nephrology conference

Nephrology Nephrology conferenceconference

報告人：報告人： R3 R3 王劭瑜王劭瑜指導老師：鄭昌錡醫師指導老師：鄭昌錡醫師

Case presentationCase presentation

A 46 years old male presented as A 46 years old male presented as

bilateral legs pain for 2 weeksbilateral legs pain for 2 weeks

Patient profilePatient profile

NameName ︰︰楊楊 XX 州州 AgeAge ：： 46-year-old46-year-old GenderGender ：： malemale Height/Weight: 170cm /75 kgHeight/Weight: 170cm /75 kg Occupation: WorkerOccupation: Worker Marriage status: marriedMarriage status: married HospitalizationHospitalization ：：

2011/01/26~2011/04/162011/01/26~2011/04/16 Chart numberChart number ：： 2141854421418544

Chief complaintChief complaint

Bilateral legs progressive pain for 2 Bilateral legs progressive pain for 2 weeksweeks

Present illnessPresent illness This 46 years old male has underlying This 46 years old male has underlying

of of Diabetes mellitus, type 2; Hypertension Diabetes mellitus, type 2; Hypertension

for 5 yearsfor 5 years=> medications control=> medications control

Chronic kidney disease? Etiology?Chronic kidney disease? Etiology?

Present illnessPresent illness Bilateral legs progressive pain for 2 weeksBilateral legs progressive pain for 2 weeks

=> Rehab clinic and Chinese herb (pain => Rehab clinic and Chinese herb (pain killer?) killer?)

Admission in Admission in 壢新壢新 H (2011/01/19)H (2011/01/19) ：： Acute kidney injury => Hemodialysis twice due Acute kidney injury => Hemodialysis twice due

to hyperkalemia and acute pulmonary edemato hyperkalemia and acute pulmonary edema Kidney echo: bilateral large renal hypertrophy Kidney echo: bilateral large renal hypertrophy

with mild right hydronephrosiswith mild right hydronephrosis Dyspnea persistent refractory to emergent Dyspnea persistent refractory to emergent

hemodialysis, with sudden onset of hemodialysis, with sudden onset of hemoptysis on 1/25 & 1/26hemoptysis on 1/25 & 1/26

Present illnessPresent illness Associated symptoms: Associated symptoms:

Decreased urine outputDecreased urine output Progressive edema Progressive edema Poor appetite Poor appetite Chest pain over left chestChest pain over left chest

Negative findings: Negative findings: Recently surgical Recently surgical

procedures/trauma/immobilizationprocedures/trauma/immobilization Fever/chills/Purulent coughFever/chills/Purulent cough

Rhinorrhea/sorethroatRhinorrhea/sorethroat

Past historyPast history

Diabetes mellitus, type 2, for 5 yearsDiabetes mellitus, type 2, for 5 years Hypertension for 5 yearsHypertension for 5 years Operation history: Traffic accident 20 Operation history: Traffic accident 20

years agoyears ago Left leg fracture status post interlocking nailLeft leg fracture status post interlocking nail

Denied major systemic disease as coronary Denied major systemic disease as coronary artery disease, asthma, hepatitis B/C, artery disease, asthma, hepatitis B/C, peptic ulcer diseasepeptic ulcer disease

Medications: DM, HTN, Pain controller?Medications: DM, HTN, Pain controller?

Personal historyPersonal history

Allergy: no known allergyAllergy: no known allergy Alcohol: DeniedAlcohol: Denied Smoking: 0.5PPD for 10+ yearsSmoking: 0.5PPD for 10+ years Betalnut: DeniedBetalnut: Denied

Family HistoryFamily HistoryUnknown cancer history

Diabetes mellitusHeart disease

Physical examinationPhysical examination BT:36.5, PP:78/min, RR:18/min, BP:BT:36.5, PP:78/min, RR:18/min, BP:201/107201/107mmHgmmHg Appearance: alert, Appearance: alert, ill-lookingill-looking, E4V5M6, E4V5M6 Sclera: not icteric; Conjunctiva: paleSclera: not icteric; Conjunctiva: pale Neck: no stiffness, no lymphadenopathyNeck: no stiffness, no lymphadenopathy Chest: Chest: bilateral diffuse crackles, wheezing, bilateral diffuse crackles, wheezing,

ronchironchi Heart: regular heart beat without audible Heart: regular heart beat without audible

