Classification in Nephropathology:
A Clinician’s Point of View
Peter Topham
Consultant Nephrologist
John Walls Renal Unit
Leicester
United Kingdom
A clinical case
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
Asymptomatic
Examination
No significant past medical history
Fit and well
No family history
BMI
22kg/m2
Non smoker
BP
118/72mmHg
Binge alcohol
Occasional cannabis use
No other drug use
Investigations
serum creatinine
eGFR
serum C-reactive protein
68µmol/L (60–110)
>90ml/min
5mg/L (<10)
Urinalysis:
blood
protein
3+
1+
Urine PCR
71mg/mmol (<30)
anti-nuclear antibody
ANCA
serum complement C3
serum complement C4
serum immunoglobulin G
serum immunoglobulin A
serum immunoglobulin M
negative
negative
74mg/dL (65–190)
28mg/dL (15–50)
11.2g/L (6.0–13.0)
3.3g/L (0.8–3.0)
2.1g/L (0.4–2.5)
antistreptolysin titre
102IU/mL (<200)
Investigations
serum creatinine
eGFR
serum C-reactive protein
68µmol/L (60–110)
>90ml/min
5mg/L (<10)
Renal tract ultrasound:
Lt kidney 10.2cm
Rt kidney 10.0cm
Normal appearance
No stones
Urinalysis:
blood
protein
3+
1+
KUB X-ray:
No renal tract calcification
Urine PCR
71mg/mmol (<30)
Cystoscopy:
No intravesical pathology
anti-nuclear antibody
ANCA
serum complement C3
serum complement C4
serum immunoglobulin G
serum immunoglobulin A
serum immunoglobulin M
negative
negative
74mg/dL (65–190)
28mg/dL (15–50)
11.2g/L (6.0–13.0)
3.3g/L (0.8–3.0)
2.1g/L (0.4–2.5)
antistreptolysin titre
102IU/mL (<200)
Clinical diagnosis of IgA nephropathy
Clinical diagnosis of IgA nephropathy
What next?
Clinical diagnosis of IgA nephropathy
What next?
?? Kidney biopsy
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?
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
What would a biopsy add to what we already (think we) know?
Reich H N et al. JASN 2007;18:3177-3183
What would a biopsy add to what we already (think we) know?
Time-average proteinuria
1 - < 1g/24h
2 – 1-2 g/24h
3 – 2-3g/24h
4 - >3g/24h
Reich H N et al. JASN 2007;18:3177-3183
Renal biopsy findings
IgA
Renal biopsy findings
IgA
IgA nephropathy
Oxford MEST Classification
Oxford MEST Classification
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%
Cellular/fibrocellular crescents were not predictive of outcome
T0 or T1 or T2
Oxford MEST Classification
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%
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
T0 or T1 or T2
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
Oxford MEST Classification:
M0 E0 S0 T0
Oxford MEST Classification: M0 E0 S0 T0
How does this help?
Oxford MEST Classification: M0 E0 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS
Combining glomerular patterns
Criteria
Minimal mesangial
Slope:
No. of
patients ml/min/1.73m2/yr
without segmental sclerosis
M0,E0,S0
12
0.7 ± 2.5
with segmental sclerosis
M0,E0,S1
22
-1.5 ± 2.7
M1,E0,S0
31
-2.2 ± 4.3
M1,E0,S1
88
-4.7 ± 7.6
M0/1,E1,S0
21
1.2 ± 1.2
M0/1,E1,S1
90
-4.9 ± 10.0
Mesangial hypercellularity without segmental sclerosis
with segmental sclerosis
Endocapillary proliferation without segmental sclerosis
with segmental sclerosis
Oxford MEST Classification: M0 E0 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS
Combining glomerular and tubulointerstitial lesions
Glomerular lesions
Minimal mesangial
Mesangial hypercellularity
Endocapillary proliferation
TA/IF
Criteria
Slope:
No. of
patients ml/min/1.73m2/yr
≤25%
M0,E0,T0
30
-0.6 ± 3.0
> 26%
M0,E0,T1-2
5
-1.0 ± 1.2
≤25%
M1,E0,T0
89
-2.7 ± 5.5
> 26%
M1,E0,T1-2
30
-7.9 ± 9.1
≤25%
M0/1,E1,T0
88
-3.0 ± 1.9
> 26%
M0/1,E1,T1-2
23
-6.9 ± 1.2
Oxford MEST Classification: M0 E0 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS
Combining glomerular and tubulointerstitial lesions
Glomerular lesions
Minimal mesangial
Mesangial hypercellularity
Endocapillary proliferation
TA/IF
Criteria
Slope:
No. of
patients ml/min/1.73m2/yr
≤25%
M0,E0,T0
30
-0.6 ± 3.0
> 26%
M0,E0,T1-2
5
-1.0 ± 1.2
≤25%
M1,E0,T0
89
-2.7 ± 5.5
> 26%
M1,E0,T1-2
30
-7.9 ± 9.1
≤25%
M0/1,E1,T0
88
-3.0 ± 1.9
> 26%
M0/1,E1,T1-2
23
-6.9 ± 1.2
These are just examples
Not enough evidence yet to directly sum risks
Oxford MEST Classification:
M1 E1 S0 T0
Oxford MEST Classification: M1 E1 S0 T0
How does this help?
