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The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility

2009; Elsevier BV; Volume: 76; Issue: 5 Linguagem: Inglês

10.1038/ki.2009.168

1523-1755

Stephen A. Roberts, H. Terence Cook, Stéphan Troyanov, Charles E. Alpers, Alessandro Amore, Jonathan Barratt, F. Berthoux, Stephen M. Bonsib, Jan A. Bruijn, Daniel Cattran, Rosanna Coppo, Vivette D. D’Agati, Giuseppe D’Amico, Steven N. Emancipator, Francesco Emma, John Feehally, Franco Ferrario, Fernando C. Fervenza, Sandrine Florquin, Agnes B. Fogo, Colin Geddes, Hermann-Josef Groene, Mark Haas, Andrew M. Herzenberg, Prue Hill, Ronald J. Hogg, Stephen I‐Hong Hsu, J. Charles Jennette, Kensuke Joh, Bruce A. Julian, Tetsuya Kawamura, Fernand Mac–Moune Lai, Lei-Shi Li, Philip Kam‐Tao Li, Zhihong Liu, Bruce Mackinnon, Sergio Mezzano, Francesco Paolo Schena, Yasuhiko Tomino, Patrick D. Walker, Haiyan Wang, Jan J. Weening, Nori Yoshikawa, Hong Zhang,

Systemic Lupus Erythematosus Research

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease. Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease. The histological diagnosis of IgA nephropathy is straightforward; it is defined by the presence of IgA-dominant or co-dominant immune deposits within glomeruli, as shown by immunohistochemistry or immunofluorescence. However, biopsies meeting this criterion may show a wide range of histological changes that reflect the clinical diversity of IgA nephropathy. Biopsy appearances may range from virtually normal histology by light microscopy to severe necrotizing, crescentic glomerulonephritis or advanced glomerulosclerosis, and tubular atrophy. There have been numerous clinicopathological studies of IgA nephropathy, the great majority being retrospective, correlating histological changes in diagnostic biopsy with clinical outcome. A number of histological lesions have been reported to be of prognostic value (Table 1).1.Nozawa R. Suzuki J. Takahashi A. et al.Clinicopathological features and the prognosis of IgA nephropathy in Japanese children on long-term observation.Clin Nephrol. 2005; 64: 171-179Crossref PubMed Google Scholar, 2.Ballardie F.W. Roberts I.S. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy.J Am Soc Nephrol. 2002; 13: 142-148PubMed Google Scholar, 3.To K.F. Choi P.C. Szeto C.C. et al.Outcome of IgA nephropathy in adults graded by chronic histological lesions.Am J Kidney Dis. 2000; 35: 392-400Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 4.Mera J. Uchida S. Nagase M. Clinicopathologic study on prognostic markers in IgA nephropathy.Nephron. 2000; 84: 148-157Crossref PubMed Scopus (39) Google Scholar, 5.Daniel L. Saingra Y. Giorgi R. et al.Tubular lesions determine prognosis of IgA nephropathy.Am J Kidney Dis. 2000; 35: 13-20Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 6.Vleming L.J. de Fijter J.W. Westendorp R.G. et al.Histomorphometric correlates of renal failure in IgA nephropathy.Clin Nephrol. 1998; 49: 337-344PubMed Google Scholar, 7.Freese P. Norden G. Nyberg G. Morphologic high-risk factors in IgA nephropathy.Nephron. 1998; 79: 420-425Crossref PubMed Scopus (47) Google Scholar, 8.Hogg R.J. Silva F.G. Wyatt R.J. et al.Prognostic indicators in children with IgA nephropathy—report of the Southwest Pediatric Nephrology Study Group.Pediatr Nephrol. 1994; 8: 15-20Crossref PubMed Scopus (108) Google Scholar, 9.Katafuchi R. Oh Y. Hori K. et al.An important role of glomerular segmental lesions on progression of IgA nephropathy: a multivariate analysis.Clin Nephrol. 1994; 41: 191-198PubMed Google Scholar, 10.Ibels L.S. Gyory A.Z. IgA nephropathy: analysis of the natural history, important factors in the progression of renal disease, and a review of the literature.Medicine (Baltimore). 1994; 73: 79-102Crossref PubMed Scopus (223) Google Scholar, 11.Okada H. Suzuki H. Konishi K. et al.Histological alterations in renal specimens as indicators of prognosis of IgA nephropathy.Clin Nephrol. 1992; 37: 235-238PubMed Google Scholar, 12.Bogenschutz O. Bohle A. Batz C. et al.IgA nephritis: on the importance of morphological and clinical parameters in the long-term prognosis of 239 patients.Am J Nephrol. 