Transcript IgA nephropathy

An international evidence-based
classification of IgA nephropathy:
the Oxford Classification
Ian Roberts
Oxford, UK
IgA nephropathy
• Biopsy is usually performed at or near to the time
of renal presentation
• Roles: Diagnosis
Renal prognosis
Therapeutic decisions
• Light microscopical changes are highly variable
IgA nephropathy is
heterogenous
Prognostic information within a
biopsy
• Active lesions (necrosis, inflammation,
proliferation) – potentially reversible
• Chronic lesions (global glomerulosclerosis;
tubular atrophy, interstitial fibrosis) – largely
irreversible
• Which histological lesions are relevant/useful in
clinical practice?
• How should the histological changes be
expressed?
Clinicopathological correlation in
IgA nephropathy
Reference
mesangial
severity
endocapillary
proliferation
crescents
capillary wall
IgA
focal seg
lesions
glomerulosclerosis
interstitial fibrosis/
tubular atrophy
Nozawa et al, 2005
X
Ballardie et al, 2002
X
To et al, 2000
X
Mera et al, 2000
X
Daniel et al, 2000
X
Vleming et al, 1998
X
Freese et al, 1998
X
Hogg et al, 1994
X
X
X
X
Katafuchi et al, 1994
X
Ibels et al, 1994
X
Okada et al, 1992
X
X
X
Bogenschutz et al, 1990
Rekola et al, 1989
D'Amico et al, 1986
Boyce et al, 1986
X
X
X
X
X
X
X
Which classification schema do
nephropathologists use?
• Renal Pathology Society survey 2006
In reporting a diagnosis of IgA nephropathy, do you use a
specific histologic classification system?
63% No
37% Yes – 5 different schemas
most popular Haas (14% of total respondents)
Do you think that a more universal histologic classification
system for IgA nephropathy would be worthwhile?
94% Yes (if it can be demonstrated to be of clinical value)
Histological classification of IgA
nephropathy
• Is important for clinical trials, comparison of
different studies, communication between
pathologists and nephrologists, management
of individual patients…
• A classification schema must be evidencebased, clinically relevant, simple, precise in
its definitions and reproducible.
Towards a new clinicopathological
classification of IgA nephropathy: the
Oxford classification
Traditional approach to development of new histological
classifications in renal pathology:
1. One individual or a group of experts publish a
classification
2. Studies attempt to validate the classification and test
reproducibility
3. Subsequent revision or rejection of the classification
Define the histological lesions, test the reproducibility,
collect evidence from a clinicopathological study…..
Then publish.
A Working Group of the International IgA Nephropathy Network & Renal Pathology Society
Nov 2004
First meeting of International working group at ASN meeting.
April 2005
Workshop, Magdalen College, Oxford
April 2006
Pathology review meeting, USCAP meeting
April 2008
Final workshop, Magdalen College
Nephrologists
Jonathan Barratt [UK]
Francois Berthoux [France]
Roberta Camilla [Italy]
Daniel Cattran [Canada]
Rosanna Coppo [Italy]
Beppe D’Amico [Italy]
John Feehally [UK]
Ron Hogg [USA]
Stephen Hsu [USA]
Bruce Julian [USA]
Tetsuya Kawamura [Japan]
Philip Li [Hong Kong]
Paolo Schena [Italy]
Stephan Troyanov [Canada]
Pathologists
Vivette d’Agati [USA]
Charles Alpers [USA]
Stephen Bonsib [USA]
Jan Bruijn [Netherlands]
Terry Cook [UK]
Steven Emancipator [USA]
Franco Ferrario [Italy]
Sandrine Florquin [Netherlands]
Agnes Fogo [USA]
Hermann-Josef Groene [Germany]
Mark Haas [USA]
Andrew Hertzenberg [Canada]
Prue Hill [Australia]
Charles Jennette [USA]
Kensuke Joh [Japan]
Fernand Lai [Hong Kong]
Ian Roberts [UK]
Patrick Walker [USA]
Jan Weening [Netherlands]
Overall strategy for development of evidence-based
consensus classification of IgAN
Agree pathological definitions
Data collection
Agree pathological scoring process
Data analysis to identify
elements with
prognostic predictive power
Agree clinical dataset
Select patient cohorts
Agree data collection process
and data verification
Refine and agree a
clinico-pathological classification
Publish
Achieve international usage
Test on further
patient cohorts
Health warning!
The clinicopathological study:
Retrospective study
Selected patient group
Not controlled for immunosuppression or other
therapy
Requires validation in other patient groups and in
prospective studies
The Study Group
Retrospective recruitment, aiming for:
300 cases comprising 250 adults and 50 children.
15 centres in 11 countries in 4 continents collaborated
Patients who had received a range of different antihypertensive agents and
different immunosuppressive treatment schedules were included.
