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Peter TophamConsultant Nephrologist
John Walls Renal UnitLeicester
United Kingdom
Classification in Nephropathology:A Clinician’s Point of View
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A clinical case
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19 year old man – 1st year sports science student at Loughborough University
Visible haematuria
Upper respiratory tract infection
No further episodes
Persistent non-visible haematuria
Dipstick positive proteinuria
Referred to the renal unit for evaluation
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Asymptomatic
No significant past medical history
No family history
Non smoker
Binge alcohol
Occasional cannabis use
No other drug use
Examination
Fit and well
BMI 22kg/m2
BP 118/72mmHg
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Investigations
serum creatinine 68µmol/L (60–110) eGFR >90ml/minserum C-reactive protein 5mg/L (<10)
Urinalysis:blood 3+protein 1+
Urine PCR 71mg/mmol (<30)
anti-nuclear antibody negativeANCA negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 11.2g/L (6.0–13.0) serum immunoglobulin A 3.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5) antistreptolysin titre 102IU/mL (<200)
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Investigations
serum creatinine 68µmol/L (60–110) eGFR >90ml/minserum C-reactive protein 5mg/L (<10)
Urinalysis:blood 3+protein 1+
Urine PCR 71mg/mmol (<30)
anti-nuclear antibody negativeANCA negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 11.2g/L (6.0–13.0) serum immunoglobulin A 3.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5) antistreptolysin titre 102IU/mL (<200)
Renal tract ultrasound:Lt kidney 10.2cmRt kidney 10.0cmNormal appearanceNo stones
KUB X-ray:No renal tract calcification
Cystoscopy:No intravesical pathology
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Clinical diagnosis of IgA nephropathy
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Clinical diagnosis of IgA nephropathy
What next?
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Clinical diagnosis of IgA nephropathy
What next?
?? Kidney biopsy
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What do we want to know?
What is the diagnosis ?
What is his individual prognosis?
How should he be treated?
What is his risk of transplant recurrence?
Does it help us understand disease mechanisms?
Is he suitable for recruitment to clinical trials?
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What would a biopsy add to what we already (think we) know?
Clinical predictors of outcome in IgA nephropathy
Poor prognosis•Proteinuria•Hypertension•Baseline renal function•Increased body mass index•Increasing age
Good prognosis•Recurrent visible haematuria
No impact on outcome•Gender•Geography•Ethnicity•Serum IgA level
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Reich H N et al. JASN 2007;18:3177-3183
What would a biopsy add to what we already (think we) know?
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Reich H N et al. JASN 2007;18:3177-3183
Time-average proteinuria1 - < 1g/24h2 – 1-2 g/24h3 – 2-3g/24h4 - >3g/24h
What would a biopsy add to what we already (think we) know?
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Renal biopsy findings
IgA
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Renal biopsy findings
IgA nephropathy
IgA
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Oxford MEST Classification
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Mesangial hypercellularity - in < or >50% of glomeruli M0 or M1
Endocapillary hypercellularity – absent/present E0 or E1
Segmental sclerosis/adhesions – absent/present S0 or S1
Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% T0 or T1 or T2
Cellular/fibrocellular crescents were not predictive of outcome
Oxford MEST Classification
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Mesangial hypercellularity - in < or >50% of glomeruli M0 or M1
Endocapillary hypercellularity – absent/present E0 or E1
Segmental sclerosis/adhesions – absent/present S0 or S1
Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% T0 or T1 or T2
Cellular/fibrocellular crescents were not predictive of outcome
Each adds predictive value to ….Initial clinical featuresFollow up clinical features In all agesIn white Europeans and East Asians
Oxford MEST Classification
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VALIDATION STUDIES FOR THE OXFORD CLASSIFICATION OF IgAN?
M E S T
Macedonia2010
98 + + + +
USA2011
54 + + - +
Japan2011
161 children + + - +
France2011
183 - + + +
USA, Canada2011
187 adults & children
+ + + +
China2011
410 - + + +
Japan 2011
702 - - + +
Sweden2012
99 + + - +
Korea2012
197 + - + +
6/10 7/10 6/10 10/10
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Oxford MEST Classification:M0 E0 S0 T0
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How does this help?
Oxford MEST Classification: M0 E0 S0 T0
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How does this help?