murmursmurmurs Abdomen: soft and flat, no tenderness, Abdomen: soft and flat, no tenderness,

normoactivenormoactive Extremities: free movable, Extremities: free movable, grade 2 pitting edemagrade 2 pitting edema

pulsation: symmetric pulsation: symmetric

HemogramHemogram 2011/01/2011/01/2626

WBCWBC 1000/uL1000/uL 12.712.7

HemoglobHemoglobinin

g/dLg/dL 6.76.7

HematocrHematocritit

%% 19.519.5

MCVMCV fLfL 75.975.9

PlateletsPlatelets 1000/uL1000/uL 266266

SegmentSegment %% 94.094.0

BandBand %% 2.02.0

LymphocyLymphocytete

%% 2.02.0

MonocyteMonocyte %% 1.01.0

EosinophiEosinophill

%% 0.00.0

BasophilBasophil %% 1.01.0

P.TP.T 　　 13.6/10.13.6/10.77

INRINR 1.31.3

APTTAPTT 35.3/2635.3/26

BiochemistryBiochemistry 2011/01/2011/01/2626

BUN (B)BUN (B) mg/dLmg/dL 91.491.4

CreatininCreatininee

mg/dLmg/dL 10.0210.02

NaNa mEg/mEg/dLdL 130130

ClCl mEq/LmEq/L 9999

KKmEq/mEq/

dLdL 5.35.3

CaCa mg/dLmg/dL 8.08.0

PP mg/dLmg/dL 7.77.7

AlbuminAlbumin g/dLg/dL 2.712.71

TPTP g/dLg/dL 5.65.6

HbA1cHbA1c mg/dLmg/dL 6.66.6

Bilirubin Bilirubin (T)(T) mg/dLmg/dL 0.20.2

AST AST (GOT)(GOT) U/LU/L 1414

ALT/GPTALT/GPT U/LU/L 2323

ALK-PALK-P U/LU/L 163163

H/D on 1/24, 1/25

UrinalysisUrinalysis 2011/012011/01/28/28

ColorColor 　　 YellowYellow

SP.GravitSP.Gravityy

　　 1.0131.013

pHpH 　　 6.06.0

LeukocytLeukocytee

　　 TraceTrace

NitriteNitrite 　　 NegativNegativee

ProteinProtein mg/dLmg/dL 2+ 2+ (100)(100)

GlucoseGlucose g/dLg/dL NegativNegativee

KetoneKetone 　　 NegativNegativee

UrobilinoUrobilinogengen EU/dLEU/dL 0.10.1

BilirubinBilirubin 　　 NegativNegativee

BloodBlood 　　 3+3+

Hyaline Hyaline castcast /ul/ul 0-20-2

BacteriaBacteria PositivePositive

RBCRBC /uL/uL 63 63

WBCWBC /uL/uL 9090

Epithelial Epithelial /uL/uL 11

Arterial blood gasArterial blood gas 2011/012011/01/28/28

TempTemp ℃℃ 3737

pHpH 7.3017.301

PCO2PCO2 mmHgmmHg 33.133.1

PaO2PaO2 mmHgmmHg 72.672.6

HCO3HCO3 mm/Lmm/L 16.016.0

SBESBE mm/Lmm/L -10.4-10.4

SatSat %% 93.393.3

2011/01/26

Marked interstitial/airspace infiltration of both lungs, with diffuse patchy opacities. Favor ongoing inflammation

Tortuous thoracic aorta and borderline cardiomegaly

ImpressionImpression

Rapidly-progressing glomerulonephritisRapidly-progressing glomerulonephritis Hemoptysis, suspect pulmonary Hemoptysis, suspect pulmonary

hemorrhagehemorrhage Bilateral lower legs pain, cause to be Bilateral lower legs pain, cause to be

determinateddeterminated Microcytic anemiaMicrocytic anemia

Diabetes mellitus, type 2, HbA1c=6.6Diabetes mellitus, type 2, HbA1c=6.6 HypertensionHypertension

Rapidly-progressing Rapidly-progressing glomerulonephritisglomerulonephritis

2011/01/262011/01/26

ANAANA NegativeNegative

C3C3 mg/dLmg/dL 110 110 (90~180)(90~180)

C4C4 mg/dLmg/dL 17.8 17.8 (10~40)(10~40)

A-DSDNAA-DSDNA WHOunit/WHOunit/mLmL

<40.5 <40.5 (Negative)(Negative)