Inclusion criteria:
Biopsy proven IgAN
Status within 3 months of biopsy
Proteinuria > 0.5g/24hr; children [age < 18 yrs] ≥ 0.5g/24hr /1.73m2
Estimated GFR [eGFR] > 30ml/min/1.73m2 at presentation [eGFR
calculated using 4 variable MDRD equation in adults or Schwartz formula
in children]
Sufficient clinical data within 3 months of biopsy
Sequential follow-up data at least annually for >3 years from biopsy
Primary clinical end point: Rate of loss of renal function.
Secondary end points: ESRD/50% loss of renal function by end of follow-up
Clinical dataset (data collected within 3 months of biopsy)
Demographics/Clinical
Laboratory data
Date of birth
Serum creatinine
Ethnicity
Estimated GFR
Gender
Serum albumin
Date of first clinical presentation
Serum cholesterol
Date of renal biopsy
Serum triglycerides
Presenting clinical features
Macroscopic haematuria
Asymptomatic microhaematuria
Asymptomatic microhaematuria and proteinuria
Nephrotic syndrome
Acute renal failure
CKD Stage 3[eGFR< 60mL/min]
Urine protein excretion
Height
Microscopic haematuria
0-3+ on dipstick analysis
Weight
Medications – before biopsy
Body Mass Index
Number of blood pressure medications prescribed
Smoker
ACE inhibitors
Angiotensin receptor blockers
Non dihydropyridine calcium channel blockers
Dihydropyridine calcium channel blockers
Statins
Diuretics
Fish oil
Corticosteroids
Cyclophosphamide
Mycophenolate
Azathioprine
Platelet aggregation inhibitors
Systolic blood pressure
Tonsillectomy
Diastolic blood pressure
Follow up dataset (data collected on at least annually over
>3 years)
Demographics/Clinical
Medications – before biopsy
Height
Number of blood pressure medications prescribed
Weight
ACE inhibitors
Angiotensin receptor blockers
Non dihydropyridine calcium channel blockers
Dihydropyridine calcium channel blockers
Statins
Diuretics
Fish oil
Corticosteroids
Cyclophosphamide
Mycophenolate
Azathioprine
Platelet aggregation inhibitors
Body Mass Index
Smoker
Systolic blood pressure
Diastolic blood pressure
Laboratory data
Serum creatinine
Estimated GFR
Serum albumin
Serum cholesterol
Serum triglycerides
Urine protein excretion
Microscopic haematuria
0-3+ on dipstick analysis
Tonsillectomy
The Study Group
Exclusion criteria:
Henoch-Schȍnlein purpura, diabetes mellitus
Proteinuria , < 0.5g/24hr; children [age < 18 yrs] < 0.5g/24hr /1.73m2
eGFR < 30ml/min/1.73m2 at presentation
Insufficient clinical data within 3 months of biopsy or on follow up
End-stage renal disease < 12 months from time of biopsy
Biopsy containing <8 glomeruli
Started with 320 patients  265 patients with adequate biopsies and
full histological and clinical dataset.
Total
Adults
Children
[age < 18yrs at biopsy]
206
59
48
14
Beijing
12
2
Hong Kong
9
1
Nanjing
7
1
Tokyo
19
1
Wakayama
1
9
73
21
265
Asia
China
Japan
Europe
France
St Etienne
23
1
Italy
Bari
23
1
Milano
16
3
Roma
-
9
Torino
3
7
Glasgow
8
-
82
24
United Kingdom
Americas
Canada
Toronto
32
0
United States
Birmingham
12
1
Mayo Clinic
14
4
South West Study Group
24
19
3
0
3
0
South America
Chile
Santiago
Pathology dataset
Histological lesions were defined by consensus at initial Oxford meeting
in 2005.
Provisional analysis of the first 40 cases, to identify areas of high interobserver variation were identified.
In order to improve reproducibility, definitions were refined at a meeting
of pathologists in Atlanta in 2006
Philosophy:
Keep an open mind on which histological lesions are important.
Collect as much information as possible – simplify only after data analysis
Pathology dataset
IgA nephropathy:
IgA nephropathy in the native kidney is defined as dominant or codominant staining with IgA in glomeruli by immunofluorescence or
immunoperoxidase. Not all glomeruli need show this positivity. SLErelated nephritis should be excluded. The intensity of IgA staining
should be more than trace. The distribution of IgA staining should
include presence in the mesangium, with or without capillary loop
staining, excluding a pure membranous, diffuse, global granular GBM
staining pattern or linear GBM staining pattern. IgG and IgM may be
present, but not in greater intensity than IgA, except that IgM may be
prominent in sclerotic areas. Complement C3 may be present. The
presence of C1q staining in more than trace intensity should bring up
consideration of lupus nephritis.
Pathology dataset
Glomerular definitions:
Diffuse: a lesion involving most (≥ 50%) glomeruli.
Focal: a lesion involving <50% of glomeruli.
Global: a lesion involving more than half of the glomerular tuft (NB see below for definitions of
segmental and global sclerosis).
