + Vasculitis (pauci-immune) PR3 = Proteinase 3 MPO = Myeloperoxidase (found in granules of neutrophils/monocytes) 50% P-ANCA (anti-MPO) + 70% 45% + Churg-Strauss Syndrome 70% P-ANCA (anti-MPO) - 50% 90% - Microscopic polyantiitis 90% C-ANCA (anti-PR3) - 90% 80% + Wegener’s granulo-matosis ANCA positive ANCA type Asthma Pulmonary Renal Granulomas Disease
  • 16. ANCA-associated small vessel vasculitis
    • More common in Caucasian and elderly (mean age is 57 years)
    • Usual presentation: nonspecific constitutional symptoms and signs
      • Lethargy
      • Mailaise
      • Anorexia
      • Weight loss
      • Fever
      • Arthralgia
      • Myalgias
  • 17. ANCA-associated small vessel vasculitis
    • Nonspecific lab abnormalities
      • Rapid sedimentation rate
      • Elevated C-reactive protein
      • Leukocytosis
      • Thrombocytosis
      • Normochromic/normocytic anemia
      • Normal complement levels (usually)
  • 18. C-ANCA  PR3
  • 19. Wegener’s
    • Granulomatous vasculitis of the upper and lower respiratory tracts together with glomerulonephritis.
    • Prevalence is 3/100,000, very rare in blacks. M:F=1:1
    • Mean age of onset = 40 (but age of onset can vary widely)
  • 20. Wegener’s
    • Pathogenesis:
      • Necrotizing vasculitis of small arteries and veins with granuloma formation (either intra- or extravascular).
      • Lung involvement typically appears as multiple bilateral, nodular cavitary infiltrates. On biopsy they reveal typical necrotizing granulomatous vasculitis.
      • Upper airway lesions (especially sinuses and nasopharynx) reveal inflammation, necrosis and granuloma formation.
      • Renal involvement can be focal and segmental glomerulitis early in the disease but typically progresses to RPGN. RARELY are granulomas seen on renal biopsy.
  • 21. Wegener’s
    • Presentation
      • 95% have upper airway involvement
        • Paranasal sinus pain
        • Purulent or bloody nasal discharge with or without nasal mucosal ulceration.
        • Nasal septal perforation can occur leading to saddle nose deformity.
        • Serous otitis media can occur as a result of blockage of eustachian tube.
        • 16% will have subglottic tracheal stenosis (from active disease or scarring) which can cause airway obstruction.
  • 22. Wegener’s
    • Presentation
      • Pulmonary involvement in 85-90%
        • Cough, hemoptysis, dyspnea, chest discomfort.
        • Endo-bronchial disease (from active disease or scarring) can leads to obstruction with atelectasis
      • Renal involvement dominates the clinical picture
        • If left untreated, it accounts directly or indirectly for most mortality of the disease.
  • 23. Wegener’s
    • Diagnosis
      • Demonstration of necrotizing granulomatous vasculitis on tissue biopsy in a patient with compatible clinical features.
        • Pulmonary tissue biopsy offers the highest diagnostic yield.
        • Renal biopsy can confirm pauci-immune glomerulonephritis.
        • Upper airway tissue biopsy usually shows granulomatous inflammation with necrosis but may or may not show vasculitis.
  • 24. Wegener’s
    • Treatment
      • Glucocorticoids (predisone 1mg/kg/day) should be started for symptomatic improvement and then tapered over 6 months.
      • Cyclophosphamide (2mg/kg/day)
        • Monitor leukocyte count to adjust dose to maintain count above 3000/microL (neutrophile count of 1500). Gives you clinical remission without severe leukopenia and associated infectious risk.
  • 25. Wegener’s
    • Treatment
      • Relapse occurs in about 25% of patients.
        • Treatment for relapse is the same (goal is to achieve remission again).
        • Methotrexate or azathioprine can be given after remission is achieved and cyclophosphamide is stopped to maintain remission in patients that do relapse.
  • 26. P-ANCA  MPO
  • 27. Churg-Strauss
    • AKA allergic angiitis and granulomatosis .
    • Asthma
    • Peripheral and tissue eosinophilia
    • Extravascular granuloma formation
    • Vasculitis of multiple organ systems.
  • 28. Churg-Strauss
    • Incidence is estimated at 1 in 3 million.
    • Can occur at any age (not documented in infants).
    • Mean age is 48yrs.
    • M:F ratio= 1:1.2
  • 29. Churg-Strauss
    • Granulomatous reaction and eosinophil infiltration can occur in any organ in the body, but the lungs predominate. Other areas involved include:
      • Skin
      • Cardiovascular system
      • Kidney
      • Peripheral nervous system
      • Gastrointestinal tract
  • 30. Churg-Strauss
    • Presentation
      • Pulmonary findings clearly dominate clinical picture
        • Severe asthma attacks and presence of pulmonary infiltrates.
