Peter Topham

1
Classification in Nephropathology A Clinicians
Point of View

• Peter Topham
• Consultant Nephrologist
• John Walls Renal Unit
• Leicester
• United Kingdom

2
A clinical case
3
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 Referre
d to the renal unit for evaluation
4
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 118/72m
mHg
5
Investigations serum creatinine 68µmol/L
(60110) eGFR gt90ml/min serum C-reactive
protein 5mg/L (lt10) Urinalysis blood 3 prot
ein 1 Urine PCR 71mg/mmol (lt30) anti-nuclear
antibody negative ANCA negative serum
complement C3 74mg/dL (65190) serum complement
C4 28mg/dL (1550) serum immunoglobulin
G 11.2g/L (6.013.0) serum immunoglobulin
A 3.3g/L (0.83.0) serum immunoglobulin M 2.1g/L
(0.42.5) antistreptolysin titre 102IU/mL
(lt200)
6
Investigations serum creatinine 68µmol/L
(60110) eGFR gt90ml/min serum C-reactive
protein 5mg/L (lt10) Urinalysis blood 3 prot
ein 1 Urine PCR 71mg/mmol (lt30) anti-nuclear
antibody negative ANCA negative serum
complement C3 74mg/dL (65190) serum complement
C4 28mg/dL (1550) serum immunoglobulin
G 11.2g/L (6.013.0) serum immunoglobulin
A 3.3g/L (0.83.0) serum immunoglobulin M 2.1g/L
(0.42.5) antistreptolysin titre 102IU/mL
(lt200)
Renal tract ultrasound Lt kidney 10.2cm Rt
kidney 10.0cm Normal appearance No stones KUB
X-ray No renal tract calcification Cystoscopy
No intravesical pathology
7
Clinical diagnosis of IgA nephropathy
8
Clinical diagnosis of IgA nephropathy
What next?
9
Clinical diagnosis of IgA nephropathy
What next?
?? Kidney biopsy
10
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?
11
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

