Transcript 投影片 1

Nephrology conference
報告人：R3 王劭瑜
指導老師：鄭昌錡醫師
Case presentation
A 46 years old male presented as
bilateral legs pain for 2 weeks
Patient profile
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Name︰楊X州
Age：46-year-old
Gender：male
Height/Weight: 170cm /75 kg
Occupation: Worker
Marriage status: married
Hospitalization：2011/01/26~2011/04/16
Chart number：21418544
Chief complaint
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Bilateral legs progressive pain for 2 weeks
Present illness
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This 46 years old male has underlying of
Diabetes mellitus, type 2; Hypertension for 5 years
=> medications control
 Chronic kidney disease? Etiology?
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Present illness
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Bilateral legs progressive pain for 2 weeks
=> Rehab clinic and Chinese herb (pain killer?)
Admission in 壢新H (2011/01/19)：
Acute kidney injury => Hemodialysis twice due to
hyperkalemia and acute pulmonary edema
 Kidney echo: bilateral large renal hypertrophy with
mild right hydronephrosis
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Dyspnea persistent refractory to emergent
hemodialysis, with sudden onset of hemoptysis on
1/25 & 1/26
Present illness
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Associated symptoms:
Decreased urine output
 Progressive edema
 Poor appetite
 Chest pain over left chest
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Negative findings:
Recently surgical procedures/trauma/immobilization
 Fever/chills/Purulent cough
Rhinorrhea/sorethroat
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Past history
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Diabetes mellitus, type 2, for 5 years
Hypertension for 5 years
Operation history: Traffic accident 20 years ago
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Left leg fracture status post interlocking nail
Denied major systemic disease as coronary artery
disease, asthma, hepatitis B/C, peptic ulcer disease
Medications: DM, HTN, Pain controller?
Personal history
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Allergy: no known allergy
Alcohol: Denied
Smoking: 0.5PPD for 10+ years
Betalnut: Denied
Family History
Unknown
cancer history
Diabetes mellitus
Heart disease
Physical examination
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BT:36.5, PP:78/min, RR:18/min, BP:201/107mmHg
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Appearance: alert, ill-looking, E4V5M6
Sclera: not icteric; Conjunctiva: pale
Neck: no stiffness, no lymphadenopathy
Chest: bilateral diffuse crackles, wheezing, ronchi
Heart: regular heart beat without audible murmurs
Abdomen: soft and flat, no tenderness, normoactive
Extremities: free movable, grade 2 pitting edema
pulsation: symmetric
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Hemogram
2011/01/26
WBC
1000/uL
Hemoglobin
g/dL
Hematocrit
%
MCV
Biochemistry
2011/01/26
12.7
BUN (B)
mg/dL
91.4
6.7
Creatinine
mg/dL
10.02
19.5
Na
mEg/dL
130
fL
75.9
Cl
mEq/L
99
Platelets
1000/uL
266
K
mEq/dL
5.3
Segment
%
94.0
Ca
mg/dL
8.0
Band
%
2.0
P
mg/dL
7.7
Lymphocyte
%
2.0
Albumin
g/dL
2.71
Monocyte
%
1.0
TP
g/dL
5.6
Eosinophil
%
0.0
HbA1c
mg/dL
6.6
Basophil
%
1.0
Bilirubin (T) mg/dL
0.2
P.T
INR
APTT
13.6/10.7
1.3
35.3/26
AST (GOT)
U/L
14
ALT/GPT
U/L
23
ALK-P
U/L
163
H/D on 1/24, 1/25
Urinalysis
2011/01/28
Color
Yellow
SP.Gravity
1.013
pH
6.0
Arterial blood gas
Leukocyte
Trace
Temp
Nitrite
Negative
pH
℃
2011/01/28
37
7.301
Protein
mg/dL
2+ (100)
PCO2
mmHg
33.1
Glucose
g/dL
Negative
PaO2
mmHg
72.6
Ketone
Negative
HCO3
mm/L
16.0
Urobilinogen EU/dL
0.1
SBE
mm/L
-10.4
Bilirubin
Negative
Sat
%
93.3
Blood
3+
Hyaline cast
/ul
Bacteria
0-2
Positive
RBC
/uL
63
WBC
/uL
90
Epithelial
/uL
1
2011/01/26
Marked interstitial/airspace
infiltration of both lungs,
with diffuse patchy opacities.
