IgA nephropathy: what’s new since
the Oxford Classification
Ian Roberts
Oxford, UK
Session plan
Oxford Classification of IgA nephropathy – a
brief overview
what’s new…
Immunostaining pattern
Crescents
Validation studies of the Oxford Classification
FSGS in IgA nephropathy
Why was a new classification of IgA
nephropathy needed?
IgA nephropathy is heterogeneous, both clinically and histologically.
No consensus on how to best manage patients.
There were a number of previous “lumped” classifications, none widely
accepted as clinically useful.
Approach of the International IgA
nephropathy Working Group
A classification schema must be evidence-based, clinically relevant, simple,
precise in its definitions and reproducible.
Evidence based on a retrospective analysis of 265 adults and children from
15 centres in 11 countries.
Reproducible and independent histological variables:
Mesangial cellularity score
Segmental glomerulosclerosis/adhesion
Endocapillary hypercellularity
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?
Model A: multivariate - initial GFR, MAP, proteinuria.
Model B: multivariate - initial GFR + follow-up MAP, proteinuria
Mesangial hypercellularity
]
Segmental glomerulosclerosis
] predict slope and/or renal survival
Tubular atrophy/interstitial fibrosis
]
Endocapillary proliferation predicted outcome in patients who did not receive
immunosuppressive therapy
Conclusions equally applicable to children and adults and to different ethnic
groups
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)
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.
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
How should the histological data be combined with clinical
indices?
Immunostaining pattern in IgA nephropathy
– does it matter?
Diagnosis of IgA nephropathy is based on
immunohistology
Immunostaining pattern in IgA nephropathy
– does it matter?
Capillary wall deposits present in 24-54% of cases of IgA nephropathy
Capillary wall IgA associated with:
Higher proteinuria at presentation
Greater histological activity & chronicity
Poorer outcome (persistent proteinuria, renal failure)
Immunostaining pattern in IgA nephropathy
– does it matter?
Up to 50% of cases of IgA nephropathy show mesangial IgG deposits
IgG is associated with a poorer outcome
Should the presence of IgG and capillary wall IgA be included in the Oxford
Classification?
Almost all centres used immunofluorescence rather than immunoperoxidase
staining and slides were not available for review.
Original biopsy reports were available for 211 patients; 175 included
sufficient detail to subclassify the immunostaining findings,119 included
details of IgG staining.
Reports reviewed & classified:
1. Pattern of glomerular IgA staining: mesangial vs. mesangial + capillary
wall.
2. Presence or absence of glomerular IgG staining: > trace when present
was taken as positive.
Immunostaining pattern in IgA nephropathy
– does it matter?
Mesangial-only IgA
(n=149)
Capillary wall IgA
(n=26)
P value
No/trace IgG
(n=119)
IgG >trace
(n=30)
P value
Mesangial cellularity score
0.89 ±0.51
1.28 ±0.65
0.004
0.91 ±0.54
1.16 ±0.64
0.059
% global glomerulosclerosis
15.8 ±18.0
13.4 ±14.7
0.779
16.2 ±17.5
14.9 ±17.9
0.421
% segmental glomerulosclerosis
14.0 ±14.1
14.9 ±14.6
0.816
13.2 ±13.8
17.9 ±17.2
0.353
% endocapillary proliferation
5.3 ±12.1
12.2 ±16.0
0.003
5.1 ±12.1
10.4 ±14.1
0.005
% cellular + fibrocellular crescents
5.5 ±10.1
5.4 ±8.8
0.665
5.4 ±10.2
4.3 ±7.9
0.953
% glomeruli showing necrosis
0.2 ±1.6
0.0 ±0.0
0.345
0.2 ±1.6
0.0 ±0.0
0.381
% tubular atrophy
14.7 ±15.1
13.2 ±9.4
0.648
14.8 ±14.7
15.8 ±16.7
0.910
% interstitial fibrosis
15.3 ±15.0
13.7 ±9.0
0.699
15.5 ±14.6
16.1 ±16.2
0.858
Arteriosclerosis score
0.63 ±0.85
0.44 ±0.8
0.241
0.68 ±0.88
0.55 ±0.81
0.499
Arteriolar hyalinosis score
0.41 ±0.76
0.29 ±0.53
0.645
0.46 ±0.78
0.37 ±0.71
0.479
Bellur SS, et al. Nephrol Dial Transplant 2011;26:2533-6
Immunostaining pattern in IgA nephropathy
– does it matter?
