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快快快快快快快快 快快 快快快快快快快快 快快 Rapidly progressive Rapidly progressive glomerulonephritis glomerulonephritis (RPGN) (RPGN)

快速進行性腎絲球體腎炎 Rapidly progressive glomerulonephritis (RPGN)

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Text of 快速進行性腎絲球體腎炎 Rapidly progressive glomerulonephritis (RPGN)

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  • Rapidly progressive glomerulonephritis (RPGN)
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  • Historical background 1914 Volhard and Fahr 1914 Volhard and Fahr Post mortem findings Post mortem findings Extracapillary proliferation (or crescentic GN) Extracapillary proliferation (or crescentic GN) 1942 Ellis 1942 Ellis From a clinical standpoint From a clinical standpoint Introduce the term 'rapidly progressive glomerulonephritis (most of these patients having severe poststreptococcal disease) Introduce the term 'rapidly progressive glomerulonephritis (most of these patients having severe poststreptococcal disease) 1948 Davson, Ball and Platt 1948 Davson, Ball and Platt Described patients with systemic small vessel vasculitis and prominent crescent formation Described patients with systemic small vessel vasculitis and prominent crescent formation Distinguished microscopic polyarteritis from poststreptococcal disease Distinguished microscopic polyarteritis from poststreptococcal disease
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  • By the mid-1960s By the mid-1960s Crescentic' nephritis was a large and heterogeneous group Crescentic' nephritis was a large and heterogeneous group Crescents occur whenever breaks in glomerular capillaries allow leakage of cells and plasma proteins into Bowman's space Crescents occur whenever breaks in glomerular capillaries allow leakage of cells and plasma proteins into Bowman's space By the end of the 1960s By the end of the 1960s RPGN had been separated into the three groups on the basis of immunopathological findings RPGN had been separated into the three groups on the basis of immunopathological findings
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  • RPGN separated on the immunopathological findings Immunohistology Serological markers Disease Circulating anti-GBM Abs and linear deposition of Abs along the GBM Anti-GBM antibodies Anti-GBM disease or Goodpastures disease Renal microscopic vasculitis characterized by scanty glomerular deposits of immunoglobulin with or without signs of systemic vasculitis C-ANCAP-ANCA Wegeners granulomatosis Microscopic polyangiitis Heterogeneous group, often associated with granular deposits of immunoglobulin, in which crescent formation complicates an identifiable form of nephritis Anti-DNA antibodies Cryoglobulinemia Complement reduction Systemic infections, e.g. post- streptococal nephritis, HIV, systemic immune disease, e.g. SLE, Henoch-scholein purpura, rheumatoid arthritis. Crescents complicating pre- existing nephritis, e.g. IgA, mesangiocapillary nephritis
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  • Rapidly progressive glomerulonephritis Definition: Definition: Clinical entity: Clinical entity: A rapid loss of renal function (usually a 50 % decline in GFR) within three months A rapid loss of renal function (usually a 50 % decline in GFR) within three months Pathological finding: Pathological finding: Extensive crescent formation (usually involving over 50% of the glomeruli) Extensive crescent formation (usually involving over 50% of the glomeruli) Crescents occur whenever breaks in glomerular capillaries allow leakage of cells and plasma proteins into Bowmans space Crescents occur whenever breaks in glomerular capillaries allow leakage of cells and plasma proteins into Bowmans space
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  • Infectious diseases Infectious diseases Poststreptococcal GN Poststreptococcal GN Infectious endocarditis Infectious endocarditis Visceral sepsis Visceral sepsis Hepatitis B or C infection with vasculitis and/or cryoimmunoglobulinemia Hepatitis B or C infection with vasculitis and/or cryoimmunoglobulinemia Multisystemi diseases Multisystemi diseases Systemic lupus erythematosus Systemic lupus erythematosus Goodpasture s disease Goodpasture s disease Henoch-Schonlein purpura Henoch-Schonlein purpura Necrotizing vasculitis (including Wegener s gransulomatosis) Necrotizing vasculitis (including Wegener s gransulomatosis) Cryoimmunoglobinemia (hepatitis B or C related) Cryoimmunoglobinemia (hepatitis B or C related) Neoplasia Neoplasia Relapsing polychondritis Relapsing polychondritis Bechet s disease Bechet s disease Drugs and toxic agents Allopurinol D-Penicillamine Hydralazine Rifampicin Superimposed on primary glomerular disease Membranoproliferative GN (type I, II) Membranous GN IgA nephropathy Idiopathic Type I: Antiglomerular basement membrane antibody disease Type II: immune complex-mediated disease Type III: pauci-immune (ANCA- associated) disease Type IV: mixed and anti-GBM and anti-ANCA associated disease
