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

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

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• 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

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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
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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

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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 (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

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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
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Clinical features

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

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

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Dysmorphic red blood cells (RBC)
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Pathological finding
Crescent
Bowmans space
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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

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

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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

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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

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

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

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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

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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.

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• 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.

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• 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.

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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

• 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.

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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 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.

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Standard Treatment of RPGN

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

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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

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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
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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.

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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.

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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

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• 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

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ANCA-positive vasculitis diagnosis

• Clinical findings
• Biopsy of a relevant involved organ (typically
  kidney, nasal mucosa, or occassionally lung)
• The presence of ANCA

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

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Uremic bleeding
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Introduction

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

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Clinical features

• Frequent -- easy bruising, mucosal bleeding
• Less freqeunt epistaxia, gingival bleeding,
  hematuria
• Uncertain GI bleeding ?

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Pathogenesis

• 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
• 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

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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