Immunostaining pattern in IgA nephropathy
– does it matter?
Conclusion: The location of glomerular IgA and the presence of IgG
correlate with greater histological activity but do not independently predict
clinical outcome.
The data does not support inclusion in the Oxford Classification. But….
Capillary wall IgA and the presence of IgG were associated with trends to
greater immunosuppression.
35% of patients with capillary wall IgA received IS vs 23% with mesangial
only IgA
37% of patients with IgG staining received IS vs 21% with no IgG staining
Validation is required in other patient cohorts, in view of the potential bias in
outcome data resulting from immunosuppressive therapy in some patients.
It is recommended that the location and intensity of IgA and IgG staining is
routinely included in the renal biopsy report.
What about crescents?
Crescents are not included in the Oxford
classification
Why?
Evaluation of cellular crescents is highly reproducible
ICC
Extracapillary 1
Extracapillary 2
Extracapillary 3
Extracapillary 4
Extracapillary 5
0.62
0.63
0.65
0.30
0.33
% total glomeruli showing cellular crescents
% total glomeruli showing cellular + fibrocellular crescents
mean cellular + fibrocellular crescent score
% total gloms showing fibrous crescents
mean fibrous crescent score
The presence of cellular/fibrocellular crescents was not
significantly associated with outcome (ESRD or 50% loss
of renal function).
Why were crescents not found to be of
prognostic value?
1. Because they aren’t.
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
Why were crescents not found to be of
prognostic value?
Walsh et al. Clin J Am Soc Nephrol 2010;5:425-30
146 patients with IgA nephropathy, median follow-up 5.8 years
Primary outcome doubling serum creatinine, ESRD or death
In univariate analysis, clinical predictors of outcome were initial creatinine,
proteinuria, systolic BP.
Multivariate analysis adjusted for clinical characteristics, independent
predictors of primary outcome were:
Interstitial fibrosis & glomerulosclerosis
Glomerular crescents (HR 2.4;95%CI 1.2-5.1)
Why were crescents not found to be of
prognostic value?
2. Study design: Exclusion of patients who progressed to ESRD in <1 year
Immunosuppression-associated bias
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
>0.1
<0.001
19
30
27
29
>0.1
>0.1
Endocapillary hypercellularity
absent
76
present
73
>0.1
17
44
Crescent
absent
present
72
78
20
39
<0.001
>0.1
Tubular atrophy
0-25%
26-50%
>50%
72
83
85
28
24
50
>0.1
Artery score
absent
Mild
Moderate
Severe
69
83
86
75
32
24
19
50
>0.1
* Intend to treat.
>0.1
0.006*
<0.001
Why were crescents not found to be of
prognostic value?
Choi et al. Clin Nephrol 2009;72:353-9
50 patients with IgA nephropathy treated with steroids & ARB, mean followup of 4 years
43 (86%) stable renal function, 7 (14%) progressed (>20%  eGFR)
Mean change in eGFR +0.3±0.74 ml/min/1.73m2/month
In multivariate analysis, final urine PCR & age were determinants of slope of
eGFR.
No histological feature, including crescents, predicted slope.
Validation studies
Validation studies
Validation of the Oxford Classification is needed in other patient groups:
1.
Unselected for proteinuria – is the classification valid in patients at low
risk of progression?
2.
In patients with rapidly progressive disease?
3.
In cohorts who receive little or no immunosuppression, irrespective of
histology? In the Oxford Classification (& most other studies),
conclusions regarding impact of crescents and endocapillary
hypercellularity are limited due to treatment bias.