Favor ongoing inflammation
Tortuous thoracic aorta and
borderline cardiomegaly
Impression
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Rapidly-progressing glomerulonephritis
Hemoptysis, suspect pulmonary hemorrhage
Bilateral lower legs pain, cause to be
determinated
Microcytic anemia
Diabetes mellitus, type 2, HbA1c=6.6
Hypertension
Rapidly-progressing
glomerulonephritis
2011/01/26
ANA
2011/01/26
Negative
Total Protein
5.6 gm/dL
C3
mg/dL
110 (90~180)
Albumin
2.5 mg/dL (43.80%)
C4
mg/dL
17.8 (10~40)
α1-globulin
0.5 mg/dL ( 9.40%)
A-DSDNA
WHOunit/mL
<40.5 (Negative)
α2-globulin
0.9 mg/dL (16.80%)
ANCA
C-ANCA
Positive
β-globulin
0.7 mg/dL (12.70%)
P-ANCA
Negative
γ-globulin
1.0 mg/dL (17.30%)
HBsAg
Negative
A/G
0.77
Anti-HCV Ab
Negative
RPR
Negative
Protein loss or malnutrition pattern
with decrease of protein and albumin
HIV 1+2 Ab
Negative
ASLO
IU/mL
<49.70 (<200)
IFE
No paraprotein is identified
IgG
976.00 mg/dl (700~1600)
IgA
171.00 mg/dL (70~400)
IgM
51.60 mg/dL (40~230)
IgE
1030.00 IU/mL(<100)
Clinical course
Hydrocortisone 100mg q8h
Heparin
1/26
1/27
1/28
1/29
1/30
1/31
2/1
2/2
2/3
2/4
Bun 91.4
95.3
136.9
150.8
167.7
Cr
10.28
11.42
11.43
11.6
Exam
10.02
HRCT
2D
CTA
Clinical course
Hydrocortisone 100mg q8h
Heparin
2/5
2/6
2/7
2/8
2/9
2/10
2/11
2/12
Bun
83
103.4
Cr
6.64
7.36
Exam
Doppler
Kidney echo
2/13
2/14
Clinical course
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Hydrocortisone => Prednisolone
Heparin => Warfarin
Channel ulcer bleeding (pyloric ring, GC site)
PES failure => operation on 3/17
Discharge with OPD follow up on 4/16
1/26
4/5
c-ANCA >400 u/ml
29.55 u/ml
p-ANCA negative
negative
Diagnosis
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C-ANCA associated vasculitis
Deep vein thrombosis
Channel ulcer bleeding, status post endoscope
and operation
Diabetes mellitus, type 2, HbA1c=6.6
Hypertension
Discussion
Outline
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Pulmonary-renal syndrome
ANCA-associated Vasculitides
Wegener's granulomatosis
Diagnostic procedure
Case correlation
Pulmonary Renal Syndrome
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1919, Ernest Goodpasture:
A case of pulmonary hemorrhage and glomerulonephritis
1955, Parkin:
Lung hemorrhage and nephritis, absence of arteritis
1958, Stanton and Tang:
Pulmonary hemorrhage with glomerulonephritis
1950s, Krakower and Greenspun:
Identified GBM as the antigen
1967, Lerner, Glassock, and Dixon:
Anti-GBM antibodies => Pathogenesis
Pulmonary Renal Syndrome
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Anti-GBM antibody disease (Goodpasture)
Systemic vasculitis: Wegener's granulomatosis
Acute glomerulonephritis:
Complicated with pulmonary edema
 Uremia-induced increase in
pulmonary capillary permeability
 Pulmonary infection
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1 Disease or 2 Diagnosis
Specks U. Diffuse alveolar hemorrhage syndromes
CURR OPIN RHEUMATOL 2001;13:12-17
Pulmonary Renal Syndrome
ANCA
Anti-GBM Ab
Both
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48: pauci-immune glomerulonephritis
with pulmonary symptoms
8: good evidence for Wegener's
granulomatosis
6
7
The remaining patients had a variety of disorders
including pulmonary emboli, infection, and lupus
Niles 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-associated Vasculitides
Classifications
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Primary:
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Giant cell (temporal) arteritis
Immune complex mediated Takayasu arteritis
ANCA
Medium-sized-vessel Vasculitis
Secondary:
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Large-vessel Vasculitis
Polyarteritis nodosa
Connective tissue disorders Kawasaki disease
Small-vessel Vasculitis
Viral infection
Wegener’s granulomatosis
Churg-Strauss syndrome
Microscopic polyangiitis
Henoch-Schönlein purpura
Essential cryoglobulinemic vasculitis
Cutaneous leukocytoclastic angiitis
Diagnostic criteria
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The American College of Rheumatology (ACR)
Vessel size, Histopathology, Clinical symptoms
study criteria rather than diagnostic criteria
Chapel Hill Consensus Conference (CHCC)
Definitions, but not Diagnostic criteria
European Medicines Agency algorithm: Watts et al. 2007
ANCA: permit the diagnosis of WG
