A novel classification for IgA nephropathy
Authors: Ryohei Yamamoto, Enyu Imai
Journal: Kidney International (2009)

IgA nephropathy is a common glomerulonephritis. About 30% of patients develop end-stage kidney disease within 20 years. A strategy for predicting prognosis from biopsy-based pathological evaluation has not been well established because of lack of reproducibility and inappropriate categorization. The new Oxford classification of IgA nephropathy provides a histopathological grading system with reproducibility for prediction of renal prognosis of IgA nephropathy independent of the clinical features. The classification must be validated in the different cohorts. IgA nephropathy is a common glomerulonephritis. About 30% of patients develop end-stage kidney disease within 20 years. A strategy for predicting prognosis from biopsy-based pathological evaluation has not been well established because of lack of reproducibility and inappropriate categorization. The new Oxford classification of IgA nephropathy provides a histopathological grading system with reproducibility for prediction of renal prognosis of IgA nephropathy independent of the clinical features. The classification must be validated in the different cohorts. IgA nephropathy is the most common glomerulonephritis in the world. Despite the wide variability of its clinical presentation from persistent microscopic hematuria to rapidly progressive renal failure, progression of IgA nephropathy is generally slow, but up to 30% of patients progress to end-stage renal disease within 20 years. Multiple observational cohort studies identified renal function, urinary protein, blood pressure, and histopathological lesions as major risk factors for progression of IgA nephropathy. In the majority of randomized controlled trials to test the efficacy of treatment modalities for IgA nephropathy, including blockers of the renin–angiotensin system, corticosteroids, immunosuppressants, fish oil, and so on, the inclusion and exclusion criteria of the subjects were based mainly on renal function, urinary protein, and/or blood pressure, but rarely on histopathological lesions. One of the main reasons why histopathological lesions were not included in the inclusion and exclusion criteria of the trials was probably the absence of an international consensus on the histopathological classification with adequate reproducibility. Two of the most important attributes of any histopathological classification are clinical relevance and reproducibility. The reports concerning histopathological classifications often assessed their relevance to clinical outcomes but rarely examined their reproducibility. Reproducibility refers to the agreement of measurements obtained by two or more observers, commonly assessed with the use of κ statistics and intraclass correlation coefficients (ICCs). Clinically useful histopathological classifications should have, first, high reproducibility—that is, different observers should score the same grade for the same section—and, second, a strong predictive power for clinical outcomes. Only a few studies of renal histopathological classifications, however, evaluated the reproducibility, which has been relatively well investigated for classifications of renal transplants and lupus nephritis. Among studies assessing the reproducibility of grading of histopathological lesions in renal-transplant biopsies, the most extensive one was a report of the Convergence of European Renal Transplant Pathology Assessment Procedures (CERTPAP) project in 2001.1.Furness P.N. Taub N. International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project.Kidney Int. 2001; 60: 1998-2012Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar In this international study, 22 major transplant centers throughout Europe graded 32 different histopathological features of 55 renal-transplant biopsy sections stained with hematoxylin and eosin and periodic acid–Schiff (PAS). In comparison with previous studies reported by small groups of colleagues, the reproducibility of these features was much lower (κ value: 0.05 to 0.53), suggesting a great need for caution in histopathological evaluation in multicenter trials. The relatively lower reproducibility of the previous World Health Organization (WHO) classification system for lupus nephritis was one of its major weaknesses and was one of the reasons for the recent introduction of the current classification revised by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) in 2003.2.Weening J.J. D'Agati V.D. Schwartz M.M. et al.The classification of glomerulonephritis in systemic lupus erythematosus revisited.J Am Soc Nephrol. 2004; 15: 241-250Crossref PubMed Scopus (1466) Google Scholar Although several studies assessed the reproducibility of the WHO classification and the ISN/RPS classification, the most extensive study was reported by Furness and Taub in 2006.3.Furness P.N. Taub N. Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis: a UK-wide study.Am J Surg Pathol. 2006; 30: 1030-1035Crossref PubMed Scopus (82) Google Scholar In a comparison of the WHO and the ISN/RPS classifications, 30 pathologists throughout the United Kingdom graded 20 renal biopsy sections of lupus nephritis stained by hematoxylin and eosin and methenamine silver. The κ value was significantly higher in the ISN/RPS classification than in the WHO classification (0.53 versus 0.44, P=0.002), suggesting that reproducibility was remarkably improved in the ISN/RPS compared with the WHO classification. In a smaller study, Grootscholten et al. deliberately assessed the reproducibility of 54 histopathological features in 126 renal biopsy sections among six pathologists.4.Grootscholten C. Bajema I.M. Florquin S. et al.Interobserver agreement of scoring of histopathological characteristics and classification of lupus nephritis.Nephrol Dial Transplant. 