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  • Relationship of vasculitic clinicopathologic syndromes to immunopathologic categories of vascular injury in patients with crescentic GN Immune complex Disease P-ANCA Disease C-ANCA Disease Glomerulonephritis Alone Systemic vasculitis Pulmonary- Renal vasculitic syndrome Wegeners Granulomatosis Anti-GBM Disease
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  • Clinical features Clinical features common to the three forms of RPGN include Clinical features common to the three forms of RPGN include Hematuria Hematuria Proteinuria Proteinuria Decreased urine output Decreased urine output Edema Edema Hypertension Hypertension
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  • The urinalysis typically reveals The urinalysis typically reveals Hematuria, with dysmorphic red blood cells (RBC), RBC casts Hematuria, with dysmorphic red blood cells (RBC), RBC casts Variable degrees of proteinuria Variable degrees of proteinuria
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  • Dysmorphic red blood cells (RBC)
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  • Pathological finding Bowmans space Crescent
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  • Crescent glomerulonephritis (Histological classification) Type I: Anti-glomerular basement membrane (anti- GBM) antibody-associated RPGN (95% crescents) Type I: Anti-glomerular basement membrane (anti- GBM) antibody-associated RPGN (95% crescents) Goodpastures syndrome Goodpastures syndrome Type II: Immune complex RPGN (20~50% crescents) Type II: Immune complex RPGN (20~50% crescents) Systemic lupus erythematosus Systemic lupus erythematosus IgA nephropathy (including Henoch-Schonlein purpura) IgA nephropathy (including Henoch-Schonlein purpura) Cryoglobulinemic vasculitis Cryoglobulinemic vasculitis Type III: Pauci immune-associated glomerulonephritis Type III: Pauci immune-associated glomerulonephritis Idiopathic crescentic GN Idiopathic crescentic GN Wegeners granulomatosis GN Wegeners granulomatosis GN Microscopic polyarteritis (polyangiitis) GN Microscopic polyarteritis (polyangiitis) GN
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  • Immunopathological findings Linear deposits Scanty deposits Granular deposits Anti-GBM antibody- associated RPGN Immune complex RPGN Pauci immune- associated glomerulonephritis
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  • Pauci-immune RPGN Definition Absence or paucity of glomerular staining for immunoglobulins In approximately 80% of patients, pauci- immune crescentic GN is associated with ANCA and thus can be called ANCA-associated crescentic GN
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  • ANCA ANCA: Antibody to Neutrophil Cytoplasmic Antigen (proteins in the granules of neutrophils and the lysosomes of monocytes) Two main target antigens have been identified in patients with small vessel vasculitis: Proteinase-3(PR3): C (cytoplasmic) -ANCA Myeloperoxidase (MPO): P (peri-nuclear) -ANCA
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  • ANCA-positive vasculitis: Pathogenesis ANCA can bind and activate neutrophil leading to ANCA can bind and activate neutrophil leading to Enhanced adhesion of activated neutrophil to activate endothelial cells Enhanced adhesion of activated neutrophil to activate endothelial cells Dysregulated apotosis, secondary necrosis (nPMN) Dysregulated apotosis, secondary necrosis (nPMN) Enhanced neutrophil migration across the endothelial barrier Enhanced neutrophil migration across the endothelial barrier
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  • Approximately 3/4 of patients with pauci- immune or ANCA-associated crescentic glomerulonephritis have systemic small-vessel vasculitis. Approximately 3/4 of patients with pauci- immune or ANCA-associated crescentic glomerulonephritis have systemic small-vessel vasculitis.