in the absence of biopsy
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CSS criteria
WG criteria
Proteinase 3 ANCA disease
Myeloperoxidase ANCA disease
Seronegative ANCA disease
Prognositc significance
Response to therapy
Porpensity for relapse
Patient outcome
Churg-Strauss syndrome
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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
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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%
Pathogenesis
Abbreviations:
CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;
PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene
ANCAs in the pathogenesis of AAV
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Neonate glomerulonephritis and pulmonary hemorrhage:
Transplacental of ANCA IgG from the mother
who had anti-MPO-antibody-positive MPA
ANCAs: serological markers
 cANCA: proteinase-3 (PR3) / cytoplasmic
 pANCA: myeloperoxidase (MPO) / perinuclear
Pathogenesis
Abbreviations:
CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;
PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene
Pathogenesis
Caucasians
African-Americans
German
Netherlands
Japan
Abbreviations:
CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;
PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene
Pathogenesis
Respiratory tract: Silica exposure
Accdelerated apoptosis of
PolyMorphoNuclear and Macrophages:
a trigger in the development of AAV
Abbreviations:
CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;
PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene
Pathogenesis
Staphylococcus aureus: strongest association
Superantigens from S. aureus: stimulate B & T cells, leading to AAV
Directly prime neutrophils => membrance expression of PR3
Gram-negative bacteria: E. coli & K. pneumoniae
LAMP-2 antibiotis: homologous to the bacterial adhesion protein FimH
(Lysosomal membrane protein 2)
Abbreviations:
CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;
PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene
Pathogenesis
Anti-Plasminogen antibodies —
correlates with both venous thromboembolic events and with
characteristic glomerular histologic lesions and reduced renal function
Abbreviations:
CD, cluster of differentiation; CTLA4, tyotoxic T-lymphocyte antigen4 gene;
PTPN22, protein tyrosine phosphagase, non-receptor type 22 gene
Granulomatosis with polyangiitis
(Wegener’s granulomatosis)
Background
Clinical manifestations
Diagnosis
Treatment
Background
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1897, Peter McBride: the first written description
1931, Klinger: 70-year-old physician with constitutional
symptoms, joint symptoms, proptosis, widespread upper
respiratory tract inflammation leading to saddle nose
deformity, glomerulonephritis and pulmonary lesions
1936, Dr. Frederich Wegener:
Distinct clinical and histopathologic findings
1954, Goodman and Churg: triad
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Systemic necrotizing angiitis
Necrotizing granulomatous inflammation of the respiratory tract
Necrotizing glomerulonephritis
2011: Granulomatosis with polyangiitis (Wegener’s)
Epidemiology
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Frequency: rare disease, indeterminate incidence
Prevalence in United States: 3/100,000
Mortality: disease severity, intensity of Tx
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Untreated: mean survival=5months
1-year mortality rate: 11% (2.2~25%)
5-year survival rate: 74~79%
Cause of death: infection, respiratroy & renal failure,
malignancy and cardiovascular events
Morbidity: currently treatment related
Race: White individuals
Sex: European populations male-to-female=1.5:1
Age: 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 presentation
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Constitutional symptoms:
fever, migratory arthralgias, malaise, anorexia and
weight loss
Prodromal symptoms:
weeks to months without specific organ involvement
Ear, Nose and Throat
Pulmonary
Renal
Cutaneous
ENT
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Nasal crusting, sinusitis,
otitis media, persistent
rhinorrhea, oral or nasal
ulcers, purulent/bloody
nasal discharge,
polychondritis
Saddle nose deformity
more typically in WG
Pulmonary disease