PROGNOSTIC IMPACT OF COMBINATIONS OF PATHOLOGICAL LESIONS
Combining glomerular and tubulointerstitial lesions
Glomerular lesions
Minimal mesangial
Mesangial hypercellularity
Endocapillary proliferation
TA/IF
Criteria
Slope:
No. of
patients ml/min/1.73m2/yr
≤25%
M0,E0,T0
30
-0.6 ± 3.0
> 26%
M0,E0,T1-2
5
-1.0 ± 1.2
≤25%
M1,E0,T0
89
-2.7 ± 5.5
> 26%
M1,E0,T1-2
30
-7.9 ± 9.1
≤25%
M0/1,E1,T0
88
-3.0 ± 1.9
> 26%
M0/1,E1,T1-2
23
-6.9 ± 1.2
Immunosuppression had no influence on relationship
between pathology variables and the rate
of renal function decline
…..except for endocapillary lesions
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
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
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
Does it help us understand disease mechanisms?
No
Is he suitable for recruitment to clinical trials?
Probably
Why were crescents not related to outcome
in this classification?
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
WHEN ARE CRESCENTS SIGNIFICANT
IN IgA NEPHROPATHY ?
Patients meeting
‘Oxford’ criteria
Patients outside
‘Oxford’ criteria
Katafuchi R et al. CJASN 2011; 6: 2806
Why is the classification based just on light
microscopy?
Would the addition of immunohistochemistry and/or EM data add any value?
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
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
Another clinical case
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
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+
Investigations
serum creatinine
eGFR
serum albumin
Serum cholesterol
serum C-reactive protein
172µmol/L (60–110)
47ml/min
19g/L (35-45)
9.8mmol/L
5mg/L (<10)
Urine PCR
781mg/mmol (<30)
anti-nuclear antibody
negative
serum 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
Investigations
serum creatinine
eGFR
serum albumin
Serum cholesterol
serum C-reactive protein
172µmol/L (60–110)
47ml/min
19g/L (35-45)
9.8mmol/L
5mg/L (<10)
Renal tract ultrasound:
Lt kidney 10.6cm
Rt kidney 10.9cm
Normal appearance
No stones
Urine PCR
781mg/mmol (<30)
KUB X-ray:
No renal tract calcification
anti-nuclear antibody
negative
serum 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
Investigations
serum creatinine
eGFR
serum albumin
Serum cholesterol
serum C-reactive protein
172µmol/L (60–110)
47ml/min
19g/L (35-45)
9.8mmol/L
5mg/L (<10)
Renal tract ultrasound:
Lt kidney 10.6cm
Rt kidney 10.9cm
Normal appearance
No stones
Urine PCR
781mg/mmol (<30)
KUB X-ray:
No renal tract calcification
anti-nuclear antibody
negative
serum 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
Kidney biopsy
Renal biopsy
Renal biopsy
Focal segmental glomerulosclerosis
Renal biopsy
Focal segmental glomerulosclerosis
Not Otherwise Specified
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
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
D’Agati V et al. N Engl J Med 2011;365:2398
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
D’Agati V et al. N Engl J Med 2011;365:2398
PATHOLOGICAL CLASSIFICATION OF FSGS
Cellular variant
Collapsing variant
NOS
Tip lesion variant
Perihilar variant
D’Agati V et al. AJKD 2004
Demographics, clinical presentation, and outcomes of FSGS
variants
Thomas DB et al. KI 2006; 69: 920
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?