Slope:
ml/min/1.73m2/yr
Minimal mesangial without segmental sclerosis M0,E0,S0 12 0.7 ± 2.5
with segmental sclerosis M0,E0,S1 22 -1.5 ± 2.7
Mesangial hypercellularity without segmental sclerosis M1,E0,S0 31 -2.2 ± 4.3
with segmental sclerosis M1,E0,S1 88 -4.7 ± 7.6
Endocapillary proliferation without segmental sclerosis M0/1,E1,S0 21 1.2 ± 1.2
with segmental sclerosis M0/1,E1,S1 90 -4.9 ± 10.0
CriteriaNo. of
patients
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular patterns
Oxford MEST Classification: M0 E0 S0 T0
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PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular and tubulointerstitial lesions
Slope:
ml/min/1.73m2/yr
Minimal mesangial ≤25% M0,E0,T0 30 -0.6 ± 3.0
> 26% M0,E0,T1-2 5 -1.0 ± 1.2
Mesangial hypercellularity ≤25% M1,E0,T0 89 -2.7 ± 5.5
> 26% M1,E0,T1-2 30 -7.9 ± 9.1
Endocapillary proliferation ≤25% M0/1,E1,T0 88 -3.0 ± 1.9
> 26% M0/1,E1,T1-2 23 -6.9 ± 1.2
Glomerular lesions TA/IF CriteriaNo. of
patients
How does this help?
Oxford MEST Classification: M0 E0 S0 T0
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PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular and tubulointerstitial lesions
Slope:
ml/min/1.73m2/yr
Minimal mesangial ≤25% M0,E0,T0 30 -0.6 ± 3.0
> 26% M0,E0,T1-2 5 -1.0 ± 1.2
Mesangial hypercellularity ≤25% M1,E0,T0 89 -2.7 ± 5.5
> 26% M1,E0,T1-2 30 -7.9 ± 9.1
Endocapillary proliferation ≤25% M0/1,E1,T0 88 -3.0 ± 1.9
> 26% M0/1,E1,T1-2 23 -6.9 ± 1.2
Glomerular lesions TA/IF CriteriaNo. of
patients
These are just examples
NotNot enough evidence yet to directly sum risks
How does this help?
Oxford MEST Classification: M0 E0 S0 T0
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Oxford MEST Classification:M1 E1 S0 T0
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Slope:
ml/min/1.73m2/yr
Minimal mesangial ≤25% M0,E0,T0 30 -0.6 ± 3.0
> 26% M0,E0,T1-2 5 -1.0 ± 1.2
Mesangial hypercellularity ≤25% M1,E0,T0 89 -2.7 ± 5.5
> 26% M1,E0,T1-2 30 -7.9 ± 9.1
Endocapillary proliferation ≤25% M0/1,E1,T0 88 -3.0 ± 1.9
> 26% M0/1,E1,T1-2 23 -6.9 ± 1.2
Glomerular lesions TA/IF CriteriaNo. of
patients
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONSCombining glomerular and tubulointerstitial lesions
How does this help?
Oxford MEST Classification: M1 E1 S0 T0
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Immunosuppression had no influence on relationship between pathology variables and the rate
of renal function decline
…..except for endocapillary lesions
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Patients with endocapillary proliferation
Immunosuppression -1.5+/-8.3 ml/min/1.73m2 /yr
No immunosuppression -5.4+/-1.1 ml/min/1.73m2 / yr
Immunosuppression had no influence on relationship between pathology variables and the rate
of renal function decline
…..except for endocapillary lesions
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Relationship between pathology variables and the rate of renal function decline
was notnot influenced by immunosuppression
…..except for endocapillary lesions
Patients with endocapillary proliferation
Immunosuppression -1.5+/-8.3 ml/min/1.73m2 /yr
No immunosuppression -5.4+/-1.1 ml/min/1.73m2 / yr
Retrospective dataCaution against overinterpretation
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What is the diagnosis ? IgA nephropathy
What is his individual prognosis? Some insight
How should he be treated? Little clarity
What is his risk of transplant recurrence? Unhelpful
Does it help us understand disease mechanisms? No
Is he suitable for recruitment to clinical trials? Probably
What do we want to know?
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Why were crescents not related to outcome in this classification?
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Why were crescents not related to outcome in this classification?