ANCAANCA C-ANCAC-ANCA Positive Positive

P-ANCAP-ANCA Negative Negative HBsAgHBsAg NegativeNegative

Anti-HCV Anti-HCV AbAb

NegativeNegative

RPRRPR NegativeNegative

HIV 1+2 AbHIV 1+2 Ab NegativeNegative

ASLOASLO IU/mLIU/mL <49.70 <49.70 (<200)(<200)

2011/01/262011/01/26

Total Total ProteinProtein

5.6 gm/dL5.6 gm/dL

AlbuminAlbumin 2.5 mg/dL (43.80%)2.5 mg/dL (43.80%)

αα1-1-globulinglobulin

0.5 mg/dL ( 9.40%)0.5 mg/dL ( 9.40%)

αα2-2-globulinglobulin

0.9 mg/dL (16.80%)0.9 mg/dL (16.80%)

ββ--globulinglobulin

0.7 mg/dL (12.70%)0.7 mg/dL (12.70%)

γγ--globulinglobulin

1.0 mg/dL (17.30%)1.0 mg/dL (17.30%)

A/GA/G 0.770.77

Protein loss or malnutrition Protein loss or malnutrition pattern pattern with decrease of protein and with decrease of protein and albuminalbumin

IFEIFE No paraprotein is No paraprotein is identifiedidentified

IgGIgG 976.00 mg/dl 976.00 mg/dl (700~1600)(700~1600)

IgAIgA 171.00 mg/dL 171.00 mg/dL (70~400)(70~400)

IgMIgM 51.60 mg/dL 51.60 mg/dL (40~230)(40~230)

IgEIgE 1030.00 1030.00 IU/mL(<100)IU/mL(<100)

Clinical courseClinical course

1/261/26 1/271/27 1/281/28 1/291/29 1/301/30 1/311/31 2/12/1 2/22/2 2/32/3 2/42/4

BuBunn

91.491.4 95.395.3 136.9136.9 150.8150.8 167.167.77

CrCr 10.0210.02 10.2810.28 11.4211.42 11.4311.43 11.611.6EExaxamm

HRCT

22DD CTACTA

Hydrocortisone 100mg q8h Heparin


2/52/5 2/62/6 2/72/7 2/82/8 2/92/9 2/102/10 2/112/11 2/122/12 2/132/13 2/142/14

BuBunn

8383 103.4103.4

CrCr 6.646.64 7.367.36EExaxamm

DopplDopplerer

Kidney echo

Hydrocortisone 100mg q8h Heparin


Hydrocortisone => PrednisoloneHydrocortisone => Prednisolone Heparin => WarfarinHeparin => Warfarin Channel ulcer bleeding (pyloric ring, GC site)Channel ulcer bleeding (pyloric ring, GC site)

PES failure => operation on 3/17PES failure => operation on 3/17 Discharge with OPD follow up on 4/16Discharge with OPD follow up on 4/16

1/26 4/5

c-ANCA

>400 u/ml

29.55 u/ml

p-ANCA

negative negative

DiagnosisDiagnosis

C-ANCA associated vasculitisC-ANCA associated vasculitis Deep vein thrombosisDeep vein thrombosis Channel ulcer bleeding, status post Channel ulcer bleeding, status post

endoscope and operationendoscope and operation Diabetes mellitus, type 2, Diabetes mellitus, type 2,

HbA1c=6.6HbA1c=6.6 HypertensionHypertension

DiscussionDiscussion

OutlineOutline

Pulmonary-renal syndromePulmonary-renal syndrome ANCA-associated VasculitidesANCA-associated Vasculitides Wegener's granulomatosisWegener's granulomatosis Diagnostic procedureDiagnostic procedure Case correlationCase correlation

Pulmonary Renal Pulmonary Renal SyndromeSyndrome

1919, Ernest Goodpasture: 1919, Ernest Goodpasture: A case of pulmonary hemorrhage and A case of pulmonary hemorrhage and glomerulonephritisglomerulonephritis

1955, Parkin:1955, Parkin:Lung hemorrhage and nephritis, absence of Lung hemorrhage and nephritis, absence of arteritisarteritis

1958, Stanton and Tang: 1958, Stanton and Tang: Pulmonary hemorrhage with glomerulonephritisPulmonary hemorrhage with glomerulonephritis