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?
What’s the diagnosis?
Cellular variant
Collapsing variant
NOS
Tip lesion variant
Perihilar variant
D’Agati V et al. AJKD 2004
What’s the diagnosis?
NOS
D’Agati V et al. AJKD 2004
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?
PREDICTING OUTCOME FROM PATHOLOGY
IN FSGS
All other ‘variants’
P = 0.0016
Collapsing
Thomas DB et al. KI 2006; 69: 920
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’
REMISSION & ESRD IN FSGS
Remission (partial or complete)
vs. No remission
No Remission vs.
Partial remission
with a relapse
1. 0
.8
.6
.4
.2
0. 0
0
2
4
6
8
10
Ti me to RRT or death(yrs)
Stirling C et al– QJM 2005; 98: 443
Troyanov S. et al. JASN 2005; 16:1061
Demographics, clinical presentation, and outcomes of FSGS
variants
Thomas DB et al. KI 2006; 69: 920
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?
TREATMENT OF FSGS
D’Agati V et al. N Engl J Med 2011;365:2398-411
TREATMENT OF FSGS
D’Agati V et al. N Engl J Med 2011;365:2398-411
TREATMENT OF FSGS
D’Agati V et al. N Engl J Med 2011;365:2398-411
PREDICTING OUTCOME IN FSGS
Who will respond to steroids
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
Treatment and outcomes of FSGS
Stokes MB et al. KI 2006; 70: 1676
Treatment and outcomes of FSGS
Characteristics
n
Classic FSGS
36
Cellular Lesion
40
Tip Lesion
P
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
remission
9 (25%)
1
17 (43%)
1
3 (27%)
0
NS
no remission
8
16
3
treated
4
6
2
no treatment
5
11
1
Chun M et al. JASN 2004; 15: 2169
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?
Recurrence of FSGS after kidney transplantation
FSGS recurs in 30-40% of first kidney transplants
(nearly 100% in 2nd Tx if recurrence in 1st)
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
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
ummary
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
ummary
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
ANCA-associated vasculitis
Validated
European population
Berden AE et al. JASN 2010; 21: 1628
PREDICTING OUTCOME FROM PATHOLOGY
IN ANCA-ASSOCIATED GN
Berden AE et al. JASN 2010; 21: 1628
PREDICTING OUTCOME FROM PATHOLOGY
IN ANCA-ASSOCIATED GN
Berden AE et al. JASN 2010; 21: 1628
Independent validation
Chinese population
Chang D et al. Nephrol Dial Transplant (2012) 27: 2343
Renal response to treatment of the four classifications
Chang D et al. Nephrol Dial Transplant (2012) 27: 2343
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
THE FUTURE
INDIVIDUAL PROGNOSIS AND TREATMENT PLAN
FOR PATIENTS WITH GLOMERULONEPHRITIS
THE FUTURE
Histopathology
Clinical
Immune
mechanisms
Genetics
Biomarkers
INDIVIDUAL PROGNOSIS AND TREATMENT PLAN
FOR PATIENTS WITH GLOMERULONEPHRITIS
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
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
The relationship between anti-PLA2R and proteinuria
in membranous nephropathy
Hofstra JM et al. CJASN 2011;6:1286
The relationship between anti-PLA2R and proteinuria
in membranous nephropathy following treatment
Beck LH et al. JASN 2011;22:1543
INDIVIDUAL PROGNOSIS IN
IgA NEPHROPATHY
Other ?
IgA glycosylation ?
PATHOLOGY
MEST
CLINICAL
Proteinuria
Hypertension
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)
Thank you
Questions?
PATHOLOGICAL CLASSIFICATION OF GN
A classification must be
•
•
•
•
•
evidence-based
clinically relevant
simple
precise in its definitions
reproducible