Title: ??????????? Rapidly progressive glomerulonephritis (RPGN)
1???????????Rapidly progressive
glomerulonephritis (RPGN)
2Historical 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
4RPGN 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
5Rapidly 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
7Relationship 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
8Clinical 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
10Dysmorphic red blood cells (RBC)
11Pathological finding
Crescent
Bowmans space
12Crescent 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
13Immunopathological findings
Pauci immune-associated glomerulonephritis
Anti-GBM antibody-associated RPGN
Immune complex RPGN
Linear deposits
Granular deposits
Scanty deposits
14Pauci-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
15ANCA
- 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
16ANCA-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
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22Treatment
- 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
23Evidence-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
27Evidence-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
29Management 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
31Additional 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
32Predictive 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.
34Conclusion
- 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.
35Indication 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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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
38ANCA-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.
40Uremic bleeding
41Introduction
- Platelet dysfunction
- defects intrinsic to the platelet and
abnormal - platelet endothelial interaction
- Uremic toxins and anemia
42Clinical features
- Frequent -- easy bruising, mucosal bleeding
- Less freqeunt epistaxia, gingival bleeding,
hematuria - Uncertain GI bleeding ?
43Pathogenesis
- 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
45Treatment
- 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