2008; 23: 223-230Crossref PubMed Scopus (78) Google Scholar Although the reproducibility of the WHO classification and the ISN/RPS classification was low (ICC<0.4), completely sclerosed glomeruli, endocapillary proliferation, extracapillary proliferation, spikes, and activity index, interestingly, had good reproducibility (ICC>0.6). These authors' results suggested that even the reproducibility of the revised ISN/RPS classification might not be satisfactory and that reproducibility was greatly dependent on histopathological features. In contrast to studies of the histopathological classification of renal transplants and lupus nephritis, only a few studies of IgA nephropathy evaluated reproducibility, even though multiple observational cohort studies examined an association between histopathological classifications and the renal prognosis of IgA nephropathy. One of the studies assessing reproducibility was reported by Lee et al. in 2005.5.Lee H.S. Lee M.S. Lee S.M. et al.Histological grading of IgA nephropathy predicting renal outcome: revisiting H.S. Lee's glomerular grading system.Nephrol Dial Transplant. 2005; 20: 342-348Crossref PubMed Scopus (138) Google Scholar They developed a histopathological classification with five grades and demonstrated that its reproducibility among three observers, who assessed 50 renal biopsy sections, was satisfactory (κ value: 0.59 to 0.73), verifying the adequacy of their histopathological classification. Another study, reported by Katafuchi et al., assessed the reproducibility of a histopathological classification with four grades, based on the sum of multilevel scores of seven types of lesions (glomerular hypercellularity, glomerular segmental lesions, glomerular sclerosis, interstitial-cell infiltration, interstitial fibrosis, tubular atrophy, and vessel wall thickening).6.Katafuchi R. Kiyoshi Y. Oh Y. et al.Glomerular score as a prognosticator in IgA nephropathy: its usefulness and limitation.Clin Nephrol. 1998; 49: 1-8PubMed Google Scholar Three observers examined 100 renal biopsy sections, and their reproducibility was not satisfactory (κ value: 0.12 to 0.47), suggesting a great limitation of this histopathological classification. Both studies evaluated only the reproducibility of their histopathological classification systems, not that of each histopathological feature independently, such as mesangial-cell hypercellularity, extracapillary proliferative lesions, interstitial fibrosis, and so on. In 2004, representatives of the International IgA Nephropathy Network and the RPS established a working group to develop an international consensus on practical histopathological classification of IgA nephropathy.7.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Cattran D. Coppo R. Cook T. et al.The Oxford Classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar,8.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Roberts I.S.D. Cook H.T. Troyanov S. et al.The Oxford Classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar Their aim was to identify histopathological lesions of IgA nephropathy with both high reproducibility and high predictive power. Nephrologists and pathologists in 10 countries joined two international consensus meetings held in Oxford, UK, in 2005 and 2008. The current Oxford classification is the product of the strikingly largest-scale histopathological study of IgA nephropathy, based on 265 renal biopsy sections collected internationally from Asia (China and Japan), Europe (France, Italy, and the United Kingdom), North America (Canada and the United States), and South America (Chile). The process establishing the Oxford classification had two major steps (Figure 1). In the first step, histopathological features with high reproducibility were identified (Roberts et al.,8.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Roberts I.S.D. Cook H.T. Troyanov S. et al.The Oxford Classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar this issue), and in the second step, these histopathological features were distinguished on the basis of predictive power for progression of IgA nephropathy (Cattran et al.,7.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Cattran D. Coppo R. Cook T. et al.The Oxford Classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar this issue). In the first step, five pathologists graded more than 20 histopathological features of 265 PAS-stained sections, including glomerular lesions (mesangial-cell hypercellularity, endocapillary hypercellularity, extracapillary lesions, segmental sclerosis, adhesion, and so on), tubulointerstitial lesions (tubular atrophy, interstitial fibrosis, and inflammation), and vascular lesions (arteriosclerosis and arteriolar hyalinosis). The ICCs of these histopathological features ranged from 0.03 (interstitial inflammation) to 0.90 (global glomerulosclerosis).8.