快速進行性腎絲球體腎炎快速進行性腎絲球體腎炎Rapidly progressive Rapidly progressive

glomerulonephritisglomerulonephritis (RPGN) (RPGN)

Rapidly progressive glomerulonephritisRapidly progressive glomerulonephritis

Definition:Definition: ClinicalClinical entity: entity:

A rapid loss of renal function (usually a A rapid loss of renal function (usually a 50 % decline in 50 % decline in GFRGFR) within ) within three monthsthree months

PathologicalPathological finding: finding: Extensive crescent formation (usually involving over Extensive crescent formation (usually involving over

50%50% of the glomeruli) of the glomeruli) Crescents occur whenever breaks in glomerular Crescents occur whenever breaks in glomerular

capillaries allow leakage of cells and plasma proteins capillaries allow leakage of cells and plasma proteins into Bowman’s spaceinto Bowman’s space

Infectious diseasesInfectious diseases Poststreptococcal GNPoststreptococcal GN Infectious endocarditisInfectious endocarditis Visceral sepsisVisceral sepsis Hepatitis B or C infection Hepatitis B or C infection

with vasculitis and/or with vasculitis and/or cryoimmunoglobulinemiacryoimmunoglobulinemia

Multisystemi diseasesMultisystemi diseases Systemic lupus Systemic lupus

erythematosuserythematosus GoodpastureGoodpasture’’s diseases disease Henoch-Schonlein Henoch-Schonlein

purpurapurpura Necrotizing vasculitis Necrotizing vasculitis

(including Wegener(including Wegener’’s s gransulomatosis)gransulomatosis)

Cryoimmunoglobinemia Cryoimmunoglobinemia (hepatitis B or C related)(hepatitis B or C related)

NeoplasiaNeoplasia Relapsing polychondritisRelapsing polychondritis BechetBechet’’s diseases disease

Drugs and toxic agentsDrugs and toxic agents AllopurinolAllopurinol D-PenicillamineD-Penicillamine HydralazineHydralazine RifampicinRifampicin

Superimposed on primary Superimposed on primary glomerular diseaseglomerular disease Membranoproliferative GN Membranoproliferative GN

(type I, II)(type I, II) Membranous GNMembranous GN IgA nephropathyIgA nephropathy

IdiopathicIdiopathic Type I: Antiglomerular Type I: Antiglomerular

basement membrane basement membrane antibody diseaseantibody disease

Type II: immune complex-Type II: immune complex-mediated diseasemediated disease

Type III: pauci-immune Type III: pauci-immune (ANCA-associated) disease(ANCA-associated) disease

Type IV: mixed and anti-GBM Type IV: mixed and anti-GBM and anti-ANCA associated and anti-ANCA associated diseasedisease

Relationship of vasculitic Relationship of vasculitic clinicopathologic syndromes to clinicopathologic syndromes to immunopathologic categories of immunopathologic categories of vascular injury in patients with vascular injury in patients with

crescentic GNcrescentic GNImmune complex

Disease

P-ANCADisease

C-ANCADisease

GlomerulonephritisAlone

Systemic vasculitis

Pulmonary-Renal vasculitic

syndrome Wegener’sGranulomatosis

Anti-GBMDisease

Clinical featuresClinical features Clinical features common to the three forms of Clinical features common to the three forms of

RPGN includeRPGN include

HematuriaHematuria

ProteinuriaProteinuria

Decreased urine outputDecreased urine output

EdemaEdema

HypertensionHypertension

The urinalysis typically revealsThe urinalysis typically reveals Hematuria, with dysmorphic red blood Hematuria, with dysmorphic red blood

cells (RBC), RBC castscells (RBC), RBC casts Variable degrees of proteinuriaVariable degrees of proteinuria

Pathological findingPathological finding

Bowman’s space Crescent

Crescent glomerulonephritis Crescent glomerulonephritis (Histological classification)(Histological classification)

Type I: Anti-glomerular basement membrane (anti-Type I: Anti-glomerular basement membrane (anti-GBM) antibody-associated RPGN (95% crescents)GBM) antibody-associated RPGN (95% crescents) Goodpasture’s syndromeGoodpasture’s syndrome

Type II: Immune complex RPGN (20~50% crescents)Type II: Immune complex RPGN (20~50% crescents) Systemic lupus erythematosusSystemic lupus erythematosus IgA nephropathy (including Henoch-Schonlein purpura)IgA nephropathy (including Henoch-Schonlein purpura) Cryoglobulinemic vasculitisCryoglobulinemic vasculitis