There were few cases with crescents
No case had more than 30% of glomeruli with crescents
These were slowly progressive cases
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WHEN ARE CRESCENTS SIGNIFICANT IN IgA NEPHROPATHY ?
Katafuchi R et al. CJASN 2011; 6: 2806
Patients meeting ‘Oxford’ criteria
Patients outside ‘Oxford’ criteria
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Why is the classification based just on light microscopy?
Would the addition of immunohistochemistry and/or EM data add any value?
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Why is the classification based just on light microscopy?
Would the addition of immunohistochemistry and/or EM data add any value?
IgA DEPOSITS IN IgA NEPHROPATHYMesangial deposits Capillary wall deposits
Bellur SS et al. NDT 2011; 26: 2533
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IgA & IgG DEPOSITS IN IgA NEPHROPATHY
Bellur SS et al. NDT 2011; 26: 2533
Mesangial vs. capillary wall IgA
NoNo difference in 5 year outcome
Presence or absence of IgG deposits
NoNo difference in 5 year outcome
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Another clinical case
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49 year-old-man presents with progressive leg swelling
Noted that his urine had become frothy
No cardiorespiratory symptoms
Previously fit and well
No medication apart from occasional ibuprofen for headache
No family history of renal disease
Smokes 10 cigarettes per day
30-40 units of alcohol per week
Estate agent
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Examination
Not acutely unwell
Afebrile
Oedema to upper thighs and sacrum
JVP not elevated
Normal heart sounds – no murmurs or gallop rythmn
Clear lung fields
Detectable ascites – no organomegaly
Dipstick urinalysis:blood 1+protein 4+
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Investigations
serum creatinine 172µmol/L (60–110) eGFR 47ml/minserum albumin 19g/L (35-45)Serum cholesterol 9.8mmol/Lserum C-reactive protein 5mg/L (<10)
Urine PCR 781mg/mmol (<30)
anti-nuclear antibody negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 4.2g/L (6.0–13.0) serum immunoglobulin A 1.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5)serum protein electrophoresis negative
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Investigations
serum creatinine 172µmol/L (60–110) eGFR 47ml/minserum albumin 19g/L (35-45)Serum cholesterol 9.8mmol/Lserum C-reactive protein 5mg/L (<10)
Urine PCR 781mg/mmol (<30)
anti-nuclear antibody negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 4.2g/L (6.0–13.0) serum immunoglobulin A 1.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5)serum protein electrophoresis negative
Renal tract ultrasound:Lt kidney 10.6cmRt kidney 10.9cmNormal appearanceNo stones
KUB X-ray:No renal tract calcification
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Kidney biopsy
Renal tract ultrasound:Lt kidney 10.6cmRt kidney 10.9cmNormal appearanceNo stones
KUB X-ray:No renal tract calcification
Investigations
serum creatinine 172µmol/L (60–110) eGFR 47ml/minserum albumin 19g/L (35-45)Serum cholesterol 9.8mmol/Lserum C-reactive protein 5mg/L (<10)
Urine PCR 781mg/mmol (<30)
anti-nuclear antibody negativeserum complement C3 74mg/dL (65–190)serum complement C4 28mg/dL (15–50) serum immunoglobulin G 4.2g/L (6.0–13.0) serum immunoglobulin A 1.3g/L (0.8–3.0) serum immunoglobulin M 2.1g/L (0.4–2.5)serum protein electrophoresis negative
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Renal biopsy
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Focal segmental glomerulosclerosis
Renal biopsy
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Focal segmental glomerulosclerosisNot Otherwise Specified
Renal biopsy
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Focal segmental glomerulosclerosisHistological pattern – comprises a group of clinico-pathologic syndromes that
share a common glomerular lesionMediated by a variety of insults that target the podocyte
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Focal segmental glomerulosclerosisHistological pattern – comprises a group of clinico-pathologic syndromes that
share a common glomerular lesionMediated by a variety of insults that target the podocyte
D’Agati V et al. N Engl J Med 2011;365:2398
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Focal segmental glomerulosclerosis
80% have primary FSGS
50-60% of adults present with nephrotic syndrome
Histological pattern – comprises a group of clinico-pathologic syndromes that share a common glomerular lesion
Mediated by a variety of insults that target the podocyte
D’Agati V et al. N Engl J Med 2011;365:2398
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PATHOLOGICAL CLASSIFICATION OF FSGS
D’Agati V et al. AJKD 2004
Perihilar variant Tip lesion variant
NOS
Collapsing variant Cellular variant
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Thomas DB et al. KI 2006; 69: 920
Demographics, clinical presentation, and outcomes of FSGS variants
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What do we want to know?
