Transcript Document

快速進行性腎絲球體腎炎
Rapidly progressive glomerulonephritis
(RPGN)
Rapidly progressive glomerulonephritis
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Definition:
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Clinical entity:
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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
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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
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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 (ANCAassociated) disease
 Type IV: mixed and anti-GBM and
anti-ANCA associated disease
Relationship of vasculitic clinicopathologic
syndromes to immunopathologic categories of
vascular injury in patients with crescentic GN
Glomerulonephritis
Alone
P-ANCA
Disease
Immune complex
Disease
Systemic
vasculitis
PulmonaryRenal vasculitic
syndrome
Anti-GBM
Disease
Wegener’s
Granulomatosis
C-ANCA
Disease
Clinical features
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Clinical features common to the three forms of
RPGN include
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Hematuria
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Proteinuria
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Decreased urine output
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Edema
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Hypertension
 The
urinalysis typically reveals
Hematuria, with dysmorphic red blood
cells (RBC), RBC casts
 Variable degrees of proteinuria
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Pathological finding
Bowman’s space
Crescent
Crescent glomerulonephritis
(Histological classification)
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Type I: Anti-glomerular basement membrane (antiGBM) antibody-associated RPGN (95% crescents)
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Type II: Immune complex RPGN (20~50% crescents)
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Goodpasture’s syndrome
Systemic lupus erythematosus
IgA nephropathy (including Henoch-Schonlein purpura)
Cryoglobulinemic vasculitis
Type III: Pauci immune-associated
glomerulonephritis
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Idiopathic crescentic GN
Wegener’s granulomatosis GN
Microscopic polyarteritis (polyangiitis) GN
Immunopathological findings
Anti-GBM antibodyassociated RPGN
Immune complex
RPGN
Pauci immuneassociated
glomerulonephritis
Linear deposits
Granular deposits
Scanty deposits
Pauci-immune RPGN
• Definition
– Absence or paucity of glomerular staining for
immunoglobulins
• In approximately 80% of patients, pauciimmune crescentic GN is associated with
ANCA and thus can be called ANCA-associated
crescentic GN
80%
20%
Treatment
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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
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Recommendation 1.
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.
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Recommendation 2.
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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.
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Recommendation 3.
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Recommendation 4.
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Consider plasmapheresis in patients with lung hemorrhage
and those with severe disease and no response to
conventional therapy.
Monitoring for relapse with clinical follow-up, renal
function tests, and ANCA is recommended.
Recommendation 5.
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Treatment of relapses should be similar to original
treatment.
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Treatment for pauci-immune crescentic GN
should be
Pulse methylprednisolone
 Followed by oral corticosteroids and
cyclophosphamide for 6 to 12 months
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Evidence-Based Treatment
Recommendations of RPGN : Summary
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Because of the high risk of end-stage renal disease
(ESRD), early aggressive therapy is recommended.
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Treatment for anti-GBM antibody-induced crescentic
GN should be initiated early and should include
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Pulse methylprednisolone
A two-week course of plasmapheresis
Two months of treatment with corticosteroids and
cyclophosphamide.
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Treatment for pauci-immune crescentic GN
should be
Pulse methylprednisolone
 Followed by oral corticosteroids and
cyclophosphamide for 6 to 12 months
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Management of immune complexmediated RPGN
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Treat according to their specific underlying condition.
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Underlying disease including
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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
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High-dose corticosteroids
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Cytotoxic immunosuppressive drugs
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Cyclophosphamide (Endoxan)
Plasmapheresis is indicated for
Anti-GBM GN
 ANCA GN with pulmonary hemorrhage
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Additional therapeutic agents
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Other cytotoxic agents:
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Azathioprine, methotrexate, MMF, cyclosporin
Future therapies
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Leflunomide
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Inhibitor of de novo pyrimidine synthesis
Deoxyspergualin
 Tumor necrosis factor (TNF) blockade
 Antibodies against T cells
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Predictive value of the effect of plasmapheresis
on long-term prognosis of RPGN
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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).
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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.
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
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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
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Anti-GBM associated RPGN
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Pauci-immune RPGN
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Standard therapy and acceptable
Insufficient reported evidence
Acceptable for dialysis-dependent patients or patients with
pulmonary hemorrhage
Immune complex RPGN
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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
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Endothelial cells may be damaged directly by
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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,
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Further PMNs are recruited
Further enhancing vascular inflammation and injury
ANCA-positive vasculitis: diagnosis
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Clinical findings
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Biopsy of a relevant involved organ (typically
kidney, nasal mucosa, or occassionally lung)
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The presence of ANCA
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Certain drug exposures are known to induce
multiple autoantibodies, including ANCA.
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For example, hydralazine and propylthiouracil can
induce ANCA and pauci-immune crescentic
glomerulonephritis.
Uremic bleeding
Introduction
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Platelet dysfunction:
defects intrinsic to the platelet and abnormal
platelet endothelial interaction
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Uremic toxins and anemia
Clinical features
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Frequent -- easy bruising, mucosal bleeding
Less freqeunt – epistaxia, gingival bleeding,
hematuria
Uncertain – GI bleeding ?
Pathogenesis
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Decreased platelet aggregation
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
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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
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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