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??????????? Rapidly progressive glomerulonephritis (RPGN)

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Title: ??????????? Rapidly progressive glomerulonephritis (RPGN)


1
??????????? 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
  • 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 Goodpastures disease
Renal microscopic vasculitis characterized by scanty glomerular deposits of immunoglobulin with or without signs of systemic vasculitis C-ANCA P-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
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 Bowmans space

6
  • 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
  • Goodpastures disease
  • Henoch-Schonlein purpura
  • Necrotizing vasculitis (including Wegeners
    gransulomatosis)
  • Cryoimmunoglobinemia (hepatitis B or C related)
  • Neoplasia
  • Relapsing polychondritis
  • Bechets 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
Wegeners 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
Bowmans space
12
Crescent glomerulonephritis (Histological
classification)
  • Type I Anti-glomerular basement membrane
    (anti-GBM) antibody-associated RPGN (95
    crescents)
  • Goodpastures syndrome
  • Type II Immune complex RPGN (2050 crescents)
  • Systemic lupus erythematosus
  • IgA nephropathy (including Henoch-Schonlein
    purpura)
  • Cryoglobulinemic vasculitis
  • Type III Pauci immune-associated
    glomerulonephritis
  • Idiopathic crescentic GN
  • Wegeners 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

19
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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
  • 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.

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.
  • 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

36
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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 2530
  • Erythropoietic stimulating agents could increase
    the number of GP IIb/IIIa molecules on the
    platelet membrane
  • DDAVP
  • Dialysis
  • Estrogen
  • Cryoprecipitate
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