Segmental: a lesion involving less than half of the glomerular tuft (i.e. at least half of the glomerular tuft
is spared). N.B. see below for definitions of segmental and global sclerosis
Endocapillary hypercellularity: hypercellularity due to increased number of cells within glomerular
capillary lumina causing narrowing of the lumina.
Karyorrhexis: presence of apoptotic, pyknotic and fragmented nuclei.
Necrosis: is defined by (i) disruption of the glomerular basement membrane with (ii) fibrin exudation
and (iii) karyorrhexis. At least two of these three lesions need to be present to meet the criteria for
necrosis. (*2008 amendment: Necrosis should not be scored on the PAS-stained section alone; fibrin
is more easily identified on H&E or MSB-stained sections and breaks in the glomerular basement
membrane are more easily identified on silver-stained sections. A minimum requirement for the
definition of a necrotising lesion is extracapillary fibrin exudation.)
GBM duplication: a double contour of the GBM with or without endocapillary hypercellularity.
Increased mesangial matrix: an increase in the extracellular material in the mesangium such that the
width of the interspace exceeds two mesangial cell nuclei in at least two glomerular lobules.
Sclerosis: obliteration of the capillary lumen by increased extracellular matrix, with or without
hyalinosis or foam cells.
An adhesion: an area of continuity between the glomerular tuft and Bowman's capsule separate from
an extracapillary lesion or area of segmental sclerosis.
Segmental sclerosis: any amount of the tuft involved with sclerosis, but not involving the whole tuft.
Global sclerosis: the entire glomerular tuft involved with sclerosis.
Collapsed/ischaemic glomerulus: A glomerulus showing collapse of the capillary tuft with or without
thickening of Bowman’s capsule and fibrosis in Bowman’s space
Pathology dataset
Extracapillary lesions subclassified as follows:
Extracapillary proliferation or cellular crescent: extracapillary cell proliferation of more than two cell
layers with >50% of the lesion occupied by cells. It is further classified by the percentage of glomerular
circumference involved <10%, 10-25%, 26-50%, >50%.
Extracapillary fibrocellular proliferation or fibrocellular crescent: an extracapillary lesion comprising
cells and extracellular matrix, with <50% cells and <90% matrix. This is further classified by the
percentage of the glomerular circumference involved <10%, 10-25%, 26-50%, >50%.
Extracapillary fibrosis or fibrous crescent: >10% of the circumference of Bowman's capsule covered by
a lesion composed of >90% matrix. It is further classified by the percentage of the glomerular
circumference involved 10-25%, 26-50%, >50%. Ischaemic, obsolescent glomeruli should be excluded.
A crescent is one of these extracapillary lesions which involves >10% of the circumference of
Bowman’s capsule.
Mesangial hypercellularity is subclassified as follows:
If <4 mesangial cells/mesangial area = normal,
4-5 mesangial cells/mesangial area = mild mesangial hypercellularity,
6-7 mesangial cells/mesangial area = moderate mesangial hypercellularity,
8 or more mesangial cells/mesangial area = severe mesangial hypercellularity.
Note: This is scored for each glomerulus by assessing the most cellular mesangial area. Mesangial
areas immediately adjacent to the vascular stalk should not be scored. Individual mesangial areas
showing hypercellularity are separated by areas of narrowing to the width of less than 2 mesangial cell
nuclei (ie count clusters, not files of mesangial cell nuclei).
Pathology dataset
Tubulointerstitial definitions:
Tubular atrophy: is defined by thick irregular tubular basement membranes with decreased diameter of
tubules. It is scored according to the percent of cortical area involvement with 1-5% rounded to 5%
and other values rounded to the closest 10%.
Interstitial fibrosis: is defined as increased extracellular matrix separating tubules in the cortical area. It
is scored as percentage involvement with 1-5% rounded to 5% and other values rounded to the
closest 10%
Interstitial inflammation: is defined as inflammatory cells within the cortical interstitium in excess. It is
scored as percentage involvement with 1-5% rounded to 5% and other values rounded to the closest
10%. It should be noted whether the inflammation is confined to areas of interstitial fibrosis or not.
Additional tubular lesions are noted as follows: The presence of numerous red blood cells, defined as
tubules completely filled with red blood cells with or without casts, is noted as a lesion when it involves
>20% of tubules.
Acute tubular injury of the proximal tubular epithelium is defined by simplification of the epithelium
without tubular basement membrane thickening.
Vascular definitions:
Arterial lesions are scored based on the most severe lesions. Interlobular and larger arteries are
scored separately. An interlobular artery is one surrounded by cortex; an arcuate artery is one at the
corticomedullary junction. Intimal thickening is scored by comparing the thickness of the intima to that
of the media in the same segment of vessel. Score the intima variously as normal, and thickened to
more or less than the thickness of the media.
Arteriolar hyaline is noted as the proportion of arterioles affected (0, 1-25%, 26-50%, >50%).
Pathology dataset
Pathology dataset
The slide circulation:
Histological score sheet with instructions agreed at Atlanta 2006.
Batches of 5 cases circulated between 5 pathologists in a rolling
fashion – no two batches scored by the same pathologists.
