1. Rapidly progressive (crescentic) glomerulonephritis
Mini-topic
Rapidly progressive (crescentic) glomerulonephritis
박원영

2. RPGN RPGN (Rapidly progressive glomerulonephritis)
: clinical syndrome manifested
by features of glomerular disease in the urine
by progressive loss of renal function over a comparatively short period of time (days, weeks or months)
characterized morphologically by extensive crescent formation
The severity of the disease: the degree of crescent formation
: circumferential crescents in >80% of glomeruli
> advanced renal failure, not respond well to tx.
: crescents in <50%, or noncircumferential
> more indolent course

3. Pathogenesis of crescent formation
: nonspecific response to severe injury to the glomerular capillary wall
: Rents in the glomerular capillary wall
> the movement of plasma products (fibrinogen) into Bowman's space
(> with subsequent fibrin formation)
> the influx of macrophages and T cells
> the release of proinflammatory cytokines (IL-1, TNF-a)

4. Type of crescentic GN Type 1: Anti-GBM antibody disease
Type 2: Immune complex
Mesangial IgA deposits in IgA nephropathy
Antistreptococcal antibodies & subepithelial humps in Postinfectious glomerulonephritis
ANA & subendothelial deposits in lupus nephritis
Circulating cryoglobulins & intraluminal thrombi in mixed cryoglobulinemia
Membranous nephropathy (rarely)
Type 3:Pauci-immune
Necrotizing GN but few or no immune deposits
ANCA (+): 75~80% myeloperoxidase(MPO)-ANCA
> Wegener’s granulomatosis or microscopic polyangiitis

5. Type of crescentic GN Type 4: Double-antibody positive disease
Having features of both type 1 & 3
Idiopathic
Immune complex disease (type 2) that does not fit into any of the identifiable categories (rare)
Pauci-immune (type 3) disease that is ANCA-negative (<5% of crescentic GN)

6. Clinical presentation
Similar to those in severe postinfectious glomerulonephritis
: acute onset of macroscopic hematuria
decreased urine output
edema
: more commonly, insidious onset with the initial symptoms being
fatigue or edema
: renal insufficiency: at diagnosis in almost all cases, Cr > 3 mg/dL
: dysmorphic hematuria, red cell and other casts
: variable degree of proteinuria
: nephrotic syndrome : unusual, with less severe renal insufficiency

7. Clinical presentation
Systemic complaints
: common in patients with pauci-immune RPGN ( with or without ANCA)
: upper airway disease (ANCA-positive pauci-immune RPGN)
: involvement of the lower airway, musculoskeletal system, skin, and/or
nervous system ( no difference between ANCA(+) and ANCA(-))
: Anti-GBM antibody disease or Wegener’s granulomatosis
> pulmonary hemorrhage & hemoptysis

8. Clinical presentation
The relative severity of disease – vary with the underlying cause Cr
>50% glomerular crescents
Anti-GBM Ab disease
9.7
85%
ANCA positive disease
6.5
50%
Immune complex crescentic disease
4.9
<13%
Kidney Int. 2003;63(3):1164

9. Evaluation & Diagnosis
Serologic tests
ANCA
Anti-GBM antibodies
Complement
ANA
Renal biopsy

10. Treatment More specific therapy
Early diagnosis with renal biopsy and serologic testing
& early initiation of appropriate therapy!
: to minimize the degree of irreversible renal injury
Empiric therapy
Intravenous pulse methylprednisolone (500 to 1000mg/day for 3 days)
Oral or intravenous cyclophosphamide
Plasmapheresis
More specific therapy
Anti-GBM disease
ANCA-positive pauci-immune RPGN disease
ANCA-negative pauci-immune RPGN disease
Type 2 RPGN due to an identified disorder
Apparently idiopathic type 2 RPGN