1950s, Krakower and Greenspun: 1950s, Krakower and Greenspun: Identified GBM as the antigenIdentified GBM as the antigen

1967, Lerner, Glassock, and Dixon: 1967, Lerner, Glassock, and Dixon: Anti-GBM antibodies => PathogenesisAnti-GBM antibodies => Pathogenesis


Anti-GBM antibody disease Anti-GBM antibody disease (Goodpasture)(Goodpasture)

Systemic vasculitis: Wegener's Systemic vasculitis: Wegener's granulomatosisgranulomatosis

Acute glomerulonephritis: Acute glomerulonephritis: Complicated with pulmonary edemaComplicated with pulmonary edema Uremia-induced increase in Uremia-induced increase in

pulmonary capillary permeability pulmonary capillary permeability Pulmonary infectionPulmonary infection

1 Disease or 2 Diagnosis 1 Disease or 2 Diagnosis

Specks U. Diffuse alveolar hemorrhage syndromes CURR OPIN RHEUMATOL 2001;13:12-17


The remaining patients had a variety The remaining patients had a variety of disorders including pulmonary of disorders including pulmonary emboli, infection, and lupusemboli, infection, and lupusNiles JL, Böttinger EP, Saurina GR, et

al. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition Arch Intern Med 1996; 156:440

ANCA 48: pauci-immune 48: pauci-immune glomerulonephritis with glomerulonephritis with pulmonary symptomspulmonary symptoms

8: good evidence for 8: good evidence for Wegener's granulomatosisWegener's granulomatosis

Anti-GBM Ab 6

Both 7

ANCA-associated ANCA-associated VasculitidesVasculitides

ClassificationsClassifications

Primary:Primary: Immune complex Immune complex

mediated mediated ANCAANCA

Secondary:Secondary: Connective tissue Connective tissue

disordersdisorders Viral infectionViral infection

Large-vessel VasculitisLarge-vessel Vasculitis

Giant cell (temporal) Giant cell (temporal) arteritisarteritis

Takayasu arteritisTakayasu arteritis

Medium-sized-vessel Medium-sized-vessel VasculitisVasculitis

Polyarteritis nodosaPolyarteritis nodosa

Kawasaki diseaseKawasaki disease

Small-vessel VasculitisSmall-vessel Vasculitis

WegenerWegener’’s s granulomatosisgranulomatosis

Churg-Strauss syndromeChurg-Strauss syndrome

Microscopic polyangiitisMicroscopic polyangiitis

Henoch-SchHenoch-Schöönlein purpuranlein purpura

Essential cryoglobulinemic Essential cryoglobulinemic vasculitisvasculitis

Cutaneous leukocytoclastic Cutaneous leukocytoclastic angiitisangiitis

Diagnostic criteriaDiagnostic criteria

The American College of Rheumatology (ACR)The American College of Rheumatology (ACR)Vessel size, Histopathology, Clinical symptomsVessel size, Histopathology, Clinical symptomsstudy criteria rather than diagnostic criteriastudy criteria rather than diagnostic criteria

Chapel Hill Consensus Conference (CHCC)Chapel Hill Consensus Conference (CHCC)Definitions, but not Diagnostic criteriaDefinitions, but not Diagnostic criteria

European Medicines Agency algorithm: European Medicines Agency algorithm: Watts et al. Watts et al. 20072007

ANCA: permit the diagnosis of WG ANCA: permit the diagnosis of WG in the absence of biopsy in the absence of biopsy

CCSS criteriaSS criteria WWG criteriaG criteria

Seronegative ANCA disease

Proteinase 3 ANCA diseaseMyeloperoxidase ANCA disease

Prognositc significance

Response to therapy

Porpensity for relapse

Patient outcome

Churg-Strauss syndrome Asthma (a history of wheezing or the finding

of diffus high pitched wheezes on expiration) Eosniophilia of > 10 % Mononeuropathy (including multiplex) or

polyneuropathy Miugratory or transient pulmonary opacities

detected radiographically Paranasal sinus abnormality Biopsy containing a blood vessel showing

the accumulation of eosinophils in extravascular areas

Wegener’s criteria

Nasal or oral inflammation (painful or painless oral ulcers or purulent or bloody nasal discharge)

Abnormal chest radiograph showing nodules, fixed infiltrates, or cavities

Abnormal urinary sediment (microscopic hematuria or red cell casts)