Type III: Pauci immune-associated Type III: Pauci immune-associated glomerulonephritis glomerulonephritis Idiopathic crescentic GN Idiopathic crescentic GN Wegener’s granulomatosis GN Wegener’s granulomatosis GN Microscopic polyarteritis (polyangiitis) GNMicroscopic polyarteritis (polyangiitis) GN

Immunopathological Immunopathological findingsfindings

Linear deposits Scanty depositsGranular deposits

Anti-GBM antibody-associated RPGN

Immune complex RPGN

Pauci immune-associated glomerulonephritis

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

80%

20%

TreatmentTreatment

Low salt dietLow salt diet Low potassium dietLow potassium diet Low protein dietLow protein diet Hypertensive control: ACE inhibitor Hypertensive control: ACE inhibitor

or Angiotensin II receptor antagonistor Angiotensin II receptor antagonist High dose steroidHigh dose steroid Immunocytotoxic agent (endoxan)Immunocytotoxic agent (endoxan) PlasmaphresisPlasmaphresis

Evidence-Based Evidence-Based Recommendations of Recommendations of

Treatment : Pauci-immune Treatment : Pauci-immune RPGNRPGN

Recommendation 1.Recommendation 1. Initial steroid treatment Initial steroid treatment is methylprednisolone 7 is methylprednisolone 7

to 15 mg/kg/dayto 15 mg/kg/day to a maximum of 1 g/day to a maximum of 1 g/day three three daysdays, then , then

Prednisone 1 mg/kg/day for one monthPrednisone 1 mg/kg/day for one month, , gradually gradually tapered over the next 6 to 12 monthstapered over the next 6 to 12 months..

Recommendation 2.Recommendation 2. CyclophosphamideCyclophosphamide should be given either orally at a dose should be given either orally at a dose

of of 2 mg/kg/day2 mg/kg/day adjusted to maintain the leukocyte count adjusted to maintain the leukocyte count between between 3 and 5 thousand/ml3 and 5 thousand/ml or intravenously starting at or intravenously starting at 0.5 g/m0.5 g/m22/month/month and increased monthly by 0.25 g to a and increased monthly by 0.25 g to a maximum of 1 g/mmaximum of 1 g/m22 per month. per month.

The dose should be adjusted to maintain a nadir of The dose should be adjusted to maintain a nadir of leukocyte count two weeks post-treatment between 3 and 5 leukocyte count two weeks post-treatment between 3 and 5 thousand/ml.thousand/ml.

Cyclophosphamide should be continued for Cyclophosphamide should be continued for 6 to 12 months6 to 12 months.. Treatment should be given even in advanced patients.Treatment should be given even in advanced patients.

Recommendation 3.Recommendation 3. Consider plasmapheresis in patients with lung hemorrhage Consider plasmapheresis in patients with lung hemorrhage

and those with severe disease and no response to and those with severe disease and no response to conventional therapy.conventional therapy.

Recommendation 4.Recommendation 4. Monitoring for relapse with clinical follow-up, renal Monitoring for relapse with clinical follow-up, renal

function tests, and ANCA is recommended.function tests, and ANCA is recommended. Recommendation 5.Recommendation 5.

Treatment of relapses should be similar to original Treatment of relapses should be similar to original treatment.treatment.

Treatment for Treatment for pauci-immune crescentic GNpauci-immune crescentic GN should be should be Pulse methylprednisolonePulse methylprednisolone Followed by oral corticosteroids and Followed by oral corticosteroids and

cyclophosphamide for cyclophosphamide for 6 to 12 months6 to 12 months

Evidence-Based Treatment Evidence-Based Treatment Recommendations of RPGNRecommendations of RPGN : :

SummarySummary Because of the high risk of end-stage renal disease Because of the high risk of end-stage renal disease

(ESRD), (ESRD), early aggressive therapyearly aggressive therapy is recommended. is recommended.

Treatment for Treatment for anti-GBM antibody-induced crescentic anti-GBM antibody-induced crescentic

GNGN should be initiated early and should include should be initiated early and should include Pulse methylprednisolonePulse methylprednisolone A A two-week coursetwo-week course of plasmapheresis of plasmapheresis Two monthsTwo months of treatment with corticosteroids and of treatment with corticosteroids and

cyclophosphamide.cyclophosphamide.

