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An international evidence-based classification of IgA nephropathy: the Oxford Classification

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

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An international evidence-based classification of IgA nephropathy: the Oxford Classification

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  1. An international evidence-based classification of IgA nephropathy: the Oxford Classification Ian Roberts Oxford, UK

  2. 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

  3. IgA nephropathy is heterogenous

  4. 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?

  5. Clinicopathological correlation in IgA nephropathy Reference mesangial endocapillary crescents capillary wall focal seg glomerulo- interstitial fibrosis/ severity proliferation IgA lesions sclerosis 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 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

  6. 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)

  7. 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 evidence-based, clinically relevant, simple, precise in its definitions and reproducible.

  8. 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.

  9. 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 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] 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]

  10. Agree pathological definitions Agree pathological scoring process Agree clinical dataset Select patient cohorts Agree data collection process and data verification Data collection Data analysis to identify elements with prognostic predictive power Refine and agree a clinico-pathological classification Publish Achieve international usage Test on further patient cohorts Overall strategy for development of evidence-based consensus classification of IgAN

  11. 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

  12. 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

  13. Clinical dataset (data collected within 3 months of biopsy)

  14. Follow up dataset (data collected on at least annually over >3 years)

  15. 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.

  16. 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 inter-observer 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

  17. Pathology dataset IgA nephropathy: IgA nephropathy in the native kidney is defined as dominant or co-dominant staining with IgA in glomeruli by immunofluorescence or immunoperoxidase. Not all glomeruli need show this positivity. SLE-related 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.

  18. 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

  19. 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).

  20. 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%).

  21. Pathology dataset

  22. 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.

  23. Global slide circulation

  24. 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.

  25. 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

  26. 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.

  27. 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?

  28. What are the clinically relevant cut-offs for continuous quantitative lesions?

  29. Correlations between pathology and initial clinical presentation

  30. 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

  31. 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

  32. 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).

  33. 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 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)

  34. Prognostic impact of combinations of histological lesions Combining glomerular patterns:

  35. Prognostic impact of combinations of histological lesions Combining glomerular and tubulointerstitial lesions:

  36. 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? ?

  37. This work was supported by: International Society of Nephrology Kidney Research UK Vivor Pharma Aspreva plc

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