1990; 10: 137-147Crossref PubMed Scopus (147) Google Scholar, 13.Rekola S. Bergstrand A. Bucht H. IGA nephropathy: a retrospective evaluation of prognostic indices in 176 patients.Scand J Urol Nephrol. 1989; 23: 37-50PubMed Google Scholar, 14.D'Amico G. Minetti L. Ponticelli C. et al.Prognostic indicators in idiopathic IgA mesangial nephropathy.Q J Med. 1986; 59: 363-378PubMed Google Scholar, 15.Boyce N.W. Holdsworth S.R. Thomson N.M. et al.Clinicopathological associations in mesangial IgA nephropathy.Am J Nephrol. 1986; 6: 246-252Crossref PubMed Scopus (40) Google Scholar The apparently conflicting results of these studies reflect differences in patient cohort, treatment, and clinical outcome measures. In general, studies in which the clinical end point is time to dialysis/renal failure have shown that chronic lesions (tubular atrophy, interstitial fibrosis, and glomerulosclerosis) are the most powerful histological predictors of outcome. This is not surprising, as these lesions reflect an advanced stage of disease; those patients who are biopsied and diagnosed late in the course of their disease will have a shorter time to end-stage renal disease. In contrast, those studies that have correlated histological changes with rate of loss of renal function or response to immunosuppressive therapy have shown that active glomerular lesions (mesangial, endocapillary or extracapillary proliferation, necrosis) are the most significant pathological prognostic factors.Table 1Histological risk factors for progressive renal failure in IgA nephropathyReferenceMesangial cellularityEndocapillary proliferationCrescentsCapillary wall IgAFocal segmental sclerosisGlomerulosclerosisInterstitial fibrosis/tubular atrophyNozawa et al.1.Nozawa R. Suzuki J. Takahashi A. et al.Clinicopathological features and the prognosis of IgA nephropathy in Japanese children on long-term observation.Clin Nephrol. 2005; 64: 171-179Crossref PubMed Google ScholarXBallardie et al.2.Ballardie F.W. Roberts I.S. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy.J Am Soc Nephrol. 2002; 13: 142-148PubMed Google ScholarXTo et al.3.To K.F. Choi P.C. Szeto C.C. et al.Outcome of IgA nephropathy in adults graded by chronic histological lesions.Am J Kidney Dis. 2000; 35: 392-400Abstract Full Text Full Text PDF PubMed Scopus (72) Google ScholarXMera et al.4.Mera J. Uchida S. Nagase M. Clinicopathologic study on prognostic markers in IgA nephropathy.Nephron. 2000; 84: 148-157Crossref PubMed Scopus (39) Google ScholarXDaniel et al.5.Daniel L. Saingra Y. Giorgi R. et al.Tubular lesions determine prognosis of IgA nephropathy.Am J Kidney Dis. 2000; 35: 13-20Abstract Full Text Full Text PDF PubMed Scopus (88) Google ScholarXVleming et al.6.Vleming L.J. de Fijter J.W. Westendorp R.G. et al.Histomorphometric correlates of renal failure in IgA nephropathy.Clin Nephrol. 1998; 49: 337-344PubMed Google ScholarXFreese et al.7.Freese P. Norden G. Nyberg G. Morphologic high-risk factors in IgA nephropathy.Nephron. 1998; 79: 420-425Crossref PubMed Scopus (47) Google ScholarXXXHogg et al.8.Hogg R.J. Silva F.G. Wyatt R.J. et al.Prognostic indicators in children with IgA nephropathy—report of the Southwest Pediatric Nephrology Study Group.Pediatr Nephrol. 1994; 8: 15-20Crossref PubMed Scopus (108) Google ScholarXXKatafuchi et al.9.Katafuchi R. Oh Y. Hori K. et al.An important role of glomerular segmental lesions on progression of IgA nephropathy: a multivariate analysis.Clin Nephrol. 1994; 41: 191-198PubMed Google ScholarXXIbels et al.10.Ibels L.S. Gyory A.Z. IgA nephropathy: analysis of the natural history, important factors in the progression of renal disease, and a review of the literature.Medicine (Baltimore). 1994; 73: 79-102Crossref PubMed Scopus (223) Google ScholarXXOkada et al.11.Okada H. Suzuki H. Konishi K. et al.Histological alterations in renal specimens as indicators of prognosis of IgA nephropathy.Clin Nephrol. 1992; 37: 235-238PubMed Google ScholarXXBogenschutz et al.12.Bogenschutz O. Bohle A. Batz C. et al.IgA nephritis: on the importance of morphological and clinical parameters in the long-term prognosis of 239 patients.Am J Nephrol. 