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Roberts I.S.D. Cook H.T. Troyanov S. et al.The Oxford Classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar Reproducibility was good (ICC>0.6) for six histopathological features—mesangial-cell hypercellularity; segmental adhesion or sclerosis; endocapillary hypercellularity; cellular or fibrocellular extracapillary lesions; interstitial fibrosis or tubular atrophy; and arterial lesions—which were identified as candidate predictors of renal prognosis with relevant reproducibility. In the second step, associations between the six candidate histopathological predictors and renal prognosis were retrospectively examined. During 69 months of median follow-up period, 22% of the patients developed a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease.7.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Cattran D. Coppo R. Cook T. et al.The Oxford Classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar Regarding the rate of eGFR decline (ml/min/1.73 m2/y) as a dependent variable in multivariate linear regression models, segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis, not mesangial hypercellularity score, were significantly associated with the outcome, even after adjustment for the baseline covariates (mean arterial pressure, proteinuria, and eGFR) or the follow-up covariates (mean arterial pressure and proteinuria during a follow-up period and baseline eGFR). Regarding a 50% decrease in eGFR or end-stage renal disease as a dependent variable in Cox proportional-hazards models, mesangial-cell hypercellularity and tubular atrophy/interstitial fibrosis, not segmental glomerulosclerosis, were identified as significant predictors, even adjusted for the baseline covariates or the follow-up covariates. Despite imperfectly compatible results in these models, the study suggested that mesangial-cell hypercellularity, segmental glomerulonephritis, and tubular atrophy/interstitial fibrosis had predictive power. Interactions between the candidate histopathological lesions and treatment modalities such as immunosuppressive agents and renin–angiotensin system (RAS) blockers were also assessed only in univariate models, which suggested that endocapillary lesions were likely to be associated with responsiveness to immunosuppressive agents. On the basis of these results, the authors propose that four histopathological features—mesangial-cell hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis—should be clearly described in renal biopsy reports as histopathological predictors of renal prognosis of IgA nephropathy. The Oxford classification of IgA nephropathy provides substantially stronger evidence for a histopathological grading system to predict renal prognosis of IgA nephropathy, compared with previous studies. There are, however, important unresolved issues. First, the final result of reproducibility was based on observations of PAS-stained sections by only five expert pathologists—although no previous histopathological classification of IgA nephropathy has been examined for reproducibility among more than three observers. To evaluate the utility of the Oxford classification in the real world, reproducibility among a larger number of observers should be assessed with the use of silver-stained sections as well as PAS-stained sections. Second, the inconsistent results of the multivariate models with different outcomes (linear regression models and Cox proportional-hazards models) might be partly due to the retrospective study design with critical selection biases, or partly because of low statistical power due to the fact that only 58 patients (22%) developed a composite outcome (50% decline in renal function and end-stage renal disease). The results of the current studies should be verified by independent prospective cohort studies with a larger sample size. Third, it remains to be clarified which histopathological lesions predict the effectiveness of treatment modalities such as RAS blockers and immunosuppressive agents. Although the work of Cattran et al.7.A Working Group of the International IgA Nephropathy Network and the Renal PathologySociety Cattran D. Coppo R. Cook T. et al.The Oxford Classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar implies that endocapillary lesions were associated with the rate of renal-function decline, the model used was univariate, not multivariate, and did not control for critical biases, including confounding by indication. Interestingly, a randomized controlled trial assessing the efficacy of an oral corticosteroid in IgA nephropathy suggested that endocapillary proliferation was associated with renal outcome,9.Katafuchi R. Ikeda K. Mizumasa T. et al.Controlled, prospective trial of steroid treatment in IgA nephropathy: a limitation of low-dose prednisolone therapy.Am J Kidney Dis. 2003; 41: 972-983Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar which is compatible with the current study. Histopathological classifications should be developed that predict not only renal prognosis but also response to treatment modalities such as corticosteroids and RAS blockers. Nephrologists and pathologists previously stressed only the predictive capacity of histopathological classifications, assuming high reproducibility. The Oxford working group has undermined this assumption by strategically developing a classification of IgA nephropathy with both clinical relevance and reproducibility, although its clinical utility should be validated by independent study. The Oxford classification sheds light on practical ways to produce clinically useful histopathological classifications of not only IgA nephropathy but also other glomerulonephritides. The authors declared no competing interests.