12
What would a biopsy add to what we already (think
we) know?
Reich H N et al. JASN 2007183177-3183
13
What would a biopsy add to what we already (think
we) know?
Time-average proteinuria 1 - lt 1g/24h 2 1-2
g/24h 3 2-3g/24h 4 - gt3g/24h
Reich H N et al. JASN 2007183177-3183
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Renal biopsy findings
IgA
15
Renal biopsy findings
IgA
IgA nephropathy
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Oxford MEST Classification
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Oxford MEST Classification
Mesangial hypercellularity - in lt or gt50 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,
gt50 T0 or T1 or T2 Cellular/fibrocellular
crescents were not predictive of outcome
18
Oxford MEST Classification
Mesangial hypercellularity - in lt or gt50 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,
gt50 T0 or T1 or T2 Cellular/fibrocellular
crescents were not predictive of outcome
Each adds predictive value to . Initial
clinical features Follow up clinical features
In all ages In white Europeans and East Asians
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VALIDATION STUDIES FOR THE OXFORD
CLASSIFICATION OF IgAN?
M E S T
Macedonia 2010 98
USA 2011 54 -
Japan 2011 161 children -
France 2011 183 -
USA, Canada 2011 187 adults children
China 2011 410 -
Japan 2011 702 - -
Sweden 2012 99 -
Korea 2012 197 -
6/10 7/10 6/10 10/10
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Oxford MEST Classification M0 E0 S0 T0
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Oxford MEST Classification M0 E0 S0 T0
How does this help?
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Oxford MEST Classification M0 E0 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL
LESIONS Combining glomerular patterns
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Oxford MEST Classification M0 E0 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL
LESIONS Combining glomerular and
tubulointerstitial lesions
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Oxford MEST Classification M0 E0 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL
LESIONS Combining glomerular and
tubulointerstitial lesions
These are just examples Not enough evidence yet
to directly sum risks
25
Oxford MEST Classification M1 E1 S0 T0
26
Oxford MEST Classification M1 E1 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL
LESIONS Combining glomerular and
tubulointerstitial lesions
27
Immunosuppression had no influence on
relationship between pathology variables and the
rate of renal function decline ..except for
endocapillary lesions
28
Immunosuppression had no influence on
relationship between pathology variables and the
rate of renal function decline ..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
29
Relationship between pathology variables and the
rate of renal function decline was not
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 data Caution against
overinterpretation
30
What do we want to know?
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 Do
es it help us understand disease mechanisms?
No Is he suitable for recruitment to clinical
trials? Probably
31
Why were crescents not related to outcome in
this classification?
32
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
33
WHEN ARE CRESCENTS SIGNIFICANT IN IgA
NEPHROPATHY ?
Patients meeting Oxford criteria
Patients outside Oxford criteria
Katafuchi R et al. CJASN 2011 6 2806
34
Why is the classification based just on light
microscopy? Would the addition of
immunohistochemistry and/or EM data add any value?
35
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 NEPHROPATHY
Mesangial deposits
Capillary wall deposits
Bellur SS et al. NDT 2011 26 2533
36
IgA IgG DEPOSITS IN IgA NEPHROPATHY
Mesangial vs. capillary wall IgA No difference
in 5 year outcome
Presence or absence of IgG deposits No
difference in 5 year outcome
Bellur SS et al. NDT 2011 26 2533
37
Another clinical case
38
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
39
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
40
Investigations serum creatinine 172µmol/L
(60110) eGFR 47ml/min serum albumin 19g/L
(35-45) Serum cholesterol 9.8mmol/L serum
C-reactive protein 5mg/L (lt10) Urine
PCR 781mg/mmol (lt30) anti-nuclear
antibody negative serum complement C3 74mg/dL
(65190) serum complement C4 28mg/dL (1550)
serum immunoglobulin G 4.2g/L (6.013.0) serum
immunoglobulin A 1.3g/L (0.83.0) serum
immunoglobulin M 2.1g/L (0.42.5) serum protein
electrophoresis negative
41
Investigations serum creatinine 172µmol/L
(60110) eGFR 47ml/min serum albumin 19g/L
(35-45) Serum cholesterol 9.8mmol/L serum
C-reactive protein 5mg/L (lt10) Urine
PCR 781mg/mmol (lt30) anti-nuclear
antibody negative serum complement C3 74mg/dL
(65190) serum complement C4 28mg/dL (1550)
serum immunoglobulin G 4.2g/L (6.013.0) serum
immunoglobulin A 1.3g/L (0.83.0) serum
immunoglobulin M 2.1g/L (0.42.5) serum protein
electrophoresis negative
Renal tract ultrasound Lt kidney 10.6cm Rt
kidney 10.9cm Normal appearance No stones KUB
X-ray No renal tract calcification
42
Investigations serum creatinine 172µmol/L
(60110) eGFR 47ml/min serum albumin 19g/L
(35-45) Serum cholesterol 9.8mmol/L serum
C-reactive protein 5mg/L (lt10) Urine
PCR 781mg/mmol (lt30) anti-nuclear
antibody negative serum complement C3 74mg/dL
(65190) serum complement C4 28mg/dL (1550)
serum immunoglobulin G 4.2g/L (6.013.0) serum
immunoglobulin A 1.3g/L (0.83.0) serum
immunoglobulin M 2.1g/L (0.42.5) serum protein
electrophoresis negative
Renal tract ultrasound Lt kidney 10.6cm Rt
kidney 10.9cm Normal appearance No stones KUB
X-ray No renal tract calcification
Kidney biopsy
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Renal biopsy
44
Renal biopsy
Focal segmental glomerulosclerosis
45
Renal biopsy
Focal segmental glomerulosclerosis Not Otherwise
Specified
46
Focal segmental glomerulosclerosis
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
47
Focal segmental glomerulosclerosis
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
DAgati V et al. N Engl J Med 20113652398
48
Focal segmental glomerulosclerosis
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
80 have primary FSGS 50-60 of adults present
with nephrotic syndrome
DAgati V et al. N Engl J Med 20113652398
49
PATHOLOGICAL CLASSIFICATION OF FSGS
Cellular variant
Collapsing variant
NOS
Tip lesion variant
Perihilar variant
DAgati V et al. AJKD 2004
50
Demographics, clinical presentation, and outcomes
of FSGS variants
Thomas DB et al. KI 2006 69 920
51
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?
52
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?
53
Whats the diagnosis?
Cellular variant
Collapsing variant
NOS
Tip lesion variant
Perihilar variant
DAgati V et al. AJKD 2004
54
Whats the diagnosis?

