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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

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

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

10. Dysmorphic red blood cells (RBC)

11. Pathological finding
Crescent
Bowman’s space

12. 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

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

14. 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

15. 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

16. 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

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

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

21. 80%
20%

22. 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

23. 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.

24. 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.

25. 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.

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

27. 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.

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

29. 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.

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

31. 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

32. 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

33. 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.

34. 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.

35. 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

37. 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

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

39. Certain drug exposures are known to induce multiple autoantibodies, including ANCA.
For example, hydralazine and propylthiouracil can induce ANCA and pauci-immune crescentic glomerulonephritis.

40. Uremic bleeding

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

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

43. Pathogenesis Decreased platelet aggregation
Impaired platelet adhesiveness

44. 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

45. 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