11. Treatment : Pauci-immune RPGN
1. Initial treatment of pauci-immune focal and segmental necrotizing GN
1.1: We recommend that cyclophosphamide and corticosteroids be used as initial treatment. (1A)
1.2: We recommend that rituximab and corticosteroids be used as an alternative initial treatment in patients without severe disease or in whom cyclophosphamide is contraindicated. (1B)
2. Special patient populations
2.1: We recommend the addition of plasmapheresis for patients requiring dialysis or with rapidly increasing SCr. (1C)
2.2: We suggest the addition of plasmapheresis for patients with diffuse pulmonary hemorrhage. (2C)
2.3: We suggest the addition of plasmapheresis for patients with overlap syndrome of ANCA vasculitis and anti-GBM GN, according to proposed criteria and regimen for anti-GBM GN. (2D)
2.4: We suggest discontinuing cyclophosphamide therapy after 3 months in patients who remain dialysis-dependent and who do not have any extrarenal manifestations of disease. (2C)

12. Treatment : Pauci-immune RPGN
Rationale
Without therapy, ANCA vasculitis with GN > very poor outcomes
high-quality evidence for treatment with corticosteroids and cyclophosphamide that has dramatically improved the short- and long-term outcomes of ANCA vasculitis associated with systemic disease
All patients with extrarenal manifestations of disease should receive immunosuppressive therapy regardless of the degree of kidney dysfunction.
Immunosuppressive therapy may not be appropriate in patients with severe NCGN already requiring dialysis
high-quality evidence that plasmapheresis provides additional benefit in those with severe NCGN
low-quality evidence that plasmapheresis provides additional benefit for diffuse pulmonary hemorrhage
There is evidence that rituximab is not inferior to cyclophosphamide in induction therapy

13. Treatment : Pauci-immune RPGN
Cyclophosphamide
cyclophosphamide + corticosteroids > remission: 55~85%, relapse: 1/3
i.v g/m2 q 3–4 weeks, reduce dose to 0.5 g/m2 if age>60 or GFR<20
p.o. 1.5–2 mg/kg/d, reduce if age>60 or GFR<20
Adjust the daily dose to keep leukocyte count >3000/mm3
Pulse i.v. vs daily oral regimens > similar remission and relapse rates
(compliance, cost, cumulative dose, frequency of leucopenia & infection)
duration : should usually be limited to 3 months, maximum 6 months (oral)
a retrospective cohort analysis did not indicate that longer treatment with cyclophosphamide reduces the rate of relapse
still dialysis-dependent after 3 months, no evidence of ongoing extrarenal
manifestations of active vasculitis
> discontinuing cyclophosphamide

14. Treatment : Pauci-immune RPGN
Pulse Methylprednisolone
rapid anti-inflammatory effect
+ rapid reduction in ANCA-producing plasma cells
i.v. Pulse methylprednisolone: 500mg i.v. daily3 days
p.o. Prednisone 1 mg/kg/d for 4 weeks, not exceeding 60mg daily
Taper down over 3–4 months
no data that 1000 mg daily for 3 days is better than 500 mg
> lower dose : widely used
> higher dose : increased risks of infection & other complications

15. Treatment : Pauci-immune RPGN
Rituximab
i.v. 375 mg/m2 weekly x 4
Rituximab vs cyclophosphamide in initial therapy : equivalent
Plasmapheresis
advanced kidney failure (SCr>5.66 mg/dl)
diffuse alveolar hemorrhage : the reduction of mortality
( ‘‘mild’’ alveolar hemorrhage ?: unknown)
ANCA/anti-GBM overlap
60 ml/kg volume replacement
Vasculitis: 7 treatments over 14 days
diffuse pulmonary hemorrhage> daily until bleeding stops, then every other day, total 7–10 treatments
Vasculitis with anti-GBM antibodies: Daily for 14 days or until anti-GBM antibodies are undetectable

16. Treatment : Pauci-immune RPGN
3: Maintenance therapy
3.1: We recommend maintenance therapy in patients who have achieved remission. (1B)
3.2: We suggest continuing maintenance therapy for at least 18 months in patients who remain in complete remission. (2D)
3.3: We recommend no maintenance therapy in patients who are dialysis-dependent and have no extrarenal manifestations of disease. (1C)
4: Choice of agent for maintenance therapy
4.1: We recommend azathioprine 1-2 mg/kg/d orally as maintenance therapy.(1B)
4.2: We suggest that MMF, up to 1 g twice daily, be used for maintenance therapy in patients who are allergic to, or intolerant of, azathioprine. (2C)
4.3: We suggest trimethoprim-sulfamethoxazole as an adjunct to maintenance therapy in patients with upper respiratory tract disease. (2B)
4.4: We suggest methotrexate (initially 0.3mg/kg/wk, maximum 25mg/wk) for maintenance therapy in patients intolerant of azathioprine and MMF,
but not if GFR < 60 ml/min per 1.73m2. (1C)
4.5: We recommend not using etanercept as adjunctive therapy. (1A)