Treatment for Treatment for pauci-immune crescentic GNpauci-immune crescentic GN should be should be Pulse methylprednisolonePulse methylprednisolone Followed by oral corticosteroids and Followed by oral corticosteroids and

cyclophosphamide for cyclophosphamide for 6 to 12 months6 to 12 months

Management of immune Management of immune complex-mediated RPGNcomplex-mediated RPGN

Treat according to their specific underlying condition.Treat according to their specific underlying condition. Underlying disease includingUnderlying disease including

postinfectious GN, IgA nephropathy, Henoch-Schönlein postinfectious GN, IgA nephropathy, Henoch-Schönlein purpura, lupus nephritis, membranous nephropathy, and purpura, lupus nephritis, membranous nephropathy, and membranoproliferative GNmembranoproliferative GN

A few patients with A few patients with true idiopathic immune complex true idiopathic immune complex

crescentic RPGN should be treated similarly to those crescentic RPGN should be treated similarly to those with pauci-immune RPGNwith pauci-immune RPGN. .

Standard Treatment of Standard Treatment of RPGNRPGN

High-dose High-dose corticosteroidscorticosteroids

Cytotoxic immunosuppressive drugsCytotoxic immunosuppressive drugs Cyclophosphamide (Endoxan) Cyclophosphamide (Endoxan)

PlasmapheresisPlasmapheresis is indicated for is indicated for Anti-GBM GN Anti-GBM GN ANCA GN with pulmonary hemorrhage ANCA GN with pulmonary hemorrhage

Additional therapeutic Additional therapeutic agentsagents

Other cytotoxic agents:Other cytotoxic agents: Azathioprine, methotrexate, MMF, cyclosporinAzathioprine, methotrexate, MMF, cyclosporin

Future therapiesFuture therapies LeflunomideLeflunomide

Inhibitor of Inhibitor of de novode novo pyrimidine synthesis pyrimidine synthesis DeoxyspergualinDeoxyspergualin Tumor necrosis factor (TNF) blockadeTumor necrosis factor (TNF) blockade Antibodies against T cellsAntibodies against T cells

Predictive value of the effect of plasmapheresis Predictive value of the effect of plasmapheresis

on long-term prognosis of RPGNon long-term prognosis of RPGN This prospective multicenter study randomized 39 This prospective multicenter study randomized 39

patients with biopsy-proven RPGN (Couser type II, n patients with biopsy-proven RPGN (Couser type II, n = 6; pauci-immune type III, n = 33) to undergo either = 6; pauci-immune type III, n = 33) to undergo either immunosuppressive therapy with prednisone and immunosuppressive therapy with prednisone and cyclophosphamide (n = 18) or plasmapheresis in cyclophosphamide (n = 18) or plasmapheresis in addition to immunosuppression (n = 21).addition to immunosuppression (n = 21).

Patients were observed for a mean of 127 months or Patients were observed for a mean of 127 months or

until reaching the end points of hemodialysis or until reaching the end points of hemodialysis or death. death.

AJKD, Jan 2002, Vol 39 No 1

Plasmapheresis had no significant effect on renal or patient Plasmapheresis had no significant effect on renal or patient survival in type II or pauci-immune (type III) RPGN, survival in type II or pauci-immune (type III) RPGN, independently of age, sex, or serum creatinine level at the time independently of age, sex, or serum creatinine level at the time of diagnosis. of diagnosis.

Patients were dialysis dependent within 24 months if more Patients were dialysis dependent within 24 months if more than one third of glomeruli were totally sclerosed.than one third of glomeruli were totally sclerosed.

Interstitial fibrosis also correlated significantly with the risk Interstitial fibrosis also correlated significantly with the risk for progression to renal failure. for progression to renal failure.

Conversely, long-term dialysis-free survival was significantly Conversely, long-term dialysis-free survival was significantly more likely in patients with a greater number of crescents than more likely in patients with a greater number of crescents than in those with a low number of crescents. in those with a low number of crescents.

ConclusionConclusion Plasmapheresis did not improve short- or long-term outcome in Plasmapheresis did not improve short- or long-term outcome in

type II or III RPGN. type II or III RPGN. Glomerular sclerosis and interstitial fibrosis on initial histological Glomerular sclerosis and interstitial fibrosis on initial histological

examination are highly predictive of the development of ESRD.examination are highly predictive of the development of ESRD. Conversely, glomerular crescents may reflect a reversible Conversely, glomerular crescents may reflect a reversible

glomerular pathological state because their presence was glomerular pathological state because their presence was associated with improved outcome after cyclophosphamide and associated with improved outcome after cyclophosphamide and steroids as treatment of RPGN type II and III.steroids as treatment of RPGN type II and III.