1990; 10: 137-147Crossref PubMed Scopus (147) Google ScholarXRekola et al.13.Rekola S. Bergstrand A. Bucht H. IGA nephropathy: a retrospective evaluation of prognostic indices in 176 patients.Scand J Urol Nephrol. 1989; 23: 37-50PubMed Google ScholarXD'Amico et al.14.D'Amico G. Minetti L. Ponticelli C. et al.Prognostic indicators in idiopathic IgA mesangial nephropathy.Q J Med. 1986; 59: 363-378PubMed Google ScholarXXXBoyce et al.15.Boyce N.W. Holdsworth S.R. Thomson N.M. et al.Clinicopathological associations in mesangial IgA nephropathy.Am J Nephrol. 1986; 6: 246-252Crossref PubMed Scopus (40) Google ScholarXX, statistically significant association with clinical outcome. Open table in a new tab X, statistically significant association with clinical outcome. There have been a number of attempts to incorporate the various histological lesions into a pathological classification of IgA nephropathy. None has achieved widespread acceptance. Deficiencies include a lack of definitions and use of vague terminology, lack of an evidence base, and inclusion of both active and chronic lesions in the definition of single categories. For example, a recent classification divides biopsies into four categories (I–IV), namely, no, slight ( 30%) glomerulosclerosis, crescent formation, or adhesion.16.Wakai K. Kawamura T. Endoh M. et al.A scoring system to predict renal outcome in IgA nephropathy: from a nationwide prospective study.Nephrol Dial Transplant. 2006; 21: 2800-2808Crossref PubMed Scopus (115) Google Scholar Although such a schema may accurately identify those patients who will develop renal failure, it cannot be used to guide patient management; clearly, the management of patients with class IV disease due to >30% glomerular crescents will differ from those with class IV disease due to diffuse glomerulosclerosis. As described in the accompanying paper17.Cattran D. Coppo R. Cook T. et al.The Oxford Classification of IgA nephropathy: Rationale, clinicopathological correlations and classification.Kidney Int. 2009; 76 (in press): 534-545Abstract Full Text Full Text PDF PubMed Scopus (812) Google Scholar, we sought to develop an international consensus classification of IgA nephropathy with a strong evidence base. In this paper, we describe in detail the process by which histological data were collected and reviewed, and present the evidence used for selecting those pathological lesions that were included in the final schema (the ‘Oxford Classification’ of IgA Nephropathy). The overall philosophy was to collect a highly detailed initial pathological data set and to simplify this into a working schema. We recognize that a ‘successful’ classification must have clear definitions, be simple to use in routine clinical practice, be reproducible, and have a value independent of the clinical parameters at the time of biopsy. These criteria, therefore, formed the basis of our selection of which lesions to include in the final classification. An initial meeting of pathologists was held in Oxford, UK, in 2005 to define the pathological variables to be assessed in renal biopsies in cases of IgA nephropathy. After a provisional analysis of the first 40 cases, areas of high interobserver variation were identified. To improve reproducibility, the definitions were refined at a meeting of pathologists in Atlanta, USA, in 2006 (Table 2). These were subsequently used for histological scoring of the entire study group. A minor amendment (in italics in Table 2) for defining necrosis in routine practice was agreed upon at a further meeting in Oxford in 2008.Table 2Pathological definitionsIgA 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. 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 a 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 3 (C3) may be present. The presence of C1q staining in more than trace intensity should bring up consideration of lupus nephritis.Glomerular definitions Diffuse: A lesion involving most (≥50%) glomeruli Focal: A lesion involving 50% of the lesion occupied by cells. It is further classified by the percentage of glomerular circumference involved: 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: 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%, and >50%. Ischemic, obsolescent glomeruli should be excludedA crescent is