What is the diagnosis ?
What is his individual prognosis?
How should he be treated?
What is his risk of transplant recurrence?
Does it help us understand disease mechanisms?
Is he suitable for recruitment to clinical trials?
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What do we want to know?
What is the diagnosis ?
What is his individual prognosis?
How should he be treated?
What is his risk of transplant recurrence?
Does it help us understand disease mechanisms?
Is he suitable for recruitment to clinical trials?
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What’s the diagnosis?
D’Agati V et al. AJKD 2004
Perihilar variant Tip lesion variant
NOS
Collapsing variant Cellular variant
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What’s the diagnosis?
D’Agati V et al. AJKD 2004
NOS
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What do we want to know?
What is the diagnosis ?
What is his individual prognosis?
How should he be treated?
What is his risk of transplant recurrence?
Does it help us understand disease mechanisms?
Is he suitable for recruitment to clinical trials?
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PREDICTING OUTCOME FROM PATHOLOGY IN FSGS
Thomas DB et al. KI 2006; 69: 920
Collapsing
All other ‘variants’
P = 0.0016
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PREDICTING OUTCOME FROM PRESENTATION IN FSGS
Non-nephrotic 20% ESRD at 10 years
Nephrotic >50% ESRD at 5-10 years
Nephrotic >10g/day ~100% ESRD at 5-10 years ‘Malignant FSGS’
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REMISSION & ESRD IN FSGS
Troyanov S. et al. JASN 2005; 16:1061Stirling C et al– QJM 2005; 98: 443
No Remission vs. Partial remission
with a relapse
Time to RRT or death(yrs)
1086420
Perc
enta
ge S
urvi
val
1.0
.8
.6
.4
.2
0.0
Remission (partial or complete)vs. No remission
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Thomas DB et al. KI 2006; 69: 920
Demographics, clinical presentation, and outcomes of FSGS variants
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What do we want to know?
What is the diagnosis ?
What is his individual prognosis?
How should he be treated?
What is his risk of transplant recurrence?
Does it help us understand disease mechanisms?
Is he suitable for recruitment to clinical trials?
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D’Agati V et al. N Engl J Med 2011;365:2398-411
TREATMENT OF FSGS
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D’Agati V et al. N Engl J Med 2011;365:2398-411
TREATMENT OF FSGS
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D’Agati V et al. N Engl J Med 2011;365:2398-411
TREATMENT OF FSGS
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PREDICTING OUTCOME IN FSGSWho will respond to steroids
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PREDICTING OUTCOME IN FSGSWho will respond to steroids
Histological variant predicts steroid responsiveness
Stokes MB et al. KI 2006; 70: 1676
Histological variant does not does not predict steroid responsiveness
Chun M et al. JASN 2004; 15: 2169
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Stokes MB et al. KI 2006; 70: 1676
Treatment and outcomes of FSGS
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Classic FSGS Cellular Lesion Tip Lesion P
n 36 40 11Treated 17 (47%) 25 (63%) 9 (82%) NS
remission 9 (53%)c 16 (64%) 7 (78%) NS
complete 6 6 5partial 3 10 2No treatment 19 15 2remissionb 2 2 0 NS
Total remission 11 18 7 NS
No remission 25 22 4Follow-up from biopsy (mo) 73 ± 94 52 ± 45 99 ± 94 NS
ESRD 9 (25%) 17 (43%) 3 (27%) NSremission 1 1 0no remission 8 16 3treated 4 6 2no treatment 5 11 1
Chun M et al. JASN 2004; 15: 2169
Treatment and outcomes of FSGS
Characteristics
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What do we want to know?
What is the diagnosis ?
What is his individual prognosis?
How should he be treated?
What is his risk of transplant recurrence?
Does it help us understand disease mechanisms?
Is he suitable for recruitment to clinical trials?