Validation studies
Reference
Centre
No. of patients
Adults A
Children C
Inclusion criteria
% steroid or % RASB
IS
IS bias
Antihypertensive
bias
Renal survival /
Rate of loss of renal Interaction with IS
function at end of function, MV analysis
follow-up, MV
analysis inc. eGFR
at diagnosis
Oxford Classification study Multicentre, NA, Europe, Asia 265
A+C
eGFR >30, proteinuria 29%
>0.5, follow-up >12
mnths
74%
Crescents S, T
E
S, T
Alamartine et al, CJASN
2011
Single centre, France
183
A
All IgAN
31%
65%
M, S, T
eGFR at diagnosis
only
Halling et al, NDT 2012
Single centre, Sweden,
paediatric
99 (90 with bx) C
follow-up >5 yrs
11%
24%
Crescents T
E
Herzenberg et al, KI 2011
Multicentre, US & Canada
187
A 143 + C 44
eGFR >30, proteinuria 41%
>0.5, follow-up >12
mnths
87%
Crescents
E
Kang et al, NDT 2012
Single centre, Korea
197
>15 years
All IgAN (systemic
disease excluded)
38%
83%
S
Katafuchi et al, CJASN
2011
Single centre, Japan
702
A+C
All IgAN >1 year
follow-up or ESRD
32%
37%
T, Crescents
S if cres excluded
Kataoka et al, Clin Exp
Nephrol 2012
Single centre, Japan, impact 43
of BMI
A
eGFR >50, follow-up
>10 yrs
51%
58%
M, max glomerular
area
Moriyama et al, Int Urol
Nephrol 2012
Single centre, Japan, impact 42
of nephrotic syndrome
>15 years
nephrotic
64%
Shi et al, CJASN 2011
Single centre, China
410
A
Shima et al, Pediatr
Nephrol 2012
Japan, paediatric
161
C <20 years
As for Oxford
Classification study
All IgAN (systemic
disease excluded)
43% steroid 86%
20% IS
16% (26% if
>0.5g
proteinuria
Yau et al, Am J Nephrol
2011
Single centre, US
54
A
M, T
M, E25, T, S
Crescents
E
E, S, T predict
outcome in UV
analysis
M, E, T, Crescents
predict outcome in
UV analysis, 18
reached end-point
S, T
MS
Other
Crescents, E
T
Crescents, S
BMI
T
low T predicts
response to steroids
S, T
E
M, T, Cres >30%
(MV with
proteinuria, not
eGFR)
T
Optimal cut-off for
crescents 6.8%
7 reached end-point
Validation studies
Validation of the Oxford Classification is needed in other patient groups:
1.
Unselected for proteinuria – is the classification valid in patients at low
risk of progression?.
Gutierrez et al. Long term outcome of IgA nephropathy presenting with minimal or
negative proteinuria J Am Soc Nephrol in press
141 patients with IgAN and minor abnormalities (eGFR >60, proteinuria
<0.5g/24hrs) followed for a median of 108 months.
No steroid/IS therapy.
Serum Cr increase of >50% in 5 patients (3.5%), no ESRD.
Proteinuria >0.5g/24hrs developed in 21 patients (14.9%).
M1 46, E1 12, S1 22, T1 7, T2 0.
Multivariate analysis: S was the only factor predicting >50% increase in sCr.
Doubling of sCr in only one patient whose biopsy showed M1 E1 S1
Validation studies
Validation of the Oxford Classification is needed in other patient groups:
2.
In patients with rapidly progressive disease?
Katafuchi et al, CJASN 2011 702 patients with IgAN (adults & children).
12% developed ESRD, 32% received steroid therapy.
63% of biopsies showed crescents.
Multivariate analysis, all patients:
M, E, S, T + clinical parameters – S & T independently predicted ESRD
M, E, S, T, Ex + clinical parameters – Ex & T independently predicted ESRD
In 416 patients who met inclusion criteria of Oxford classification, there was
no significant difference in renal survival between patients with & without Ex
In 286 patients who did not meet Oxford inclusion criteria, kidney survival of
patients with Ex was significantly lower than in those without (p=<0.01)
Ex 0, Ex 1 (>0-<10% crescents), Ex 2 (>10% crescents)
ESRD significantly greater in Ex2 vs Ex0 (HR 1.95, 95% CI 1.01-3.76).