Glomerular lesions scored on a circled PAS-stained section.
Aims:
Median scores taken for clinicopathological correlations, to achieve
robust quantitative/semiquantitative measure of histological changes,
independent of a single pathologist’s idiosyncrasies.
Measure interobserver variation – exclude histological lesions with poor
reproducibility.
Global slide circulation
Circulation 2
Last date by which these slides should be sent on to the next pathologist on the list
Pathologist
Pathologist No. 03-Jan-07
I Roberts
1
Cases sent out
F Lai
2
Cases sent out
A Herzenberg 3
Cases sent out
A Fogo
4
Cases sent out
S Bonsib
5
Cases sent out
J Weening
6
Cases sent out
S Florquin
7
Cases sent out
H-J Grone
8
Cases sent out
C Alpers
9
Cases sent out
P Walker
10
Cases sent out
J Bruijn
11
Cases sent out
F Ferrario
12
Cases sent out
S Emancipator 13
Cases sent out
M Haas
14
Cases sent out
C Jennette
15
Cases sent out
V D'Agati
16
Cases sent out
K Joh
17
Cases sent out
P Hill
18
Cases sent out
T Cook
19
Cases sent out
29-Jan-07 26-Feb-07 19-Mar-07 9-Apr-07
96-100
191-195 186-190 181-185
106-110 96-100
191-195 186-190
111-115 106-110 96-100
191-195
116-120 111-115 106-110 96-100
121-125 116-120 111-115 106-110
126-130 121-125 116-120 111-115
131-135 126-130 121-125 116-120
136-140 131-135 126-130 121-125
141-145 136-140 131-135 126-130
146-150 141-145 136-140 131-135
151-155 146-150 141-145 136-140
156-160 151-155 146-150 141-145
161-165 156-160 151-155 146-150
166-170 161-165 156-160 151-155
171-175 166-170 161-165 156-160
176-180 171-175 166-170 161-165
181-185 176-180 171-175 166-170
186-190 181-185 176-180 171-175
191-195 186-190 181-185 176-180
30-Apr-07
Return 176-180 to Oxford
Return 181-185 to Oxford
Return 186-190 to Oxford
Return 191-195 to Oxford
Return 96-100 to Oxford
Return 106-110 to Oxford
Return 111-115 to Oxford
Return 116-120 to Oxford
Return 121-125 to Oxford
Return 126-130 to Oxford
Return 131-135 to Oxford
Return 136-140 to Oxford
Return 141-145 to Oxford
Return 146-150 to Oxford
Return 151-155 to Oxford
Return 156-160 to Oxford
Return 161-165 to Oxford
Return 166-170 to Oxford
Return 171-175 to Oxford
Column A
Mesangial cell hypercellularity
no hypercellularity (0)
mild (1) (4-5 cells)
moderate (2) (6-7 cells)
severe (3) (≥8 cells)
Total number of scorable glomeruli
Indeterminate
Total number of glomeruli
Column B
Normal glomerulus
Segmental sclerosis
Adhesion
Ischaemia/collapse
Endocapillary hypercellularity
Segmental
Global
GBM duplication
Necrosis
Extracapillary lesions - cellular
Tiny focus (<10%)
Crescent (10-25%)
Crescent (26-50%)
Crescent (>50%)
Extracapillary lesions - fibrocellular
Tiny focus (<10%)
Crescent (10-25%)
Crescent (26-50%)
Crescent (>50%)
Extracapillary lesions - fibrous
Crescent (10-25%)
Crescent (26-50%)
Crescent (>50%)
ISN/RPS IgA nephropathy Working Group score sheet
Total
Mesangial score
Case Number
Scorer
Date
A
B
Mean mesangial score (B divided by A)
Indeterminate mesangial cellularity due to:
Global sclerosis/advanced segmental sclerosis
Global endocapillary hypercellularity
Retracted glomerular tuft (ischaemic/collapse)
Incomplete mesangial area
Crescent only (type in col. B)
Total
Column C
Mesangial matrix expansion out of proportion to cellularity
Tubular atrophy (%) score 0%, 1-5% as 5%, >5% to nearest 10%
Interstitial fibrosis (%) score as for tubular atrophy
Interstitial inflammation (%) score as for tubular atrophy
check in scarred areas only
in scarred and non-scarred
Arteriosclerosis
interlobular arteries
None present
No intimal thickening
intima thickened and < thickness of media
intima thickened and > thickness of media
arcuate arteries & larger
None present
No intimal thickening
intima thickened and < thickness of media
intima thickened and > thickness of media
Arteriolar hyalinosis
absent
1-25% of arterioles present
26-50% of arterioles present
>50% of arterioles present
Other
Total Glom
Mesangial 1
Median mesangial score
Mesangial 2
% scorable glomeruli showing severe mesangial hypercellularity (median of group)
Global GS
% of total glomeruli showing global sclerosis or retracted glomerular tuft (median of group)
Normal glomeruli
% of total glomeruli noted as normal (median of group)
Segmental GS
% of total glomeruli showing segmental sclerosis (median of group)
Adhesion
% of total glomeruli showing adhesions (median of group)
Endocapillary 1
% of total glomeruli showing segmental endocapillary hypercellularity (median of group)
Endocapillary 2
% of total glomeruli showing segmental + global endocapillary hypercellularity (median of group)
GBM duplication
% of total glomeruli showing GBM duplication (median of group)
Necrosis
% of total glomeruli showing necrosis (median of group)
Extracapillary 1
% total glomeruli showing cellular crescents (median)
Extracapillary 2
% total glomeruli showing cellular + fibrocellular crescents (median)
Extracapillary 3
mean cellular + fibrocellular crescent score (median of group)
Extracapillary 4
% total gloms showing fibrous crescents (median)
Extracapillary 5
mean fibrous crescent score (median of group)
Tubular atrophy
% of cortex showing tubular atrophy (median of group)
Interstitial fibrosis
% of cortex showing interstitial fibrosis (median of group)
Interstitial inflammation 1
% of cortex showing interstitial inflammation (median of group)
Interstitial inflammation 2
% of cortex showing interstitial inflammation if majority (3 or more) checked scarred and non-scarred. Score as
0 if majority checked scarred areas only. Scarred only 0; Scarred and non-scarred 1
Arterial 1
Median arcuate artery score. Leave blank if none present.
