IgA nephropathy: what’s new since the Oxford Classification Ian Roberts Oxford, UK

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


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)


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


Bellur SS, et al. Nephrol Dial Transplant 2011;26:2533-6



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.


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)


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.


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


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


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%.


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


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.


Two potential mechanisms of segmental sclerosis in IgA nephropathy:

1. Fibrosis within segmental necrotising/proliferative lesions


Two potential mechanisms of segmental sclerosis in IgA nephropathy:

2. Podocyte injury analogous to primary FSGS.


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.


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


- = 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

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IgA nephropathy: what’s new since the Oxford Classification Ian Roberts Oxford, UK