ROC curve - optimal cut off of Ex for predicting ESRD 6.8%.
Validation studies
Validation of the Oxford Classification is needed in other patient groups:
3.
Reference
In cohorts who receive no immunosuppression, irrespective of
histology?
Centre
No. of patients
Adults A
Children C
Inclusion criteria
% steroid or % RASB
IS
IS bias
Antihypertensive
bias
Renal survival /
Rate of loss of renal Interaction with IS
function at end of function, MV analysis
follow-up, MV
analysis inc. eGFR
at diagnosis
Oxford Classification study Multicentre, NA, Europe, Asia 265
A+C
eGFR >30, proteinuria 29%
>0.5, follow-up >12
mnths
74%
Crescents S, T
E
S, T
Alamartine et al, CJASN
2011
Single centre, France
183
A
All IgAN
31%
65%
M, S, T
eGFR at diagnosis
only
Halling et al, NDT 2012
Single centre, Sweden,
paediatric
99 (90 with bx) C
follow-up >5 yrs
11%
24%
Crescents T
E
Herzenberg et al, KI 2011
Multicentre, US & Canada
187
A 143 + C 44
eGFR >30, proteinuria 41%
>0.5, follow-up >12
mnths
87%
Crescents
E
Kang et al, NDT 2012
Single centre, Korea
197
>15 years
All IgAN (systemic
disease excluded)
38%
83%
S
Katafuchi et al, CJASN
2011
Single centre, Japan
702
A+C
All IgAN >1 year
follow-up or ESRD
32%
37%
T, Crescents
S if cres excluded
Kataoka et al, Clin Exp
Nephrol 2012
Single centre, Japan, impact 43
of BMI
A
eGFR >50, follow-up
>10 yrs
51%
58%
M, max glomerular
area
Moriyama et al, Int Urol
Nephrol 2012
Single centre, Japan, impact 42
of nephrotic syndrome
>15 years
nephrotic
64%
Shi et al, CJASN 2011
Single centre, China
410
A
Shima et al, Pediatr
Nephrol 2012
Japan, paediatric
161
C <20 years
As for Oxford
Classification study
All IgAN (systemic
disease excluded)
43% steroid 86%
20% IS
16% (26% if
>0.5g
proteinuria
Yau et al, Am J Nephrol
2011
Single centre, US
54
A
M, T
M, E25, T, S
Crescents
E
E, S, T predict
outcome in UV
analysis
M, E, T, Crescents
predict outcome in
UV analysis, 18
reached end-point
S, T
MS
Other
Crescents, E
T
Crescents, S
BMI
T
low T predicts
response to steroids
S, T
E
M, T, Cres >30%
(MV with
proteinuria, not
eGFR)
T
Optimal cut-off for
crescents 6.8%
7 reached end-point
Validation studies
Validation of the Oxford Classification is needed in other patient groups:
3.
In cohorts who receive little or no immunosuppression, irrespective of
histology?
Single centre retrospective study of 237 adult IgAN patients in Oxford
Mean eGFR at diagnosis 50.9
Number with adequate biopsies and clinical dataset: 156
M1 39, E1 34, S1 108, T1 39, T2 17, Crescents 18
8/156 received steroid or IS following biopsy (5%)
In multivariate analysis (eGFR + uPCR + histological variables), E and T are
independent predictors of fast loss of GFR (>5ml/min/yr).
VALIGA
ERA-EDTA funded clinicopathological study, PI Rosanna Coppo
Co-ordinating committee: Coppo R, Feehally J, Roberts I, Cook T, Cattran
D, Troyanov S
Co-ordinating centre: Turin
Pathology review centre: Oxford
18 months duration, starting 2010.
1178 IgAN patients from 55 centres in 13 countries
Mean follow-up 5.8 years ± 4.5, loss of e-GFR (slope) of -2.0±8.1
ml/min/year. ESRD developed in 141 cases (12%), 50% loss of e-GFR
in 171 (15%) and combined end point in 195 (16.5%).