Arterial 2
Median interlobular artery score. Leave blank if none present.
Arterial 3
Median artery score - worst of arcuate and interlobular. Leave blank if none present.
Arteriole 1
Absent=0; Present=1. Take majority verdict
Arteriole 2
Median arteriolar hyalinosis score
Histol No. Mesang1 Mesang2 Global GS Norm glomSeg GS Adhesion Endocap1 Endocap2 GBM dup Necrosis Extracap1 Extracap2 Extracap3
5
1.3
10
17
0
27
7
0
0
0
0
7
29
0.75
Total glom
29
30
29
30
28
28
1.3
1.3
1.6
1.3
0.65
1
10
22
19
0
0
10
17
17
24
10
11
21
0
0
0
33
11
0
27
23
34
27
39
14
7
10
28
3
4
7
0
10
0
0
0
11
0
10
0
0
0
0
Extracap3 Extracap4 Extracap5 Tub atrophyInt fibrosis Int inflam1 Int inflam2 Arterial1
0.75
7
0.11
20
20
10
0
0.75
0.33
0.9
0.87
0.36
0.75
7
3
28
3
21
7
0.11
0.03
0.62
0.1
0.5
0.11
20
20
20
20
40
30
20
20
15
20
50
30
10
0
15
20
10
0
1
0
0
0
10
0
0
0
0
Arterial2
0
0
0
0
0
0
0
Arterial3
7
7
10
10
7
7
29
13
34
33
14
29
0
0
Arteriole1 Arteriole2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
1
0
0
0
0
0.75
0.33
0.9
0.87
0.36
0.75
Study No. Histol No. Mesang1 Mesang2 Global GS Norm glomSeg GS Adhesion Endocap1 Endocap2 GBM dup Necrosis Extracap1 Extracap2
501
1
0.89
0
0
14
11
11
0
0
0
0
0
0
502
2
0.69
0
0
15
0
0
0
0
0
0
0
0
503
3
0.2
0
40
40
17
0
0
0
0
0
0
0
504
4
0.14
0
21
36
0
0
0
0
0
0
0
0
505
5
1.3
10
17
0
27
7
0
0
0
0
7
29
506
6
0.6
0
19
62
7
0
0
0
0
0
0
5
507
7
1
8
7
50
0
0
0
0
0
0
0
0
508
8
0.84
0
2
79
0
6
0
0
0
0
0
0
509
9
510
10
1.5
8
40
0
17
13
0
0
0
0
0
0
511
11
0.8
0
30
20
18
22
0
0
0
0
0
0
512
12
0.6
0
30
25
20
11
0
0
0
0
0
0
513
13
0.09
0
0
77
0
0
0
0
0
0
0
0
514
14
1.13
13
0
0
0
0
9
9
0
0
0
9
515
15
1.5
8
0
21
0
0
0
0
0
0
0
0
516
16
1.32
0
0
13.5
10
10
0
0
0
0
9
15
517
17
0.55
0
21
50.5
0
4.5
0
0
0
0
0
0
518
18
0.91
0
30
19.5
0
2
5.5
5.5
0
0
0
0
519
19
0.6
0
11
42
1
4.5
1
1
0
0
0
0
520
20
1.13
5.5
28
10.5
5
12.5
0
0
0
0
0
0
521
21
0.67
0
5
42.5
5
23
0
0
0
0
0
0
522
22
2.2
50
0
0
13
16
0
0
0
0
0
0
23
0.73
0
25.5
13.5
0
5
0
0
0
0
0
0
524
24
0.8
3
1
33
0
0
0
0
0
0
0
0
25
1.5
8
16
0
0
11
31
39
0
0
8
29
526
26
0.6
0
0
8
0
0
0
0
0
0
0
0
527
27
1.12
6
3
3
21.5
7
0
0
0
0
0
11
528
28
0.9
8
4
0
0
4
0
0
0
0
0
0
529
29
1.7
0
67
0
6
0
0
0
0
0
0
0
530
30
0.8
0
10
0
13
10
0
0
0
0
0
10
531
31
2.24
47
0
0
6
11
18
24
11
0
0
0
32
533
33
1.4
14
0
0
11
11
0
0
0
0
0
0
534
34
1.5
40
43
0
29
25
0
0
14
0
0
0
35
0
0
0
0
0
0
0
0
0
0
0
0
• 83% of the cases were scored by four or more pathologists, 17% by
three pathologists.