Overall, approximately 50% of patients are alive and off dialysis Overall, approximately 50% of patients are alive and off dialysis therapy 10 years after the diagnosis of type II or type III RPGN therapy 10 years after the diagnosis of type II or type III RPGN using immunosuppression with cyclophosphamide and using immunosuppression with cyclophosphamide and prednisone. prednisone.

Indication of plasmapheresis Indication of plasmapheresis in RPGNin RPGN

Anti-GBM associated RPGNAnti-GBM associated RPGN Standard therapy and acceptableStandard therapy and acceptable

Pauci-immune RPGNPauci-immune RPGN Insufficient reported evidenceInsufficient reported evidence Acceptable for dialysis-dependent patients or patients Acceptable for dialysis-dependent patients or patients

with pulmonary hemorrhagewith pulmonary hemorrhage Immune complex RPGNImmune complex RPGN

HUS-TTP: standard therapy and acceptHUS-TTP: standard therapy and accept Insufficienct reported evidence: Multiple myeloma, Insufficienct reported evidence: Multiple myeloma,

lupus nephritis, IgA nephropathy, Henoch-Sconlein lupus nephritis, IgA nephropathy, Henoch-Sconlein purpura, sepsispurpura, sepsis

Cryoglobulinemia: insufficient reported evidence; Cryoglobulinemia: insufficient reported evidence; acceptable for patients with acute active and severe acceptable for patients with acute active and severe diseasedisease

Endothelial cellsEndothelial cells may be may be damageddamaged directly by directly by Inflammatory mediators released from activated Inflammatory mediators released from activated

neutrophils, orneutrophils, or Damaged as neutrophils undergo secondary necrosis in the Damaged as neutrophils undergo secondary necrosis in the

vascular lumina, amplifying inflammationvascular lumina, amplifying inflammation

After initiation of After initiation of vasculitic lesionvasculitic lesion by the by the interactions interactions ofof neutrophils,neutrophils, ANCAANCA, and , and endothelial cellsendothelial cells, , Further PMNs are recruited Further PMNs are recruited Further enhancing vascular inflammation and injuryFurther enhancing vascular inflammation and injury

ANCA-positive vasculitis: ANCA-positive vasculitis: diagnosisdiagnosis

Clinical findingsClinical findings

Biopsy of a relevant involved organ (typically Biopsy of a relevant involved organ (typically kidney, nasal mucosa, or occassionally lung)kidney, nasal mucosa, or occassionally lung)

The presence of ANCAThe presence of ANCA

Certain Certain drugdrug exposures are known to induce exposures are known to induce multiple autoantibodies, including ANCA.multiple autoantibodies, including ANCA.

For example, For example, hydralazinehydralazine and and propylthiouracilpropylthiouracil can can

induce ANCA and pauci-immune crescentic induce ANCA and pauci-immune crescentic glomerulonephritis.glomerulonephritis.

Uremic bleedingUremic bleeding

IntroductionIntroduction

Platelet dysfunction: Platelet dysfunction:

defects intrinsic to the platelet and defects intrinsic to the platelet and abnormal abnormal

platelet endothelial interactionplatelet endothelial interaction

Uremic toxins and anemiaUremic toxins and anemia

Clinical featuresClinical features

Frequent -- easy bruising, mucosal Frequent -- easy bruising, mucosal bleedingbleeding

Less freqeunt – epistaxia, gingival Less freqeunt – epistaxia, gingival bleeding, hematuriableeding, hematuria

Uncertain – GI bleeding ?Uncertain – GI bleeding ?

PathogenesisPathogenesis

Decreased platelet aggregation Decreased platelet aggregation Impaired platelet adhesivenessImpaired platelet adhesiveness

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

TreatmentTreatment

Correction of anemiaCorrection of anemia

raising the hematocrit to above 25~30%raising the hematocrit to above 25~30% Erythropoietic stimulating agents Erythropoietic stimulating agents could could

increase the number of GP IIb/IIIa increase the number of GP IIb/IIIa molecules on the platelet membranemolecules on the platelet membrane

DDAVPDDAVP DialysisDialysis EstrogenEstrogen CryoprecipitateCryoprecipitate