NOS
DAgati V et al. AJKD 2004
55
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?
56
PREDICTING OUTCOME FROM PATHOLOGY IN FSGS
All other variants
P 0.0016
Collapsing
Thomas DB et al. KI 2006 69 920
57
PREDICTING OUTCOME FROM PRESENTATION IN FSGS
Non-nephrotic 20 ESRD at 10 years Nephrotic
gt50 ESRD at 5-10 years Nephrotic
gt10g/day 100 ESRD at 5-10 years Malignant FSGS
58
REMISSION ESRD IN FSGS
No Remission vs. Partial remission with a
relapse
Remission (partial or complete) vs. No remission
Troyanov S. et al. JASN 2005 161061
Stirling C et al QJM 2005 98 443
59
Demographics, clinical presentation, and outcomes
of FSGS variants
Thomas DB et al. KI 2006 69 920
60
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?
61
TREATMENT OF FSGS
DAgati V et al. N Engl J Med 20113652398-411
62
TREATMENT OF FSGS
DAgati V et al. N Engl J Med 20113652398-411
63
TREATMENT OF FSGS
DAgati V et al. N Engl J Med 20113652398-411
64
PREDICTING OUTCOME IN FSGS Who will respond to
steroids
65
PREDICTING OUTCOME IN FSGS Who will respond to
steroids
Histological variant predicts steroid
responsiveness Stokes MB et al. KI 2006 70
1676
Histological variant does not predict steroid
responsiveness Chun M et al. JASN 2004 15 2169
66
Treatment and outcomes of FSGS
Stokes MB et al. KI 2006 70 1676
67
Treatment and outcomes of FSGS
n
36
40
11
Treated
17 (47)
25 (63)
9 (82)
NS
remission
9 (53)c
16 (64)
7 (78)
NS
complete
6
6
5
partial
3
10
2
No treatment
19
15
2
remissionb
2
2
0
NS
Total remission
11
18
7
NS
No remission
25
22
4
Follow-up from biopsy (mo)
73 94
52 45
99 94
NS
ESRD
9 (25)
17 (43)
3 (27)
NS
remission
1
1
0
no remission
8
16
3
treated
4
6
2
no treatment
5
11
1
Chun M et al. JASN 2004 15 2169
68
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?
69
Recurrence of FSGS after kidney transplantation
FSGS recurs in 30-40 of first kidney transplants
(nearly 100 in 2nd Tx if recurrence in 1st)
70
Recurrence of FSGS after kidney transplantation
FSGS recurs in 30-40 of first kidney transplants
(nearly 100 in 2nd Tx if recurrence in 1st)

• 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

71
Recurrence of FSGS after kidney transplantation
FSGS recurs in 30-40 of first kidney transplants
(nearly 100 in 2nd Tx if recurrence in 1st)

• 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

72
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
73
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
Obliged to treat with steroids no a priori
idea about likelihood of response
74
ANCA-associated vasculitis
Validated European population
Berden AE et al. JASN 2010 21 1628
75
PREDICTING OUTCOME FROM PATHOLOGY IN
ANCA-ASSOCIATED GN
Berden AE et al. JASN 2010 21 1628
76
PREDICTING OUTCOME FROM PATHOLOGY IN
ANCA-ASSOCIATED GN
Berden AE et al. JASN 2010 21 1628
77
Independent validation
Chinese population
Chang D et al. Nephrol Dial Transplant (2012) 27
2343
78
Renal response to treatment of the four
classifications
Chang D et al. Nephrol Dial Transplant (2012) 27
2343
79
PREDICTING OUTCOME FROM PATHOLOGY IN
ANCA-ASSOCIATED GN
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
phenotype May provide reassurance that avoiding
immunosuppression is justifiable
80
THE FUTURE
INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR
PATIENTS WITH GLOMERULONEPHRITIS
81
THE FUTURE
Biomarkers
INDIVIDUAL PROGNOSIS AND TREATMENT PLAN FOR
PATIENTS WITH GLOMERULONEPHRITIS
82
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
83
PATHOLOGICAL CLASSIFICATION OF MEMBRANOUS
NEPHROPATHY

• Logical systematic
• Covers progression of lesions
• BUT
• 11 reports 1979-1992
• 8/11 suggested this classification
• did not predict outcome or duration of disease

Ehrenreich Churg, 1968
84
The relationship between anti-PLA2R and
proteinuria in membranous nephropathy
Hofstra JM et al. CJASN 201161286
85
The relationship between anti-PLA2R and
proteinuria in membranous nephropathy following
treatment
Beck LH et al. JASN 2011221543
86
INDIVIDUAL PROGNOSIS IN IgA NEPHROPATHY
Other ?
IgA glycosylation ?
PATHOLOGY MEST
CLINICAL Proteinuria Hypertension
87
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) Classificat
ion 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)
88
Thank you Questions?
89
PATHOLOGICAL CLASSIFICATION OF GN

• A classification must be
• evidence-based
• clinically relevant
• simple
• precise in its definitions
• reproducible