17. Treatment : Pauci-immune RPGN
Rationale
moderate-quality evidence that maintenance therapy is required in those at high risk of relapse or who have received less than 6 months induction treatment with cyclophosphamide
low-quality evidence that the duration of maintenance therapy should be at least 18 months
moderate-quality evidence that azathioprine is the preferred maintenance immunosuppressive agent, being equivalent in efficacy to cyclophosphamide in an RCT with a more favorable adverse-effect profile
moderate-quality evidence that trimethoprimsulfamethoxazole as an adjunct to maintenance therapy reduces the risk of relapse, but only in those with upper respiratory disease due to vasculitis

18. Treatment : Pauci-immune RPGN
Risk of relapse
Persistence of PR3-ANCA (compared to MPO-ANCA)
History of upper respiratory tract disease (ex. Sinusitis, subglottic stenosis)
lower respiratory tract disease (ex. alveolar hemorrhage, cavities, or nodules )
one of three risk factors (+) : 1.7-fold increased risk of relapse
All of three risk factors (+): 4.7-fold incrased risk of relapse
None of risk factors for relapse > maintenance immunosuppression?
: unknown

19. Treatment : Pauci-immune RPGN
Choice of immunosuppressive agent for maintenance therapy
azathioprine 1-2 mg/kg/d for 6-18 months
Maintenance therapy with azathioprine appears superior to MMF
> azathioprine as the first choice
using MMF in patients who are allergic to or intolerant of azathioprine
the use of trimethoprim-sulfamethoxazole
> decreased rate of upper airway-relapse
no impact on the rate of relapse in other organs
Azathioprine vs methotrexate
: relapse, adverse event: no difference
> but, the severity of the adverse effects with methotrexate : greater
> not recommended in patients with a reduced GFR<30
the dose should be adjusted in patients with a GFR<60
Etanercept : tumor necrosis factor receptor–Fc fusion protein
: not reduce the rate or the severity of relapses, higher rate of solid tumors
> not recommended

20. Treatment : Pauci-immune RPGN
Duration of maintenance thereapy
no direct data to support a recommendation for the duration of maintenance therapy
Given the lower risk of relapse and higher risk of infection and death,
the risk-benefit ratio does not support the routine use of maintenance immunosuppression therapy in ANCA vasculitis patients on chronic dialysis, in the absence of active extrarenal disease
Continued maintenance therapy is associated with the risks of immunosuppression, bone marrow suppression(leucopenia, anemia, thrombocytopenia), and possibly increased risk of cancer(skin cancer)

21. Treatment : Pauci-immune RPGN
5: Treatment of relapse
5.1: We recommend treating patients with severe relapse of ANCA vasculitis (life- or organ-threatening) according to the same guidelines as for the initial therapy. (1C)
5.2: We suggest treating other relapses of ANCA vasculitis by reinstituting immunosuppressive therapy or increasing its intensity with agents other than cyclophosphamide, including instituting or increasing dose of corticosteroids, with or without azathioprine or MMF. (2C)
6: Treatment of resistant disease
6.1: In ANCA GN resistant to induction therapy with cyclophosphamide and corticosteroids, we recommend the addition of rituximab (1C), and suggest i.v. immunoglobulin (2C) or plasmapheresis (2D) as alternatives
7: Monitoring
7.1: We suggest not changing immunosuppression based on changes in ANCA titer alone. (2D)

22. Treatment : Pauci-immune RPGN
8: Transplantation
8.1: We recommend delaying transplantation until patients are in complete extrarenal remission for 12 months. (1C)
8.2: We recommend not delaying transplantation for patients who are in complete remission but are still ANCA-positive. (1C)