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  • The three clinicopathologic categories of ANCA-associated, systemic, small-vessel vasculitis The three clinicopathologic categories of ANCA-associated, systemic, small-vessel vasculitis Microscopic polyangiitis Microscopic polyangiitis Wegener's granulomatosis Wegener's granulomatosis Churg-Strauss syndrome Churg-Strauss syndrome
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  • 80% 20%
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  • Treatment Low salt diet Low salt diet Low potassium diet Low potassium diet Low protein diet Low protein diet Hypertensive control: ACE inhibitor or Angiotensin II receptor antagonist Hypertensive control: ACE inhibitor or Angiotensin II receptor antagonist High dose steroid High dose steroid Immunocytotoxic agent (endoxan) Immunocytotoxic agent (endoxan) Plasmaphresis Plasmaphresis
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  • Evidence-Based Recommendations of Treatment : Pauci-immune RPGN Recommendation 1. Recommendation 1. Initial steroid treatment is methylprednisolone 7 to 15 mg/kg/day to a maximum of 1 g/day three days, then Initial steroid treatment is methylprednisolone 7 to 15 mg/kg/day to a maximum of 1 g/day three days, then Prednisone 1 mg/kg/day for one month, gradually tapered over the next 6 to 12 months. Prednisone 1 mg/kg/day for one month, gradually tapered over the next 6 to 12 months.
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  • Recommendation 2. Recommendation 2. Cyclophosphamide should be given either orally at a dose of 2 mg/kg/day adjusted to maintain the leukocyte count between 3 and 5 thousand/ml or intravenously starting at 0.5 g/m 2 /month and increased monthly by 0.25 g to a maximum of 1 g/m 2 per month. Cyclophosphamide should be given either orally at a dose of 2 mg/kg/day adjusted to maintain the leukocyte count between 3 and 5 thousand/ml or intravenously starting at 0.5 g/m 2 /month and increased monthly by 0.25 g to a maximum of 1 g/m 2 per month. The dose should be adjusted to maintain a nadir of leukocyte count two weeks post-treatment between 3 and 5 thousand/ml. The dose should be adjusted to maintain a nadir of leukocyte count two weeks post-treatment between 3 and 5 thousand/ml. Cyclophosphamide should be continued for 6 to 12 months. Cyclophosphamide should be continued for 6 to 12 months. Treatment should be given even in advanced patients. Treatment should be given even in advanced patients.
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  • Recommendation 3. Recommendation 3. Consider plasmapheresis in patients with lung hemorrhage and those with severe disease and no response to conventional therapy. Consider plasmapheresis in patients with lung hemorrhage and those with severe disease and no response to conventional therapy. Recommendation 4. Recommendation 4. Monitoring for relapse with clinical follow-up, renal function tests, and ANCA is recommended. Monitoring for relapse with clinical follow-up, renal function tests, and ANCA is recommended. Recommendation 5. Recommendation 5. Treatment of relapses should be similar to original treatment. Treatment of relapses should be similar to original treatment.
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  • Treatment for pauci-immune crescentic GN should be Treatment for pauci-immune crescentic GN should be Pulse methylprednisolone Pulse methylprednisolone Followed by oral corticosteroids and cyclophosphamide for 6 to 12 months Followed by oral corticosteroids and cyclophosphamide for 6 to 12 months
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  • Evidence-Based Treatment Recommendations of RPGN : Summary Because of the high risk of end-stage renal disease (ESRD), early aggressive therapy is recommended. Because of the high risk of end-stage renal disease (ESRD), early aggressive therapy is recommended. Treatment for anti-GBM antibody-induced crescentic GN should be initiated early and should include Treatment for anti-GBM antibody-induced crescentic GN should be initiated early and should include Pulse methylprednisolone Pulse methylprednisolone A two-week course of plasmapheresis A two-week course of plasmapheresis Two months of treatment with corticosteroids and cyclophosphamide. Two months of treatment with corticosteroids and cyclophosphamide.
  • Slide 28
  • Treatment for pauci-immune crescentic GN should be Treatment for pauci-immune crescentic GN should be Pulse methylprednisolone Pulse methylprednisolone Followed by oral corticosteroids and cyclophosphamide for 6 to 12 months Followed by oral corticosteroids and cyclophosphamide for 6 to 12 months
  • Slide 29
  • Management of immune complex- mediated RPGN Treat according to their specific underlying condition. Treat according to their specific underlying condition. Underlying disease including Underlying disease including postinfectious GN, IgA nephropathy, Henoch-Schnlein purpura, lupus nephritis, membranous nephropathy, and membranoproliferative GN postinfectious GN, IgA nephropathy, Henoch-Schnlein purpura, lupus nephritis, membranous nephropathy, and membranoproliferative GN A few patients with true idiopathic immune complex crescentic RPGN should be treated similarly to those with pauci-immune RPGN. A few patients with true idiopathic immune complex crescentic RPGN should be treated similarly to those with pauci-immune RPGN.