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Recurrence of FSGS after kidney transplantation
FSGS recurs in 30-40% of first kidney transplants (nearly 100% in 2nd Tx if recurrence in 1st)
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Recurrence of FSGS after kidney transplantation
Risk factors for recurrence:
•young age •mesangial proliferation in the native kidneys •rapid progression to ESRD •pretransplant bilateral nephrectomy •white ethnicity •specific aspects of genetic background
FSGS recurs in 30-40% of first kidney transplants (nearly 100% in 2nd Tx if recurrence in 1st)
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Recurrence of FSGS after kidney transplantation
Risk factors for recurrence:
•young age, •mesangial proliferation in the native kidneys,
•rapid progression to ESRD, •pretransplant bilateral nephrectomy,
•white ethnicity, •specific aspects of genetic background
The histologic variant type of FSGS in native kidneys does not reliably predict recurrence in the allograft
FSGS recurs in 30-40% of first kidney transplants (nearly 100% in 2nd Tx if recurrence in 1st)
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In summary
The histologic classification can be helpful in defining diagnosis / cause
Provides some level of prognostic information but ? more than from clinical parameters
It provides no guidance in terms of steroid-responsiveness
It provides no guidance about risk of transplant recurrence
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Obliged to treat with steroids – no a priori idea about likelihood of response
In summary
The histologic classification can be helpful in defining diagnosis / cause
Provides some level of prognostic information but ? more than from clinical parameters
It provides no guidance in terms of steroid-responsiveness
It provides no guidance about risk of transplant recurrence
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ANCA-associated vasculitis
Berden AE et al. JASN 2010; 21: 1628
Validated
European population
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PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN
Berden AE et al. JASN 2010; 21: 1628
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PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN
Berden AE et al. JASN 2010; 21: 1628
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Chang D et al. Nephrol Dial Transplant (2012) 27: 2343
Chinese population
Independent validation
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Renal response to treatment of the four classifications
Chang D et al. Nephrol Dial Transplant (2012) 27: 2343
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Largely a (valuable) research tool
Extremely valuable in stratifying subjects recruited to clinical trials
Clinical utility limited
Patients will tend to be treated aggressively anyway irrespective of the pathologic class
One exception: frail patient with renal-limited disease and sclerotic phenotypeMay provide reassurance that avoiding immunosuppression is justifiable
PREDICTING OUTCOME FROM PATHOLOGY IN ANCA-ASSOCIATED GN
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THE FUTURE
INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR PATIENTS WITH GLOMERULONEPHRITIS
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Histopathology
THE FUTURE
Clinical Immune mechanisms Genetics Biomarkers
INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR PATIENTS WITH GLOMERULONEPHRITIS
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PATHOLOGICAL CLASSIFICATION OF MEMBRANOUS NEPHROPATHY
ELECTRON MICROSCOPY
Stage 1: subepithelial EDDs, no BM reaction
Stage II: ‘spikes’
Stage III: EDDs surrounded by BM
Stage IV: lucency of deposits
Ehrenreich & Churg, 1968
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PATHOLOGICAL CLASSIFICATION OF MEMBRANOUS NEPHROPATHY
Ehrenreich & Churg, 1968
• Logical & systematic
• Covers ‘progression’ of lesions
BUT
11 reports 1979-1992
8/11 suggested this classification did not predict outcome or duration of disease
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Hofstra JM et al. CJASN 2011;6:1286
The relationship between anti-PLA2R and proteinuriain membranous nephropathy
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Beck LH et al. JASN 2011;22:1543
The relationship between anti-PLA2R and proteinuriain membranous nephropathy following treatment
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INDIVIDUAL PROGNOSIS INIgA NEPHROPATHY
CLINICALProteinuria
Hypertension
PATHOLOGYMEST
IgA glycosylation ?
Other ?
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Classification in Nephropathology:My Point of View
Renal biopsy will remain a crucial part of the evaluation of patients with glomerular disease
In some situations it may become less important (eg membranous nephropathy)
Classification systems are crucial for clinical research studies
In day-to-day clinical practice in general, they are currently less helpful
The future will involve more integrated classification systems
This may result in more diagnostic clarity (rather than descriptions of histological patterns)
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Thank you
Questions?
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PATHOLOGICAL CLASSIFICATION OF GN
A classification must be
• evidence-based• clinically relevant• simple• precise in its definitions• reproducible