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Airways and/or Pulmonary parenchyma:
hoarseness, cough, dyspnea, stridor, wheezing,
hemoptysis or pleuritic pain; tracheal or
subglottic stenosis, pulmonary consolidation
Nodules and patchy or diffuse opacities
 Pulmonary fibrosis and pulmonary hypertension
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Tumor-like masses, extrathoracic
Breast
 Kidney
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Renal disease
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Acute kidney injury with hematuria, red cell and
other casts, and proteinuria
Classifications and outcome:
Focal: > 50% of glomeruli are normal
 Crescentic: cellular crescents
 Sclerotic: > 50% of glomeruli are globally sclerotic
 Mixed: normal; crescentic; globally sclerotic
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Renal biopsy
• Segmental necrotizing glomerulonephritis
• GPA: Granulomatous changes
• Almost all Pauci-immune crescentic glomerulonephritis are
ANCA positive
ANCA-negative pauci-immune GN
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As part of spectrum of WG and MPA
similar renal biopsy findings and prognosis
Significnatly younger
 Significantly higher rate of proteinuria
 Significantly lower rate of renal survival and of
extrarenal manifestations (pulmonary)
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Renal-limited vasculitis
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Indistinguishable histopathologic findings
More glomerulosclerosis change
Late stage, in the absence of extral-renal
presentations
Cutaneous manifestations
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Urticaria, livida reticularis and tender nodules
Leukocytoclastic angiitis, which cause purpura
involving lower extremities
Focal necrosis and ulceration
Diagnostic approach
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History & physical examinations
Laboratory investigation
Antineutrophil cytoplasmic antibodies
 Urinalysis
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Radiographic tests
Tissue biopsy
Tissue biopsy
Tissue biopsy
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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 obtain
Leukocytoclasic vasculitis + pulmonary nodule + c-ANCA
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Initiation of therapy without confirmatory biopsy
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Ventilator-dependent without extrapulmonary involve
lung biopsy when stable
Anti-neutrophil cytoplasmic antibodies
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1982, Davies et al.:
First described in pauci-immune glomerulonephritis
believed associated with Ross River virus infection
1985, link to granulomatosis with polyangiitis
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Two types of ANCA assays
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Indirect immunofluorescence assay: more sensitive
Enzyme-linked immunosorbent assay (ELISA): specific
Immunofluorescence
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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
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Comparison of tests for ANCA
c-ANCA
p-ANCA
Antibodies to neutral proteins or weak
cations (e.g., proteinase 3)
Antibodies to strong cations
Target antigen: protinease 3
Target antigen: usually myeloperoxidase but
nonspecific antigenic interactions occur
Highly specific for
Wegener’s granulomatosis
Most often positive in patients with
Microscopic polyangiitis or Pauci-immune,
rapidly progressive glomerulonephritis
Positive in 70~90% of patients with
Wegener’s granulomatosis
Positive in approximately 50% of patietns
with microscopic polyantiitis
Occasionally positive in patients with
Microscopic polyangiitis or
the Churg-Strauss syndrome (15~25%)
Positive in 5~30% of patient with
Wegener’s granulomatosis
Very rarely positive in patients with certain
infections disease (e.g., amoebiasis)
May be positive in patients with Systemic
Lupus Erythematosus, Goodpasture’s
syndrome, inflammatory bowel disease, or
rheumatoid arthritis
Clinical applications
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Diagnostic value:
Positive predictive value / Negative predictive value
 Preclude the need of biopsy?