Granulomatous inflammation on biopsy of an artery or perivascular area

> 2 / 4 => Sensitivity: 88%; Specificity: 92%

PathogenesisPathogenesis

Abbreviations: Abbreviations: CD, cluster of differentiation; CTLA4, tyotoxic T-CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;lymphocyte antigen4 gene;PTPN22, protein tyrosine phosphagase, non-receptor type PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene22 gene

ANCAs in the pathogenesis ANCAs in the pathogenesis of AAVof AAV

Neonate glomerulonephritis and pulmonary Neonate glomerulonephritis and pulmonary hemorrhage:hemorrhage:Transplacental of ANCA IgG from the mother Transplacental of ANCA IgG from the mother

who had anti-MPO-antibody-positive MPAwho had anti-MPO-antibody-positive MPA ANCAs: serological markersANCAs: serological markers

cANCA: proteinase-3 (PR3) / cytoplasmiccANCA: proteinase-3 (PR3) / cytoplasmic pANCA: myeloperoxidase (MPO) / pANCA: myeloperoxidase (MPO) /

perinuclearperinuclear



Caucasians African-Americans German Netherlands Japan



Respiratory tract: Silica exposure Accdelerated apoptosis of PolyMorphoNuclear and Macrophages: a trigger in the development of AAV



Staphylococcus aureus: strongest association Superantigens from S. aureus: stimulate B & T cells, leading to AAV Directly prime neutrophils => membrance expression of PR3Gram-negative bacteria: E. coli & K. pneumoniae LAMP-2 antibiotis: homologous to the bacterial adhesion protein FimH (Lysosomal membrane protein 2)



Anti-Plasminogen antibodies — correlates with both venous thromboembolic events and with characteristic glomerular histologic lesions and reduced renal function

Granulomatosis with Granulomatosis with polyangiitispolyangiitis

(Wegener (Wegener’’s granulomatosis)s granulomatosis)

BackgroundBackgroundClinical manifestationsClinical manifestations

DiagnosisDiagnosisTreatmentTreatment

BackgroundBackground 1897, Peter McBride: the first written description1897, Peter McBride: the first written description 1931, Klinger: 70-year-old physician with 1931, Klinger: 70-year-old physician with

constitutional symptoms, joint symptoms, proptosis, constitutional symptoms, joint symptoms, proptosis, widespread upper respiratory tract inflammation widespread upper respiratory tract inflammation leading to saddle nose deformity, leading to saddle nose deformity, glomerulonephritis and pulmonary lesionsglomerulonephritis and pulmonary lesions

1936, Dr. Frederich 1936, Dr. Frederich WegenerWegener: : Distinct clinical and histopathologic findingsDistinct clinical and histopathologic findings

1954, Goodman and Churg: triad1954, Goodman and Churg: triad Systemic necrotizing angiitisSystemic necrotizing angiitis Necrotizing granulomatous inflammation of the Necrotizing granulomatous inflammation of the

respiratory tractrespiratory tract Necrotizing glomerulonephritisNecrotizing glomerulonephritis

2011: Granulomatosis with polyangiitis (Wegener2011: Granulomatosis with polyangiitis (Wegener’’s)s)

Epidemiology Epidemiology Frequency: rare disease, indeterminate Frequency: rare disease, indeterminate

incidenceincidencePrevalence in United States: 3/100,000Prevalence in United States: 3/100,000

Mortality: disease severity, intensity of TxMortality: disease severity, intensity of Tx Untreated: mean survival=5monthsUntreated: mean survival=5months

1-year mortality rate: 11% (2.2~25%)1-year mortality rate: 11% (2.2~25%)5-year survival rate: 74~79%5-year survival rate: 74~79%

Cause of death: infection, respiratroy & renal failure, Cause of death: infection, respiratroy & renal failure, malignancy and cardiovascular eventsmalignancy and cardiovascular events

Morbidity: currently treatment relatedMorbidity: currently treatment related Race: White individualsRace: White individuals Sex: European populations male-to-female=1.5:1Sex: European populations male-to-female=1.5:1 Age: occur at any age, typically 35~55 years oldAge: occur at any age, typically 35~55 years old

Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol. September-October 2008;26:S94-S104

Clinical presentationClinical presentation

Constitutional symptoms: Constitutional symptoms: fever, migratory arthralgias, malaise, fever, migratory arthralgias, malaise, anorexia and weight lossanorexia and weight loss