one of these extracapillary lesions that involves >10% of the circumference of Bowman's capsuleMesangial 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, and8 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 narrowing to the width of 50%).GBM, glomerular basement membrane; H&E, hematoxylin and eosin stain; MSB, Martius scarlet blue; PAS, periodic acid Schiff; SLE, systemic lupus erythematosus. Open table in a new tab GBM, glomerular basement membrane; H&E, hematoxylin and eosin stain; MSB, Martius scarlet blue; PAS, periodic acid Schiff; SLE, systemic lupus erythematosus. A detailed pathology data set was collected initially, with the intention of working to simplify it for use in routine practice. Histology slides from each case were circulated among five pathologists in batches of five, in a rolling manner, to ensure that no two batches were scored by the same five pathologists. A score sheet was completed by individual pathologists for each biopsy (Table 3) using an agreed set of instructions (Table 4). Scoring of mesangial cellularity, together with other proliferative and sclerosing glomerular lesions, is illustrated in Figures 1 and 2. Completed score sheets were collected centrally by one of the pathologists (ISDR) and used to compile the extended pathological data set (Table 5). Completed score sheets were received from five pathologists for 47% of the cases, from four pathologists for 36% of the cases, and from three pathologists for 17% of the cases.Table 3Score sheet used for collecting detailed histological data set Open table in a new tab Table 4Guidelines for completion of the light microscopy score sheet1.1. Using the circled PAS-stained section: for every glomerulus, mark one box only in Column A. If the indeterminate for mesangial cellularity box is marked, then mark which of the five reasons for not scoring mesangial cellularity applies. At least three mesangial cell areas should be present to score a glomerulus. In the global sclerosis category include both solidified and obsolescent glomeruli, and advanced segmental sclerosis when <3 mesangial areas remain. Mesangial cellularity is difficult to score in segments showing endocapillary hypercellularity. Therefore, glomeruli showing global endocapillary hypercellularity should be classed as indeterminate for mesangial cellularity (and the endocapillary lesions noted in column B).Score 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 <2 mesangial cell nuclei (i.e., count clusters, not files, of mesangial cell nuclei). Mesangial cell nuclei are those surrounded by the matrix; do not count those projecting into a capillary lumen2.2. Using the circled PAS-stained section: for every glomerulus, mark none, one, or more than one box in Column B as appropriateA segmental lesion with capillary occlusion by both sclerosis and endocapillary hypercellularity should be scored for both. Endocapillary hypercellularity is defined by the presence of cells within capillary lumina, not by the matrix. Therefore, in the presence of segmental sclerosis, endocapillary hypercellularity can only be scored within that segment if preserved capillary loops are also presentGBM duplication: score if it involves an open capillary loop but not as part of a sclerosed segment3.3. Using any of the provided sections: for the whole biopsy, mark any box in Column C that appliesWhen noting excessive mesangial matrix increase, assess only mesangial areas away from segmental sclerosis, i.e., associated with patent capillary loopsFor scoring arteriolar hyalinosis in Column C, examine only the PAS-stained section used for glomerular scoring4.In the ‘Other’ box: note any other abnormality seen, e.g., a glomerular lesion present in one of the sections but not represented in the PAS section used for scoring, mesangiolysis, large numbers of RBC casts, ATN, and malignant vascular disease. Sections should be 2–3 μm thick for scoring. Note if the section appears thicker5.5. Total number of glomeruli=total scorable glomeruli+total indeterminate for mesangial cellularity. To produce the mesangial score, multiply the totals of the boxes in column A by 0, 1, 2, or 3 as appropriate. The mean mesangial score is the