• Median 18 glomeruli per biopsy.
• Some lesions were seen infrequently: necrosis was seen in only 6
cases and GBM duplication in 30 cases.
How to simplify in to a smaller
number of lesions/patterns to
include in a classification?
Selection of which pathological variables to
include in the final classification based on:
• Reproducibility
• Independence from other lesions
• Clinical correlation
Definition
ICC
Mesangial 1
Mesangial score
0.63
Mesangial 2
% scorable glomeruli showing severe mesangial hypercellularity
0.54
Global GS
% of total glomeruli showing global sclerosis or retracted glomerular tuft
0.89
Normal glomeruli
% of total glomeruli noted as normal
0.28
Segmental GS
% of total glomeruli showing segmental sclerosis
0.50
Adhesion
% of total glomeruli showing adhesions
0.21
Seg GS & adhesion
Summation of %segmental GS and adhesion
0.49
Endocapillary 1
% of total glomeruli showing segmental endocapillary hypercellularity
0.35
Endocapillary 2
% of total glomeruli showing segmental + global endocapillary hypercellularity
0.57
GBM duplication
% of total glomeruli showing GBM duplication
0.11
Necrosis
% of total glomeruli showing necrosis
0.31
Extracapillary 1
% total glomeruli showing cellular crescents
0.62
Extracapillary 2
% total glomeruli showing cellular + fibrocellular crescents
0.63
Extracapillary 3
mean cellular + fibrocellular crescent score
0.65
Extracapillary 4
% total gloms showing fibrous crescents
0.30
Extracapillary 5
mean fibrous crescent score
0.33
Tubular atrophy
% of cortex showing tubular atrophy
0.76
Interstitial fibrosis
% of cortex showing interstitial fibrosis
0.73
Interstitial inflammation 1
% of cortex showing interstitial inflammation
0.54
Interstitial inflammation 2
Inflammation if involving scarred and non-scarred cortex
0.09
Arterial 1
Arcuate artery score
0.79
Arterial 2
Interlobular artery score.
0.69
Arterial 3
Artery score - worst of arcuate and interlobular*
0.71
Arteriole 1
Absent=0; Present=1. Take majority verdict
0.36
Correlations between pathology variables.
“R” values (correlation coefficients) Statistically significant correlations were
determined using the Holm-Bonferroni method to minimize the probability of
making a type I statistical error.
mesang
mes1
Mesang1
Mesang2
Global GS
Seg GS
Adhesion
Endocap1
Endocap2
GBM dup
Necrosis
Extracap1
Extracap2
Extracap3
Extracap4
Extracap5
Tubatrophy
Int fibrosis
Int inflam1
Int inflam2
Arterial1
Arterial2
Arterial3
Arteriole1
Arteriole2
-
GSC
endocap
Mes2 GlobGS SeGS Adh
0.7
-
0.2
-
0.4
-
0.3
0.3
0.2
0.5
-
End1
End2
0.3
0.3
0.3
0.3
-
0.99
-
Extracap
GBMdup Necr
Extr1 Extr2 Extr3 Extr4 Extr5 TubAt IntFib
0.2
0.3
0.3
-
Interstitium
0.4
0.4
0.2
0.4
0.3
0.5
0.5
0.4
0.3
0.5
0.5
0.7
-
0.7
0.99
-
0.3
0.2
0.3
0.2
0.4
0.4
-
0.4
0.4
0.99
-
0.7
0.5
0.3
vessels
Intinfl1 Intinfl2 Art1
0.2
0.3
0.8
0.5
0.3
0.6
0.4
0.3
Art2
Art3
Artiol1 Artiol2
0.3
0.3
0.4
0.3
0.8
0.8
0.3
0.3
0.3
0.3
0.4
0.4
0.3
0.4
0.4
-
0.8
-
0.9
0.9
-
0.6
0.5
0.5
-
-
0.2
-
0.98
-
0.9
0.9
-
0.5
0.5
0.95
-
Pathology variables selected for inclusion
in the clinicopathological analysis
Mesangial cellularity score
Segmental glomerulosclerosis/adhesion
Endocapillary hypercellularity (segmental + global)
Cellular/fibrocellular crescents
Tubular atrophy/interstitial fibrosis
Arterial score
Can these histological lesions add value to clinical variables
(at the time of biopsy and follow-up) in predicting outcome?