Initial UP, e-GFR and MAP and follow-up UP and MAP were strongly
correlated by multivariate analysis with 50% loss of eGFR or combined
end points, and slope of e-GFR (all P<0.0001). ROC analysis indicated
the best cut-off value for UP was 0.96 g/day
FSGS in IgA nephropathy
FSGS in IgA nephropathy – what’s the link?
Is there a link?
The frequency of the association indicates that there is.
Segmental glomerulosclerosis is common in IgA nephropathy –
76% in the Oxford Classification patient cohort, selected for proteinuria
>0.5g/24hrs.
35% in the study of “mild IgA nephropathy” by Weber et al, 2009 - selected
for no or minimal mesangial proliferation (<50% of glomeruli); Lee class I-II.
FSGS in IgA nephropathy – what’s the link?
Two potential mechanisms of segmental sclerosis in IgA nephropathy:
1. Fibrosis within segmental necrotising/proliferative lesions
FSGS in IgA nephropathy – what’s the link?
Two potential mechanisms of segmental sclerosis in IgA nephropathy:
2. Podocyte injury analogous to primary FSGS.
FSGS in IgA nephropathy – what’s the link?
Histological clues to indicate podocyte injury:
Podocyte hypertrophy/hyperplasia
Hyalinosis
Endocapillary foam cells
Protein resorption droplets
Tip lesions
FSGS in IgA nephropathy
Segmental necrosis may been seen in association with segmental sclerosing
lesions suggesting podocyte injury.
Does the presence of FSGS influence outcome?
Yes
Weber et al. Nephrol Dial Transplant 2009;24:483-88
Univariate analysis FSGS was
associated with progressive disease
slope of GFR
FSGS+ - 2.56 mL/min/year
FSGS− +1.14 mL/min/year
(p = 0.03)
FSGS+ group – more chronic
damage in biopsy
Does the presence of FSGS influence outcome?
Yes
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
Is subclassification of FSGS in IgA nephropathy of
clinical value?
El Karoui et al. Kidney Int 2011;79:643-54.
Segmental sclerosis in 101/128 patients with IgA nephropathy
FSGS having other glomerular lesions (mesangial hyperplasia,
endocapillary hypercellularity, glomerular necrosis, extracapillary
proliferation) did significantly worse than cases of pure FSGS.
Patients with pure FSGS had relatively poor survival even without
other superimposed glomerular abnormalities.
Collapsing pattern associated with worse outcome.
Is subclassification of FSGS in IgA nephropathy of
clinical value?
Oxford Classification cohort:
147 with FSGS had slides available for second review, 138 with a full clinical
dataset. The slides were reviewed by a single pathologist and the segmental
sclerosing lesions subclassified – by individual histological lesions, not
Columbia classification of FSGS.
Endocapillary hypercellularity
62 (42%)
Hyalinosis
16 (11%)
Tip lesions
9 (6%)
Podocyte hypertrophy
54 (37%)
Podocyte resorption droplets
13 (9%)
Adhesions without sclerosis
10 (7%)
Collapsing FSGS
0
Is subclassification of FSGS in IgA nephropathy of
clinical value?
- = absent
+ = present
Endocapillary
proliferation
Tip lesion
Podocyte
hypertrophy
Hyalinosis
Initial urine protein
(g/24hrs)
mean±SD
-
2.5±2.3
+
2.6±1.9
-
2.4±1.9
+
4.9±3.3
-
2.2±1.8
+
3.1±2.4
-
2.6±2.1
+
2.2±2.2
ns
Follow-up urine
protein (g/24hrs)
mean±SD
1.9±1.8
ns
1.6±1.2
p=<0.02
1.7±1.4
1.7±1.5
ns
1.8±1.6
1.9±1.8
ns
77±37
ns
79±37
ns
78±37
60±28
ns
-4.6±8.4
ns
-2.4±9.5
ns
73±36
ns
-3.7±5.9
-5.4±10.8
68±21
2.0±1.7
ns
71±35
Rate of loss of
renal function
(ml/min/1.73m2/yr)
84±38
2.9±3.2
p=<0.02
Initial GFR
(ml/min)
mean±SD
-4.2±6.5
ns
-4.8±10.9
ns
-4.6±8.8
-3.2±4.3
ns
The End