Prodromal symptoms: Prodromal symptoms: weeks to months without specific organ weeks to months without specific organ involvementinvolvement

Ear, Nose and ThroatEar, Nose and Throat PulmonaryPulmonary RenalRenal CutaneousCutaneous

ENTENT

Nasal crusting, Nasal crusting, sinusitis, otitis media, sinusitis, otitis media, persistent rhinorrhea, persistent rhinorrhea, oral or nasal ulcers, oral or nasal ulcers, purulent/bloody nasal purulent/bloody nasal discharge, discharge, polychondritispolychondritis

Saddle nose Saddle nose deformitydeformitymore typically in WGmore typically in WG

Pulmonary diseasePulmonary disease Airways and/or Pulmonary parenchyma: Airways and/or Pulmonary parenchyma:

hoarseness, cough, dyspnea, stridor, hoarseness, cough, dyspnea, stridor, wheezing, hemoptysis or pleuritic pain; wheezing, hemoptysis or pleuritic pain; tracheal or subglottic stenosis, tracheal or subglottic stenosis, pulmonary consolidationpulmonary consolidation Nodules and patchy or diffuse opacitiesNodules and patchy or diffuse opacities Pulmonary fibrosis and pulmonary Pulmonary fibrosis and pulmonary

hypertensionhypertension Tumor-like masses, extrathoracicTumor-like masses, extrathoracic

BreastBreast KidneyKidney

Renal diseaseRenal disease

Acute kidney injury with hematuria, red Acute kidney injury with hematuria, red cell and other casts, and proteinuriacell and other casts, and proteinuria

Classifications and outcome:Classifications and outcome: Focal: > 50% of glomeruli are normalFocal: > 50% of glomeruli are normal Crescentic: cellular crescentsCrescentic: cellular crescents Sclerotic: > 50% of glomeruli are globally Sclerotic: > 50% of glomeruli are globally

scleroticsclerotic Mixed: normal; crescentic; globally scleroticMixed: normal; crescentic; globally sclerotic

Renal biopsyRenal biopsy

• Segmental necrotizing glomerulonephritis

• GPA: Granulomatous changes

• Almost all Pauci-immune crescentic glomerulonephritis are ANCA positive

AANCA-negative pauci-NCA-negative pauci-immune GNimmune GN

AAs part of spectrum of WG and MPAs part of spectrum of WG and MPAsimilar renal biopsy findings and similar renal biopsy findings and prognosisprognosis Significnatly youngerSignificnatly younger Significantly higher rate of proteinuriaSignificantly higher rate of proteinuria Significantly lower rate of renal survival Significantly lower rate of renal survival

and of extrarenal manifestations and of extrarenal manifestations (pulmonary)(pulmonary)

Renal-limited vasculitisRenal-limited vasculitis

Indistinguishable histopathologic Indistinguishable histopathologic findingsfindings

More glomerulosclerosis changeMore glomerulosclerosis change LLate stage, in the absence of extral-ate stage, in the absence of extral-

renal presentationsrenal presentations

Cutaneous manifestations

Urticaria, livida reticularis and tender nodules

Leukocytoclastic angiitis, which cause purpura involving lower extremities

Focal necrosis and ulceration

Diagnostic approach

History & physical examinations Laboratory investigation

Antineutrophil cytoplasmic antibodies Urinalysis

Radiographic tests Tissue biopsy

Tissue biopsy

Tissue biopsy

Tissue diagnosis may not be required if the clinical gestalt is convincing and a sit for biopsy is not apparent or would be too invasive to obtainLeukocytoclasic vasculitis + pulmonary nodule + c-ANCA

Initiation of therapy without confirmatory biopsy Ventilator-dependent without extrapulmonary

involvelung biopsy when stable

Anti-neutrophil cytoplasmic antibodies

1982, Davies et al.: 1982, Davies et al.: First described in pauci-immune First described in pauci-immune glomerulonephritisglomerulonephritisbelieved associated with Ross River virus believed associated with Ross River virus infectioninfection

1985, link to granulomatosis with polyangiitis1985, link to granulomatosis with polyangiitis