Can a change in a biopsy predict what will happen to renal
function years later?
Clinical characteristics at time of biopsy and follow-up (n=265)
Follow=up
At time of biopsy
Age (years)
Female
Ethnicity
Caucasian/African/Asian/Other
BMI
MAP (mmHg)
% taking bp meds (% RAS blockade)
GFR (ml/min/1.73m2)
% Stage I, II, III, IV
Proteinuria (g/day)*
Previous macroscopic haematuria
Serum albumin (g/L)
Serum cholesterol (mmol/L)
Serum triglycerides (mmol/L)
Previous immunosuppression
Previous use of fish oil (%)
Known previous tonsillectomy
32 ± 15
28%
66, 3, 27, 4%
25 ± 5
98 ± 18
31 (23)
82 ± 36
35, 49, 22, 4
1.7 (0.5-18.5)
33%
38 ± 6
5.5 ± 1.5
1.9 ± 1.6
11%
6%
6%
*proteinuria in children expressed in g/day/1.73m2.
Duration of follow-up (mo)
MAP (mmHg)
No. of antihypertensive drugs
Use of RAS blockade % (ACEi, ARB)
Proteinuria (g/day)*
Serum albumin
Serum cholesterol (mmol/L)
Serum triglycerides (mmol/L)
Immunotherapy (any form)
Prednisone
Second line (cyclophosphamide, others)
Use of fish oil
Use of statins
Tonsillectomy during follow-up
Rate of renal function decline (ml/min/1.73m2/y)
50% decline in renal function
Renal failure (<15 ml/min/1.73m2)
69 (12*-268)
95 ± 11
0.9 (0-4.7)
75 (68, 22)
1.4 (0.1-9.3)
40 ± 6
5.3 ± 1.2
1.9 ± 1.0
26%
26%
8% (6%, 4%)
16%
13%
0
- 3.5 ± 8.4
22%
13%
What are the clinically relevant cut-offs for continuous quantitative lesions?
Su rvival Fu nctio n s
Su rvival Fu nctio n s
1 .1
1 .2
1 .0
1 .0
.9
m es 4 _0 .5_1 _1 .5
.8
1 .5 +
.8
1 .5 + - cen s o red
SEGADH2
.7
> 20
1 - 1 .5
.6
.6
Cu m Su rvival
0 .5 - 1
.4
0 .5 - 1 - cen s o red
< 0 .5
< 0 .5 - cen s o red
.2
0
24
48
72
96
> 2 0 - cen s o red
< 20%
.5
< 2 0 %- cen s o red
.4
ab s en t
ab s en t - cen s o red
.3
0
120
24
48
Tim e to com b in e even t
Tim e to com b in e even t
Su rvival Fu nctio n s
1 .2
1 .0
In ters titial fib ros i
s evere (> 5 0)
.8
s evere (> 5 0)
- cen s o red
m o d erat e (25 - 5 0 )
.6
m o d erat e (25 - 5 0 )
- cen s o red
.4
Cu m Su rvival
Cu m Su rvival
1 - 1 .5 - cen s o red
m ild (< 2 5 )
m ild (< 2 5 )- cen s o red
.2
none
n o n e- cen s ored
0 .0
0
24
48
Tim e to com b in e even t
72
96
120
72
96
120
Correlations between pathology and initial
clinical presentation
MAP
mmHg
p
GFR
mL/min/1.73m
p
2
Proteinuria
g/day
p
Mesangial score ≤0.5
Mesangial score >0.5
100 ± 18
98 ± 17
>0.1
84 ± 28
82 ± 38
>0.1
1.4 (0.6-9.2)
2.0 (0.5-18.5)
0.001
No segmental GS or Adhesion
Any segmental GS or adhesion
94 ± 16
99 ± 18
0.04
94 ± 40
79 ± 34
0.004
1.5 (0.5-7.2)
1.9 (0.6-18.5)
0.01
No endocapillary hypercellularity
Any endocapillary hypercellularity
101 ± 18
94 ± 16
0.003
76 ± 31
92 ± 40
0.002
1.5 (0.5-11.3)
2.0 (0.5-18.5)
0.008
No crescent
Any crescents
98 ± 17
98 ± 18
>0.1
84 ± 37
80 ± 35
>0.1
1.5 (0.5-18.5)
2.2 (0.5-12.0)
0.002
Tubular atrophy
None (0%)
Mild (1-25%)
Moderate (26-50%)
Severe (51%+)
91 ± 17
99 ± 18
99 ± 11
105 ± 24
0.04
109 ± 35
85 ± 35
59 ± 17
46 ± 27
<0.001
1.5 (0.5-7.2)
1.7 (0.5-18.5)
1.7 (0.6-7.5)
3.0 (1.1-9.0)
0.06
Artery score
None
Mild
Moderate
Severe
95 ± 17
103 ± 15
101 ± 20
102 ± 7
0.01
91 ± 40
67 ± 19
70 ± 25
72 ± 33
<0.001
1.8 (0.5-18.5)
1.5 (0.6-4.6)
1.6 (0.8-.7.3)
1.7 (1.1-2.2)
>0.1
Mean ± SD, Median (range),
Therapy received during follow-up*
% with received
RAS blockade
p
% given
Immunosuppression
p
Mesangial score
≤0.5
>0.5
72
75
Segmental GS or Adhesion
absent
54
present
81
Endocapillary hypercellularity
absent
76
present
73
Crescent
absent
present
72
78
Tubular atrophy
0-25%
26-50%
>50%
72
83
85
Artery score
absent
Mild
Moderate
Severe
69
83
86
75
* Intend to treat.