        • Mononeuritis multiplex
        • Allergic rhinitis and sinusitis
      • Heart disease (14%) = Most frequent cause of death.
  • 31. Churg-Strauss
    • Presentation
      • Skin involvement 51%
        • Include purpura in addition to cutaneous and subcutaneous nodules.
      • Renal involvement 45%
        • Less common than seen in Wegener’s and MPA
        • Severe glomerulonephritis
  • 32. Churg-Strauss
    • Biopsy of affected tissue (lung).
      • Microgranulomas , fibrinoid necrosis and throbosis of small arteries and veins ( necrotizing vasculitis ) with eosinophilic infiltrates.
    • Classification criteria (4 of 6 criteria is 85% Sensitive and 99.7% specific)
      • Asthma
      • Eosinophilia >10%
      • Mono- or polyneuropathy
      • Migratory or transitory pulm infiltrates
      • Paranasal sinus abnormality
      • Extravascular eosinophils on biopsy
  • 33. Churg-Strauss
    • Treatment
      • Glucocorticoids; high dose.
        • Attempt to taper. Asthma makes tapering difficult, patients may need to be maintained on low-dose prednisone for years after clinical recovery from vasculitis to control asthma.
      • Patients who do not respond to glucocorticoids alone, can be treated with cyclophosphamide and prednisone (similar to Wegener’s treatment).
  • 34. P-ANCA  MPO
  • 35. Microscopic Polyangiitis.
    • Necrotizing vasculitis with few or no immune complexes affecting small vessels (capillaries, venules, or arterioles).
    • Glomerulonephritis and pulmonary capillaritis are common in Microscopic Polyangiitis. ( NO pulmonary capillaritis in PAN).
    • Not associated with HBV like PAN
    • ABSENCE of granulomatous inflammation differentiates this disease from Wegener’s granulomatosis.
  • 36. Microscopic Polyangiitis
    • Incidence not really established because it use to be included in PAN.
    • Age of onset is about 57 years.
    • Slightly more occurrence in males than females.
  • 37. Microscopic Polyangiitis
    • Presentation
      • Vascular lesion is a necrotizing inflammation of capillaries, venules, as well as small and medium-sized arteries.
      • Rare immunoglobulin deposition seen in the vascular lesions.
      • Renal lesion is identical to that of Wegener’s granulomatosis lesion.
  • 38. Microscopic Polyangiitis
    • Renal involvement 90%
      • Glomerulonephritis, often rapidly progressive.
      • Can quickly lead to renal failure
    • Lung involvement 50%
      • Alveolar hemorrhage (12%)= hemoptysis
    • Mononeuritis multiplex
    • Gastrointestinal tract vasculitis
    • Cutaneous vasculitis.
    • (upper airway disease and pulmonary nodules are not typically found - if found: suggests Wegener’s)
  • 39. Microscopic Polyangiitis
    • Diagnosis
      • Biopsy of affected tissue.
        • Necrotizing pauci-immune inflammation of arterioles, capillaries and venules WITHOUT granulomas or eosinophilic infiltrates .
      • ANCA positive
  • 40. Microscopic Polyangiitis
    • Treatment
      • Similar approach to that of Wegener’s.
      • Relapse occurs in up to 34% of patients.
  • 41.  
  • 42. Differential Diagnosis for Pulmonary-Renal Syndrome
    • Goodpasture’s Disease
    • Systemic Vasculitis
      • Wegener’s Granulomatosis
      • Microscopic Polyangiitis
      • Churg-Strauss syndrome
      • Cryoglobulinemia
      • Henoch-Schonlein Purpura
    • Connective Tissue Disease
      • Polymyositis/Dermatomyositis
      • Progressive Systemic Sclerosis
      • SLE
    • Primary Glomerular Disease
      • IgA nephropathy
      • Post-Infectious GN
      • Membranoproliferative GN
    Pleural effusions/Lupus Pneumonitis + SLE GN + ASO titer, can continue to have pulmonary symptoms by the time renal symptoms manifest.
  • 43.  
  • 44. references
    • Harrison et. al, (2005), Principles of Internal Medicine, 16 th Edition, McGraw-Hill, NY
    • Jennette J. (1997), Small Vessel Vasculitis. New England Journal of Medicine; 21: 1512-1523.
    • PubMed: Renal-Pulmonary Syndrome. Retrieved on (9/1/09) from: http://www.ncbi.nlm.nih.gov/pubmed/15905974
    • Sabatine, Marc S,(2008) Pocket Medicine, 3 rd Edition, Lippincott Williams &Wilkins, Philadelphia
    • Toy, et.al. (2007), Case Files: Internal Medicine, Second Edition, McGraw-Hill, NY

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