iga nephropathy: what’s new since the oxford classification ian roberts oxford, uk
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IgA nephropathy: what’s new since IgA nephropathy: what’s new since the Oxford Classificationthe Oxford Classification
Ian Roberts
Oxford, UK
Session plan
Oxford Classification of IgA nephropathy – a brief overview
what’s new…
Immunostaining patternCrescentsValidation studies of the Oxford ClassificationFSGS 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 scoreSegmental glomerulosclerosis/adhesionEndocapillary hypercellularity Cellular/fibrocellular crescentsTubular atrophy/interstitial fibrosisArterial 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 (M 0/1)Endocapillary hypercellularity – present/absent (E 0/1)Segmental sclerosis/adhesions – present/absent (S 0/1)Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% (T 0/1/2)
In addition: Total number of glomeruliEndocapillary 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.
How should the histological data be combined with clinical indices?
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
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.
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
Immunostaining pattern in IgA nephropathy – does it matter?
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?
Why?
Crescents are not included in the Oxford classification
Evaluation of cellular crescents is highly reproducible ICC
Extracapillary 1 % total glomeruli showing cellular crescents 0.62Extracapillary 2 % total glomeruli showing cellular + fibrocellular crescents 0.63Extracapillary 3 mean cellular + fibrocellular crescent score 0.65Extracapillary 4 % total gloms showing fibrous crescents 0.30Extracapillary 5 mean fibrous crescent score 0.33
The presence of cellular/fibrocellular crescents was not significantly associated with outcome (ESRD or 50% loss of renal function).
Reference mesangial endocapillary crescents capillary wall focal seg glomerulo- interstitial fibrosis/
severity proliferation IgA lesions sclerosis tubular atrophy
Nozawa et al, 2005X
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 X X
Hogg et al, 1994 X X
Katafuchi et al, 1994 X X
Ibels et al, 1994 X X
Okada et al, 1992 X X
Bogenschutz et al, 1990 X
Rekola et al, 1989 X
D'Amico et al, 1986 X X X
Boyce et al, 1986 X
Why were crescents not found to be of prognostic value?
1. Because they aren’t.
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 72 19 >0.5 75 >0.1 30 >0.1
Segmental GS or Adhesion absent 54 <0.001 27 >0.1 present 81 29
Endocapillary hypercellularity absent 76 17 present 73 >0.1 44 <0.001
Crescent absent 72 20 <0.001 present 78 >0.1 39
Tubular atrophy 0-25% 72 >0.1 28 >0.1 26-50% 83 24 >50% 85 50
Artery score absent 69 32 >0.1 Mild 83 0.006* 24 Moderate 86 19 Severe 75 50 * Intend to treat.
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 follow-up 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 studiesValidation 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 IS
% RASB IS bias Anti-hypertensive bias
Renal survival / function at end of follow-up, MV analysis inc. eGFR at diagnosis
Rate of loss of renal function, MV analysis
Interaction with IS Other
Oxford Classification study Multicentre, NA, Europe, Asia 265 A + C eGFR >30, proteinuria >0.5, follow-up >12 mnths
29% 74% Crescents E
S, T S, T M, T E
Alamartine et al, CJASN 2011
Single centre, France 183 A All IgAN 31% 65% M, S, T eGFR at diagnosis only
E, S, T predict outcome in UV analysis
Halling et al, NDT 2012 Single centre, Sweden, paediatric
99 (90 with bx) C follow-up >5 yrs 11% 24% Crescents E
T M, E, T, Crescents predict outcome in UV analysis, 18 reached end-point
Herzenberg et al, KI 2011 Multicentre, US & Canada 187 A 143 + C 44 eGFR >30, proteinuria >0.5, follow-up >12 mnths
41% 87% Crescents E
S, T Crescents, E
Kang et al, NDT 2012 Single centre, Korea 197 >15 years All IgAN (systemic disease excluded)
38% 83% S M S T
Katafuchi et al, CJASN 2011
Single centre, Japan 702 A + C All IgAN >1 year follow-up or ESRD
32% 37% T, CrescentsS if cres excluded
Crescents, S Optimal cut-off for crescents 6.8%
Kataoka et al, Clin Exp Nephrol 2012
Single centre, Japan, impact of BMI
43 A eGFR >50, follow-up >10 yrs
51% 58% M, max glomerular area
BMI
Moriyama et al, Int Urol Nephrol 2012
Single centre, Japan, impact of nephrotic syndrome
42 >15 years nephrotic 64% T low T predicts response to steroids
Shi et al, CJASN 2011 Single centre, China 410 A As for Oxford Classification study
43% steroid20% IS
86% M, E25, T, Crescents
S S, T E
Shima et al, Pediatr Nephrol 2012
Japan, paediatric 161 C <20 years All IgAN (systemic disease excluded)
16% (26% if >0.5g proteinuria
M, T, Cres >30% (MV with proteinuria, not eGFR)
7 reached end-point
Yau et al, Am J Nephrol 2011
Single centre, US 54 A T
Validation studiesValidation 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 studiesValidation 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 ESRDM, E, S, T, Ex + clinical parameters – Ex & T independently predicted ESRD
In 416 patients who met inclusion criteria of Oxford classification, there wasno 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 studiesValidation of the Oxford Classification is needed in other patient groups:
3. In cohorts who receive no immunosuppression, irrespective of histology?
Reference Centre No. of patients Adults A Children C
Inclusion criteria % steroid or IS
% RASB IS bias Anti-hypertensive bias
Renal survival / function at end of follow-up, MV analysis inc. eGFR at diagnosis
Rate of loss of renal function, MV analysis
Interaction with IS Other
Oxford Classification study Multicentre, NA, Europe, Asia 265 A + C eGFR >30, proteinuria >0.5, follow-up >12 mnths
29% 74% Crescents E
S, T S, T M, T E
Alamartine et al, CJASN 2011
Single centre, France 183 A All IgAN 31% 65% M, S, T eGFR at diagnosis only
E, S, T predict outcome in UV analysis
Halling et al, NDT 2012 Single centre, Sweden, paediatric
99 (90 with bx) C follow-up >5 yrs 11% 24% Crescents E
T M, E, T, Crescents predict outcome in UV analysis, 18 reached end-point
Herzenberg et al, KI 2011 Multicentre, US & Canada 187 A 143 + C 44 eGFR >30, proteinuria >0.5, follow-up >12 mnths
41% 87% Crescents E
S, T Crescents, E
Kang et al, NDT 2012 Single centre, Korea 197 >15 years All IgAN (systemic disease excluded)
38% 83% S M S T
Katafuchi et al, CJASN 2011
Single centre, Japan 702 A + C All IgAN >1 year follow-up or ESRD
32% 37% T, CrescentsS if cres excluded
Crescents, S Optimal cut-off for crescents 6.8%
Kataoka et al, Clin Exp Nephrol 2012
Single centre, Japan, impact of BMI
43 A eGFR >50, follow-up >10 yrs
51% 58% M, max glomerular area
BMI
Moriyama et al, Int Urol Nephrol 2012
Single centre, Japan, impact of nephrotic syndrome
42 >15 years nephrotic 64% T low T predicts response to steroids
Shi et al, CJASN 2011 Single centre, China 410 A As for Oxford Classification study
43% steroid20% IS
86% M, E25, T, Crescents
S S, T E
Shima et al, Pediatr Nephrol 2012
Japan, paediatric 161 C <20 years All IgAN (systemic disease excluded)
16% (26% if >0.5g proteinuria
M, T, Cres >30% (MV with proteinuria, not eGFR)
7 reached end-point
Yau et al, Am J Nephrol 2011
Single centre, US 54 A T
Validation studiesValidation 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 OxfordMean eGFR at diagnosis 50.9
Number with adequate biopsies and clinical dataset: 156M1 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/hyperplasiaHyalinosisEndocapillary foam cellsProtein resorption dropletsTip 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
FSGS+ group – more chronic damage in biopsy
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)
Does the presence of FSGS influence outcome?
Yes
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
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
Initial urine protein (g/24hrs) mean±SD
Follow-up urine protein (g/24hrs) mean±SD
Initial GFR (ml/min) mean±SD
Rate of loss of renal function (ml/min/1.73m2/yr)
Endocapillary proliferation
- 2.5±2.3 ns 1.9±1.8 ns 71±35 ns -3.7±5.9 ns
+ 2.6±1.9 1.6±1.2 84±38 -5.4±10.8
Tip lesion - 2.4±1.9 p=<0.02 1.7±1.4 ns 77±37 ns -4.6±8.4 ns
+ 4.9±3.3 2.9±3.2 68±21 -2.4±9.5
Podocyte hypertrophy
- 2.2±1.8 p=<0.02 1.7±1.5 ns 79±37 ns -4.2±6.5 ns
+ 3.1±2.4 2.0±1.7 73±36 -4.8±10.9
Hyalinosis - 2.6±2.1 ns 1.8±1.6 ns 78±37 ns -4.6±8.8 ns
+ 2.2±2.2 1.9±1.8 60±28 -3.2±4.3
The End