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ANCA titer with disease activity
ANCA
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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
Rapidly progressive glomerulonephritis*
66 percent (82/124)
99 percent
65 percent
Hematuria, proteinuria, and creatinine >3 mg/dL
30 percent (147/497)
95 percent
89 percent
Hematuria, proteinuria, and creatinine 1.5-3 mg/dL
11 percent (36/311)
85 percent
97 percent
Hematuria, proteinuria, and creatinine <1.5 mg/dL
4 percent (7/195)
66 percent
99 percent
> 50 y/o
Rapidly progressive glomerulonephritis*
48 percent (10/21)
98 percent
80 percent
Hematuria, proteinuria, and creatinine >3 mg/dL
16 percent (6/38)
90 percent
95 percent
Hematuria, proteinuria, and creatinine 1.5-3 mg/dL
15 percent (6/39)
89 percent
95 percent
Hematuria, proteinuria, and creatinine <1.5 mg/dL
1 percent (1/162)
30 percent
100 percent
Diagnostic value of standardized assays for antineutrophil cytoplasmic antibodies in idopathic
systemic vasculitis. EC/BCR Project for ANCA
ASSAy Standardization. Kidney Int 1998; 53:743
Hagen EC et al.
< 18 y/o
Diagnostic predictive value of ANCA
serology. Kidney Int 1998; 53: 796
Jannette JC et al.
ANCA level and Disease activity
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Controversial
ANCA levels & disease relapse from 0-20 months
 Multicenter prospective cohort study:
c-ANCA↓not associated ↓with a shorter time to remission
c-ANCA↑not associated with relapse
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Treatment decisions: don’t base on ANCA titers
Finkielman, J. D. et al. Antiproteinase 3 antineutrophil
cytoplasmic antibodies and disease activity in Wegener
granulomatosis. Ann. Intern. Med. 147, 611-619 (2007)
Summery
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Pulmonary-renal syndrome
Diagnostic procedure:
Differential diagnosis
 C-ANCA ; Tissue biopsy
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Treatment associated complications
Thank you for your attention
High resolution computed tomography
High resolution computed tomography
Kidney echo
Left Kidney Length: 13.2 cm
Right Kidney Length: 13.3 cm
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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 dilated
No renal stone, mass or hydronephrosis is noted
Impression:
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C/W Acute parenchymal renal disease
Bilateral large kidneys
Bilateral pelviectasis to mild hydronephrosis status
Treatment course
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Fortum 1/26~; Teico 1/27
Consult Derma/Hema 1//28
Crofibrinogen/crioglobulin 1/31
CTA 2/3; Consult Plasty 2/3 acute compartment syndromw
Consult CVS 2/3; Heparin 2/3
Duppler 2/7; 3/26
Kidney echo 2/11
Warfarin 2/17~
Symptoms improve after steroid: Hydrocortisone 100mg q8h 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 3/18 => Prednisolone 3# BID 4/3~9; 1#
BID 4/12
Consult CVS for hickman2/21 => 2/23
f/u ANCA 2/22; 3/2; 4/5
Lab 3/9 anti-cardiolipin, lupus
2/27 加洗 dyspnea?
PPI 3/14
3/17 consult GI, ET + MV airway protection
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FDL dysfunction => Bilateral deep vein thrombosis => Heparin =>
Warfarin => refuse Thrombectomy 2/11
Coaguloapthy
Pitting edema, hypoalbuminemia
General weakness with black stool=>Channel ulcer bleeding 3/14
Emergent operation for PPU 3/17
LMWH for DVT (proven on 3/31) => Warfarin
Steroid => held due to recurrent UGIB
Follow up C-ANCA => taper steroid
PPI~6/15
Warfarin + Prednisolon for DVT & Vasculitis => DC warfarin after doppler
2011/07
Renal biopsy due to anti-anticoagulopathy
Consultation
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1/28 Derma: 1/28 Hema & Rheuma:
Wenger’s/Goodpasture related RPGN
dyspnea improve after steroid
2/3 Plasty & CVS: acute compartment syndrome
remove left FDL
DVT on Warfarin; UGIB 3/15 EGD
3/18 GS: gastrostomy and duodenorrhaphy
Reddish macula-papula lesions over bilteral feet