total of the mesangial scores divided by the number of scorable glomeruliATN, acute tubular necrosis; GBM, glomerular basement membrane; PAS, periodic acid Schiff; RBC, red blood cell. Open table in a new tab Figure 1An illustration of mesangial cellularity scoring (objective × 40 original magnification, periodic acid Schiff stain).View Large Image Figure ViewerDownload (PPT)Figure 2Proliferative and sclerosing glomerular lesions. All figures objective × 40 original magnification, periodic acid Schiff stain. (a) Normal glomerulus by light microscopy. (b) Tuft adhesion (arrow) without segmental sclerosis. This lesion should be included with segmental sclerosis lesions for scoring purposes. (c) Segmental sclerosis (arrow) with a lobule away from the sclerosis showing moderate mesangial hypercellularity (arrowhead). (d) Extensive segmental sclerosis (arrow). This glomerulus should not be used for mesangial scoring. (e) A glomerulus showing severe mesangial hypercellularity (arrow) and a small cellular crescent (arrowhead; 10–25% of the glomerular circumference). (f) A glomerulus showing mild mesangial hypercellularity (arrow). There is segmental endocapillary hypercellularity (arrowhead); this segment should not be used for mesangial scoring. In addition, there is a cellular crescent (asterisk; 25–50% of the glomerular circumference).View Large Image Figure ViewerDownload (PPT)Table 5Extended pathology dataset: definitions and reproducibilityICCMesangial 1Median mesangial score0.64Mesangial 2% of scorable glomeruli showing severe mesangial hypercellularity (median of group)0.54Global GS% of total glomeruli showing global sclerosis or retracted glomerular tuft (median of group)0.90Normal glomeruli% of total glomeruli noted as normal (median of group)0.27Segmental GS% of total glomeruli showing segmental sclerosis (median of group)0.46Adhesion% of total glomeruli showing adhesions (median of group)0.20Endocapillary 1% of total glomeruli showing segmental endocapillary hypercellularity (median of group)0.36Endocapillary 2% of total glomeruli showing segmental+global endocapillary hypercellularity (median of group)0.57GBM duplication% of total glomeruli showing GBM duplication (median of group)0.10Necrosis% of total glomeruli showing necrosis (median of group)0.31Extracapillary 1% of total glomeruli showing cellular crescents (median)0.62Extracapillary 2% of total glomeruli showing cellular+fibrocellular crescents (median)0.64Extracapillary 3Mean cellular+fibrocellular crescent score (median of group)0.66Extracapillary 4% of total glomeruli showing fibrous crescents (median)0.32Extracapillary 5Mean fibrous crescent score (median of group)0.34Tubular atrophy% of the cortex showing tubular atrophy (median of group)0.79Interstitial fibrosis% of the cortex showing interstitial fibrosis (median of group)0.78Interstitial inflammation 1% of the cortex showing interstitial inflammation (median of group)0.58Interstitial inflammation 2% of the 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 10.03Arterial 1Median arcuate artery score. Leave blank if none present0.77Arterial 2Median interlobular artery score. Leave blank if none present0.69Arterial 3Median artery score—worst of arcuate and interlobular arteries. Leave blank if none present.0.69Arteriole 1Absent=0; present=1. Take majority verdict0.36Arteriole 2Median arteriolar hyalinosis score0.35GBM, glomerular basement membrane; GS, glomerulosclerosis; ICC, intraclass correlation coefficient. Open table in a new tab ATN, acute tubular necrosis; GBM, glomerular basement membrane; PAS, periodic acid Schiff; RBC, red blood cell. GBM, glomerular basement membrane; GS, glomerulosclerosis; ICC, intraclass correlation coefficient. For most histological variables, the median score was taken for analysis (Table 5). For scoring of glomerular crescents, the mean cellular and fibrocellular crescent scores were obtained by weighing the extracapillary lesions by size. A multiplication factor of 1 was applied for lesions 50% of the glomerular circumference. The resulting scores were summed and divided by the total number of glomeruli in the biopsy. Additional data items were derived from the completed score sheets to addres