Two types of ANCA assaysTwo types of ANCA assays Indirect immunofluorescence assay: more sensitiveIndirect immunofluorescence assay: more sensitive Enzyme-linked immunosorbent assay (ELISA): Enzyme-linked immunosorbent assay (ELISA):

specificspecific

Immunofluorescence

Subjective interpretation Unstandardized, references for

normal ranges Tertiary care centers with research

laboratories High sensitivity but not specific

Antibodies to azurophilic granule proteins

False positive in individuals with ANA

Comparison of tests for ANCAComparison of tests for ANCA

c-ANCAc-ANCA p-ANCAp-ANCAAntibodies to neutral proteins or Antibodies to neutral proteins or weak cations (e.g., proteinase 3)weak cations (e.g., proteinase 3)

Antibodies to strong cationsAntibodies to strong cations

Target antigen: protinease 3Target antigen: protinease 3 Target antigen: usually Target antigen: usually myeloperoxidase but nonspecific myeloperoxidase but nonspecific antigenic interactions occurantigenic interactions occur

Highly specific for Highly specific for WegenerWegener’’s granulomatosiss granulomatosis

Most often positive in patients Most often positive in patients with Microscopic polyangiitis or with Microscopic polyangiitis or Pauci-immune, rapidly Pauci-immune, rapidly progressive glomerulonephritisprogressive glomerulonephritis

Positive in 70~90% of patients Positive in 70~90% of patients with Wegenerwith Wegener’’s granulomatosiss granulomatosis

Positive in approximately 50% of Positive in approximately 50% of patietns with microscopic patietns with microscopic polyantiitispolyantiitis

Occasionally positive in patients Occasionally positive in patients with Microscopic polyangiitis or with Microscopic polyangiitis or the Churg-Strauss syndrome the Churg-Strauss syndrome (15~25%)(15~25%)

Positive in 5~30% of patient with Positive in 5~30% of patient with WegenerWegener’’s granulomatosiss granulomatosis

Very rarely positive in patients Very rarely positive in patients with certain infections disease with certain infections disease (e.g., amoebiasis)(e.g., amoebiasis)

May be positive in patients with May be positive in patients with Systemic Lupus Erythematosus, Systemic Lupus Erythematosus, GoodpastureGoodpasture’’s syndrome, s syndrome, inflammatory bowel disease, or inflammatory bowel disease, or rheumatoid arthritisrheumatoid arthritis

Clinical applications

Diagnostic value: Positive predictive value / Negative

predictive value Preclude the need of biopsy?

ANCA titer with disease activity

ANCA

Predictive value of ANCA varied markedly depending on the degree of renal disease at presentation

Clinical presentation Prevalence of PI-CGN PPV for PI-CGN NPV for PI-CGN

Rapidly progressive glomerulonephritis* 47 percent (106/224) 98 percent 80 percent

Hematuria, proteinuria, and creatinine >3 mg/dL 21 percent (181/862) 92 percent 93 percent

Hematuria, proteinuria, and creatinine 1.5-3 mg/dL 7 percent (51/685) 77 percent 98 percent

Hematuria, proteinuria, and creatinine <1.5 mg/dL 2 percent (13/768) 47 percent 99 percent









> 18 y/o

> 50 y/o

< 18 y/oDiagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idopathic systemic vasculitis. EC/BCR Project for ANCA ASSAy Standardization. Kidney Int 1998; 53:743 Hagen EC et al.

Diagnostic predictive value of ANCA serology. Kidney Int 1998; 53: 796 Jannette JC et al.

ANCA level and Disease ANCA level and Disease activityactivity

ControversialControversial ANCA levels & disease relapse from 0-20 ANCA levels & disease relapse from 0-20

monthsmonths Multicenter prospective cohort study: Multicenter prospective cohort study:

c-ANCA↓not associated with a shorter time c-ANCA↓not associated with a shorter time to remissionto remissionc-ANCA↑not associated with relapsec-ANCA↑not associated with relapse

Treatment decisions: donTreatment decisions: don’’t base on t base on ANCA titersANCA titers Finkielman, J. D. Finkielman, J. D. et alet al. Antiproteinase 3 . Antiproteinase 3

antineutrophil cytoplasmic antibodies antineutrophil cytoplasmic antibodies and disease activity in Wegener and disease activity in Wegener granulomatosis. granulomatosis. Ann. Intern. Med. Ann. Intern. Med. 147, 147, 611-619 (2007)611-619 (2007)

↓

Summery

Pulmonary-renal syndrome Diagnostic procedure:

Differential diagnosis C-ANCA ; Tissue biopsy

Treatment associated complications

Thank you for your Thank you for your attentionattention

High resolution computed High resolution computed tomographytomography

High resolution computed tomography

Kidney echoLeft Kidney Length: 13.2 cm Right Kidney Length: 13.3 cm Both kidneys are large and swollen in

appearance The cortical echogenicity increased to the level of liver The papillae is prominent The pelvocalyceal systems of kidneys are mildly dilatedNo renal stone, mass or hydronephrosis is noted

Impression: C/W Acute parenchymal renal disease Bilateral large kidneys Bilateral pelviectasis to mild hydronephrosis status

Treatment courseTreatment course Fortum 1/26~; Teico 1/27Fortum 1/26~; Teico 1/27 Consult Derma/Hema 1//28Consult Derma/Hema 1//28 Crofibrinogen/crioglobulin 1/31Crofibrinogen/crioglobulin 1/31 CTA 2/3; Consult Plasty 2/3 acute compartment syndromwCTA 2/3; Consult Plasty 2/3 acute compartment syndromw Consult CVS 2/3; Heparin 2/3Consult CVS 2/3; Heparin 2/3 Duppler 2/7; 3/26Duppler 2/7; 3/26 Kidney echo 2/11Kidney echo 2/11 Warfarin 2/17~Warfarin 2/17~ Symptoms improve after steroid: Hydrocortisone 100mg q8h Symptoms improve after steroid: Hydrocortisone 100mg q8h

1/27; q12h 2/20~2/25; Prednisolon 5mg 7# BID => 6# BID 1/27; q12h 2/20~2/25; Prednisolon 5mg 7# BID => 6# BID 3/12 => 8# QD 3/17; hydrocortisone 1# q12h 3/18 => QD 3/12 => 8# QD 3/17; hydrocortisone 1# q12h 3/18 => QD 3/18 => Prednisolone 3# BID 4/3~9; 1# BID 4/123/18 => Prednisolone 3# BID 4/3~9; 1# BID 4/12

Consult CVS for hickman2/21 => 2/23Consult CVS for hickman2/21 => 2/23 f/u ANCA 2/22; 3/2; 4/5f/u ANCA 2/22; 3/2; 4/5 Lab 3/9 anti-cardiolipin, lupusLab 3/9 anti-cardiolipin, lupus 2/27 2/27 加洗加洗 dyspnea?dyspnea? PPI 3/14PPI 3/14 3/17 consult GI, ET + MV airway protection3/17 consult GI, ET + MV airway protection

FDL dysfunction => Bilateral deep vein thrombosis => FDL dysfunction => Bilateral deep vein thrombosis => Heparin => Warfarin => refuse Thrombectomy 2/11Heparin => Warfarin => refuse Thrombectomy 2/11

Coaguloapthy Coaguloapthy Pitting edema, hypoalbuminemiaPitting edema, hypoalbuminemia General weakness with black stool=>Channel ulcer General weakness with black stool=>Channel ulcer

bleeding 3/14 bleeding 3/14 Emergent operation for PPU 3/17Emergent operation for PPU 3/17 LMWH for DVT (proven on 3/31) => WarfarinLMWH for DVT (proven on 3/31) => Warfarin Steroid => held due to recurrent UGIBSteroid => held due to recurrent UGIB Follow up C-ANCA => taper steroidFollow up C-ANCA => taper steroid PPI~6/15PPI~6/15 Warfarin + Prednisolon for DVT & Vasculitis => DC Warfarin + Prednisolon for DVT & Vasculitis => DC

warfarin after doppler 2011/07warfarin after doppler 2011/07 Renal biopsy due to anti-anticoagulopathyRenal biopsy due to anti-anticoagulopathy

ConsultationConsultation

1/28 Derma: 1/28 Hema & Rheuma: 1/28 Derma: 1/28 Hema & Rheuma: WengerWenger’’s/Goodpasture related RPGN s/Goodpasture related RPGN dyspnea improve after steroiddyspnea improve after steroid

2/3 Plasty & CVS: acute compartment 2/3 Plasty & CVS: acute compartment syndromesyndromeremove left FDLremove left FDL

DVT on Warfarin; UGIB 3/15 EGDDVT on Warfarin; UGIB 3/15 EGD3/18 GS: gastrostomy and duodenorrhaphy3/18 GS: gastrostomy and duodenorrhaphy

Reddish macula-papula lesions over Reddish macula-papula lesions over bilteral feet bilteral feet

nephrology conference

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