  • Slide 30
  • Standard Treatment of RPGN Standard Treatment of RPGN High-dose corticosteroids High-dose corticosteroids Cytotoxic immunosuppressive drugs Cytotoxic immunosuppressive drugs Cyclophosphamide (Endoxan) Cyclophosphamide (Endoxan) Plasmapheresis is indicated for Plasmapheresis is indicated for Anti-GBM GN Anti-GBM GN ANCA GN with pulmonary hemorrhage ANCA GN with pulmonary hemorrhage
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  • Additional therapeutic agents Other cytotoxic agents: Other cytotoxic agents: Azathioprine, methotrexate, MMF, cyclosporin Azathioprine, methotrexate, MMF, cyclosporin Future therapies Future therapies Leflunomide Leflunomide Inhibitor of de novo pyrimidine synthesis Inhibitor of de novo pyrimidine synthesis Deoxyspergualin Deoxyspergualin Tumor necrosis factor (TNF) blockade Tumor necrosis factor (TNF) blockade Antibodies against T cells Antibodies against T cells
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  • Predictive value of the effect of plasmapheresis on long-term prognosis of RPGN This prospective multicenter study randomized 39 patients with biopsy-proven RPGN (Couser type II, n = 6; pauci-immune type III, n = 33) to undergo either immunosuppressive therapy with prednisone and cyclophosphamide (n = 18) or plasmapheresis in addition to immunosuppression (n = 21). This prospective multicenter study randomized 39 patients with biopsy-proven RPGN (Couser type II, n = 6; pauci-immune type III, n = 33) to undergo either immunosuppressive therapy with prednisone and cyclophosphamide (n = 18) or plasmapheresis in addition to immunosuppression (n = 21). Patients were observed for a mean of 127 months or until reaching the end points of hemodialysis or death. Patients were observed for a mean of 127 months or until reaching the end points of hemodialysis or death. AJKD, Jan 2002, Vol 39 No 1
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  • Plasmapheresis had no significant effect on renal or patient survival in type II or pauci-immune (type III) RPGN, independently of age, sex, or serum creatinine level at the time of diagnosis. Plasmapheresis had no significant effect on renal or patient survival in type II or pauci-immune (type III) RPGN, independently of age, sex, or serum creatinine level at the time of diagnosis. Patients were dialysis dependent within 24 months if more than one third of glomeruli were totally sclerosed. Patients were dialysis dependent within 24 months if more than one third of glomeruli were totally sclerosed. Interstitial fibrosis also correlated significantly with the risk for progression to renal failure. Interstitial fibrosis also correlated significantly with the risk for progression to renal failure. Conversely, long-term dialysis-free survival was significantly more likely in patients with a greater number of crescents than in those with a low number of crescents. Conversely, long-term dialysis-free survival was significantly more likely in patients with a greater number of crescents than in those with a low number of crescents.
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  • Conclusion Plasmapheresis did not improve short- or long-term outcome in type II or III RPGN. Plasmapheresis did not improve short- or long-term outcome in type II or III RPGN. Glomerular sclerosis and interstitial fibrosis on initial histological examination are highly predictive of the development of ESRD. Glomerular sclerosis and interstitial fibrosis on initial histological examination are highly predictive of the development of ESRD. Conversely, glomerular crescents may reflect a reversible glomerular pathological state because their presence was associated with improved outcome after cyclophosphamide and steroids as treatment of RPGN type II and III. Conversely, glomerular crescents may reflect a reversible glomerular pathological state because their presence was associated with improved outcome after cyclophosphamide and steroids as treatment of RPGN type II and III. Overall, approximately 50% of patients are alive and off dialysis therapy 10 years after the diagnosis of type II or type III RPGN using immunosuppression with cyclophosphamide and prednisone. Overall, approximately 50% of patients are alive and off dialysis therapy 10 years after the diagnosis of type II or type III RPGN using immunosuppression with cyclophosphamide and prednisone.
