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

Historical background 1914 Volhard and Fahr Post mortem findings Extracapillary proliferation (or crescentic GN) 1942 Ellis From a clinical standpoint Introduce the term 'rapidly progressive glomerulonephritis‘ (most of these patients having severe poststreptococcal disease) 1948 Davson, Ball and Platt Described patients with systemic small vessel vasculitis and prominent crescent formation Distinguished microscopic polyarteritis from poststreptococcal disease

By the mid-1960s By the end of the 1960s ‘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 By the end of the 1960s RPGN had been separated into the three groups on the basis of immunopathological findings

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 Goodpasture’s disease Renal microscopic vasculitis characterized by scanty glomerular deposits of immunoglobulin with or without signs of systemic vasculitis C-ANCA P-ANCA Wegener’s 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

Rapidly progressive glomerulonephritis Definition: Clinical entity: A rapid loss of renal function (usually a 50 % decline in GFR) within three months Pathological finding: 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 Bowman’s space

Infectious endocarditis Visceral sepsis 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 Infectious diseases Poststreptococcal GN Infectious endocarditis Visceral sepsis Hepatitis B or C infection with vasculitis and/or cryoimmunoglobulinemia Multisystemi diseases Systemic lupus erythematosus Goodpasture’s disease Henoch-Schonlein purpura Necrotizing vasculitis (including Wegener’s gransulomatosis) Cryoimmunoglobinemia (hepatitis B or C related) Neoplasia Relapsing polychondritis Bechet’s disease

Relationship of vasculitic clinicopathologic syndromes to immunopathologic categories of vascular injury in patients with crescentic GN Immune complex Disease Glomerulonephritis Alone P-ANCA Disease Systemic vasculitis Pulmonary- Renal vasculitic syndrome Wegener’s Granulomatosis C-ANCA Disease Anti-GBM Disease

Clinical features Clinical features common to the three forms of RPGN include Hematuria Proteinuria Decreased urine output Edema Hypertension

The urinalysis typically reveals Hematuria, with dysmorphic red blood cells (RBC), RBC casts Variable degrees of proteinuria

Dysmorphic red blood cells (RBC)

Pathological finding Crescent Bowman’s space

Crescent glomerulonephritis (Histological classification) Type I: Anti-glomerular basement membrane (anti-GBM) antibody-associated RPGN (95% crescents) Goodpasture’s syndrome Type II: Immune complex RPGN (20~50% crescents) Systemic lupus erythematosus IgA nephropathy (including Henoch-Schonlein purpura) Cryoglobulinemic vasculitis Type III: Pauci immune-associated glomerulonephritis Idiopathic crescentic GN Wegener’s granulomatosis GN Microscopic polyarteritis (polyangiitis) GN

Immunopathological findings Pauci immune-associated glomerulonephritis Anti-GBM antibody-associated RPGN Immune complex RPGN Linear deposits Granular deposits Scanty deposits

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

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

ANCA-positive vasculitis: Pathogenesis ANCA can bind and activate neutrophil leading to Enhanced adhesion of activated neutrophil to activate endothelial cells Dysregulated apotosis, secondary necrosis (nPMN) Enhanced neutrophil migration across the endothelial barrier

Approximately 3/4 of patients with pauci-immune or ANCA-associated crescentic glomerulonephritis have systemic small-vessel vasculitis.

The three clinicopathologic categories of ANCA-associated, systemic, small-vessel vasculitis Microscopic polyangiitis Wegener's granulomatosis Churg-Strauss syndrome

80% 20%

Treatment Low salt diet Low potassium diet Low protein diet Hypertensive control: ACE inhibitor or Angiotensin II receptor antagonist High dose steroid Immunocytotoxic agent (endoxan) Plasmaphresis

Evidence-Based Recommendations of Treatment : Pauci-immune RPGN 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.

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/m2/month and increased monthly by 0.25 g to a maximum of 1 g/m2 per month. 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. Treatment should be given even in advanced patients.

Recommendation 3. Recommendation 4. Recommendation 5. Consider plasmapheresis in patients with lung hemorrhage and those with severe disease and no response to conventional therapy. Recommendation 4. Monitoring for relapse with clinical follow-up, renal function tests, and ANCA is recommended. Recommendation 5. Treatment of relapses should be similar to original treatment.

Treatment for pauci-immune crescentic GN should be Pulse methylprednisolone Followed by oral corticosteroids and cyclophosphamide for 6 to 12 months

Evidence-Based Treatment Recommendations of RPGN : Summary 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 Pulse methylprednisolone A two-week course of plasmapheresis Two months of treatment with corticosteroids and cyclophosphamide.

Treatment for pauci-immune crescentic GN should be Pulse methylprednisolone Followed by oral corticosteroids and cyclophosphamide for 6 to 12 months

Management of immune complex-mediated RPGN Treat according to their specific underlying condition. Underlying disease including postinfectious GN, IgA nephropathy, Henoch-Schönlein 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.

Standard Treatment of RPGN High-dose corticosteroids Cytotoxic immunosuppressive drugs Cyclophosphamide (Endoxan) Plasmapheresis is indicated for Anti-GBM GN ANCA GN with pulmonary hemorrhage

Additional therapeutic agents Other cytotoxic agents: Azathioprine, methotrexate, MMF, cyclosporin Future therapies Leflunomide Inhibitor of de novo pyrimidine synthesis Deoxyspergualin Tumor necrosis factor (TNF) blockade Antibodies against T cells

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). 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

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. 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.

Conclusion 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. 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.

Indication of plasmapheresis in RPGN Anti-GBM associated RPGN Standard therapy and acceptable Pauci-immune RPGN Insufficient reported evidence Acceptable for dialysis-dependent patients or patients with pulmonary hemorrhage Immune complex RPGN HUS-TTP: standard therapy and accept 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

Endothelial cells may be damaged directly by Inflammatory mediators released from activated neutrophils, or 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, Further PMNs are recruited Further enhancing vascular inflammation and injury

ANCA-positive vasculitis: diagnosis Clinical findings Biopsy of a relevant involved organ (typically kidney, nasal mucosa, or occassionally lung) The presence of 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.

Uremic bleeding

Introduction Platelet dysfunction: defects intrinsic to the platelet and abnormal platelet endothelial interaction Uremic toxins and anemia

Clinical features Frequent -- easy bruising, mucosal bleeding Less freqeunt – epistaxia, gingival bleeding, hematuria Uncertain – GI bleeding ?

Pathogenesis Decreased platelet aggregation Impaired platelet adhesiveness

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

Treatment Correction of anemia  raising the hematocrit to above 25~30% Erythropoietic stimulating agents could increase the number of GP IIb/IIIa molecules on the platelet membrane DDAVP Dialysis Estrogen Cryoprecipitate