>0.1
<0.001
19
30
27
29
>0.1
>0.1
>0.1
17
44
<0.001
>0.1
20
39
28
24
50
>0.1
32
24
19
50
>0.1
>0.1
0.006*
<0.001
Pathology and outcomes
Model A: multivariate - 3 pathological features + initial GFR, MAP, proteinuria.
Model B: multivariate - 3 pathological features + initial GFR + follow-up MAP, proteinuria
Rate of renal function decline
(Linear regression)
Survival from renal failure or a 50% drop in GFR
(Cox regression)
Univariate
slope
Multivariate
Univariate
Multivariate
Model A Model B Hazard ratio
Model A
Model B
ß
ß
(95% CI)
(ml/min/1.73m2/y)
Mesangial
hypercellularity score
≤0.5
-0.5 ± 3.3
0.06 (0.01-0.45) 0.07 (0.01-0.53)
0.11 (0.01-0.80)
-2.2
-0.8
>0.5
-4.2 ± 9.0
1
1
1
p<0.001
0.10
p>0.1
p=0.006
p=0.01
p=0.03
Segmental glomerulosclerosis
absent
-0.5 ± 7.5
present -4.4 ± 8.4
-3.6
-2.5
p=0.001
p=0.005 p=0.03
1
3.1 (1.4-7.3)
p=0.009
Tubular atrophy/interstitial fibrosis
0-25%
-2.5 ± 7.6
1
-5.2
-3.7
26-50%
-5.7 ± 8.8
3.5 (1.9-6.5)
>50%
-11.1 ± 12.6
15.5 (7.5-31.9)
p<0.001
p<0.001 p<0.001
p<0.001
1
1.8 (0.6-5.3)
p>0.1
1
2.5 (0.9-7.3)
p=0.09
1
6.0 (2.7-13.9)
17.3 (5.9-50.9)
p<0.001
1
5.0 (2.3-11.1)
8.8 (2.9-26.4)
p<0.001
Interaction of pathological features
with immunosuppressive therapy
• Relationship between pathology variables and the rate of
renal function decline was not influenced by
immunosuppression except for endocapillary lesions.
• Patients with endocapillary proliferation:
Rate of renal function decline
+ immunosuppression -2.6+/-5.1 ml/min/1.73m2 /yr
no immunosuppression -5.4+/-11.1 ml/min/1.73m2 /yr
p=0.006
Interaction of pathological features
with age and ethnicity
• Younger patients:
Presented with significantly less segmental glomerulosclerosis,
tubular atrophy/interstitial fibrosis and vascular lesions, but had
significantly more endocapillary lesions.
The predictive value of each pathology variable on the rate of renal
function decline was not influenced by the age at the time of biopsy
(p>0.1 for interaction term).
• Ethnicity (Caucasian vs Asian patients):
For each pathology variable, the interaction term with ethnicity was
not statistically significant except for endocapillary lesions (p=0.02);
the rate of renal function decline in Asian subjects was significantly
better compared to Caucasians.
But - Asian patients were significantly more likely to receive
immunosuppressive therapy during follow-up (42% compared to
22% in Caucasians, p=0.002).
Recommendations for the
pathology report
Minimum prognostic data:
Glomerular “pattern”:
Mesangial hypercellularity in > or <50% of glomeruli
Endocapillary hypercellularity – present/absent
Segmental sclerosis/adhesions – present/absent
Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50%
(M 0/1)
(E 0/1)
(S 0/1)
(T 0/1/2)
In addition: Total number of glomeruli
Endocapillary proliferation - %
Cellular/fibrocellular crescents - %
Necrosis - %
Global glomerulosclerosis - %
Example summary line: There is an IgA nephropathy showing diffuse
mesangial proliferation with focal segmental sclerosis and moderate
chronic tubulointerstitial damage (M1,E0,S1,T1)
Prognostic impact of combinations of histological 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
Prognostic impact of combinations of histological 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
Why not a classification? (eg. class I, class II, etc)
Because the data does not support this approach – the
MEST lesions are independent predictors of outcome and
the relative risks can not be simply summed.
How should the histological data be combined
with clinical indices?
?
This work was supported by:
International Society of Nephrology
Kidney Research UK
Vivor Pharma Aspreva plc