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  • Indication of plasmapheresis in RPGN Anti-GBM associated RPGN Anti-GBM associated RPGN Standard therapy and acceptable Standard therapy and acceptable Pauci-immune RPGN Pauci-immune RPGN Insufficient reported evidence Insufficient reported evidence Acceptable for dialysis-dependent patients or patients with pulmonary hemorrhage Acceptable for dialysis-dependent patients or patients with pulmonary hemorrhage Immune complex RPGN Immune complex RPGN HUS-TTP: standard therapy and accept HUS-TTP: standard therapy and accept Insufficienct reported evidence: Multiple myeloma, lupus nephritis, IgA nephropathy, Henoch-Sconlein purpura, sepsis Insufficienct reported evidence: Multiple myeloma, lupus nephritis, IgA nephropathy, Henoch-Sconlein purpura, sepsis Cryoglobulinemia: insufficient reported evidence; acceptable for patients with acute active and severe disease Cryoglobulinemia: insufficient reported evidence; acceptable for patients with acute active and severe disease
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  • Endothelial cells may be damaged directly by Endothelial cells may be damaged directly by Inflammatory mediators released from activated neutrophils, or Inflammatory mediators released from activated neutrophils, or Damaged as neutrophils undergo secondary necrosis in the vascular lumina, amplifying inflammation Damaged as neutrophils undergo secondary necrosis in the vascular lumina, amplifying inflammation After initiation of vasculitic lesion by the interactions of neutrophils, ANCA, and endothelial cells, After initiation of vasculitic lesion by the interactions of neutrophils, ANCA, and endothelial cells, Further PMNs are recruited Further PMNs are recruited Further enhancing vascular inflammation and injury Further enhancing vascular inflammation and injury
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  • ANCA-positive vasculitis: diagnosis Clinical findings Clinical findings Biopsy of a relevant involved organ (typically kidney, nasal mucosa, or occassionally lung) Biopsy of a relevant involved organ (typically kidney, nasal mucosa, or occassionally lung) The presence of ANCA The presence of ANCA
  • Slide 39
  • Certain drug exposures are known to induce multiple autoantibodies, including ANCA. Certain drug exposures are known to induce multiple autoantibodies, including ANCA. For example, hydralazine and propylthiouracil can induce ANCA and pauci-immune crescentic glomerulonephritis. For example, hydralazine and propylthiouracil can induce ANCA and pauci-immune crescentic glomerulonephritis.
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  • Uremic bleeding
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  • Introduction Platelet dysfunction: Platelet dysfunction: defects intrinsic to the platelet and abnormal defects intrinsic to the platelet and abnormal platelet endothelial interaction platelet endothelial interaction Uremic toxins and anemia Uremic toxins and anemia
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  • Clinical features Frequent -- easy bruising, mucosal bleeding Frequent -- easy bruising, mucosal bleeding Less freqeunt epistaxia, gingival bleeding, hematuria Less freqeunt epistaxia, gingival bleeding, hematuria Uncertain GI bleeding ? Uncertain GI bleeding ?
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  • Pathogenesis Decreased platelet aggregation Decreased platelet aggregation Impaired platelet adhesiveness Impaired platelet adhesiveness
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  • Intrinsic factors: abnormal expression of platelet glycoproteins, altered release of ADP and serotonin from platelet alpha-granules, faulty arachidonic acid and depressed prostaglandin metabolism, decreased platelet thromboxane A2 and abonormal platelet cytoskeletal assembly Extrinsic factors: uremic toxins, anemia, increased nitric oxide production, von Willebrand factor abnormalities, decreased platelet production and abnormal interactions between the platelet and the endothelium of the vessel
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  • Treatment Correction of anemia Correction of anemia raising the hematocrit to above 25~30% raising the hematocrit to above 25~30% Erythropoietic stimulating agents could increase the number of GP IIb/IIIa molecules on the platelet membrane Erythropoietic stimulating agents could increase the number of GP IIb/IIIa molecules on the platelet membrane DDAVP DDAVP Dialysis Dialysis Estrogen Estrogen Cryoprecipitate Cryoprecipitate