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A proposal for standardized grading of chronic changes in native kidney biopsy specimens

2017; Elsevier BV; Volume: 91; Issue: 4 Linguagem: Inglês

10.1016/j.kint.2017.01.002

1523-1755

Sanjeev Sethi, Vivette D. D’Agati, Cynthia C. Nast, Agnes B. Fogo, An S. De Vriese, Glen S. Markowitz, Richard J. Glassock, Fernando C. Fervenza, Surya V. Seshan, Andrew D. Rule, Lorraine C. Racusen, Jai Radhakrishnan, Christopher G. Winearls, Gerald B. Appel, Ingeborg M. Bajema, Anthony Chang, Robert B. Colvin, H. Terence Cook, Sundaram Hariharan, Loren P. Herrera Hernandez, Neeraja Kambham, Michael Mengel, Karl A. Nath, Helmut G. Rennke, Pierre Ronco, Brad H. Rovin, Mark Haas,

Renal and Vascular Pathologies

Chronic changes represent an important component of native kidney biopsy evaluation and have a major bearing on predicting prognosis and guiding treatment. We propose here a uniform, semiquantitative approach to assessing such changes, which include glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis, and we report these findings as an overall chronicity grade. Chronic changes represent an important component of native kidney biopsy evaluation and have a major bearing on predicting prognosis and guiding treatment. We propose here a uniform, semiquantitative approach to assessing such changes, which include glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis, and we report these findings as an overall chronicity grade. A primary reason to perform a kidney biopsy is to determine the etiology and pathogenesis of the kidney disease.1Sethi S. Haas M. Markowitz G.S. D’Agati V.D. et al.Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.J Am Soc Nephrol. 2016; 27: 1278-1287Crossref PubMed Scopus (143) Google Scholar An important component of the kidney biopsy specimen evaluation that is sometimes inadequately or inconsistently reported is the extent of chronic changes in the individual renal compartments. Chronic changes are generally irreversible and have a major bearing on kidney function. They may be as important as the underlying disease etiology in predicting prognosis, guiding treatment, and assessing treatment response. We therefore propose that there is a need to consistently grade and report the chronic changes noted on the kidney biopsy specimen. Chronic changes involve the renal cortex and medulla, but are most evaluable in the cortex, where they can affect the glomeruli, tubules, interstitium, and arteries/arterioles. They include global and segmental glomerulosclerosis (GS), tubular atrophy (TA) and interstitial fibrosis (IF), and arteriosclerosis/arteriolosclerosis, respectively. These chronic changes may appear within weeks or months after the initiating event or develop slowly in the absence of any recognizable acute injury. GS is defined as global or segmental collapse of glomerular capillary walls and consolidation of the glomerular tuft by extracellular matrix, causing capillary luminal obliteration. GS, most notably the segmental forms, may result from a number of different etiologies: postinflammatory scarring, a compensatory maladaptive injury response after nephron loss, podocyte injury in the context of primary focal segmental GS, or other glomerular diseases such as IgA nephropathy.2Bellur S.S. Lepeytre F. Vorobyeva O. et al.Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy.Kidney Int. 2017; 91: 235-243Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar All are counted toward GS. Ischemic-appearing glomeruli characterized by nearly complete to complete collapse of wrinkled capillary walls, often with relative distention of Bowman’s space, are counted toward global GS. TA is defined as shrinkage of tubules with variable thickening of the tubular basement membrane and flattening of the tubular epithelium. Interstitial fibrosis is defined as the accumulation of fibrous tissue between the tubules. TA and IF usually occur together (designated IFTA) but rarely can develop independently of each other. Arteriosclerosis (CV) is defined as fibrous thickening and/or hyalinosis of the intima. Interstitial inflammation, irrespective of whether it is present in areas of IFTA or in preserved parenchyma, is generally not considered part of the chronic changes, but rather as an active process that potentially contributes to progression of the chronic changes. Many studies have shown that chronic changes are strong predictors of renal outcomes in various kidney diseases, including lupus nephritis, antineutrophil cytoplasmic autoantibody–associated vasculitis, and IgA nephropathy. A recent report of 654 kidney biopsies comprising cases of lupus nephritis, IgA nephropathy, diabetic nephropathy, and other primary glomerular diseases as well as nonglomerular diseases showed an independent association of GS, IFTA, and moderate/severe arteriosclerosis with renal outcomes.3Srivastava A, Kaze A, Stillman I, et al. The association of histopathological lesions with renal function decline and mortality in biopsy-confirmed kidney disease. SA-PO789. Abstract presented at: American Society of Nephrology Meeting, November 15–20, 2016; Chicago, IL.Google Scholar Similarly, in the allograft kidney, chronic changes are well-recognized markers for prognosis and form a key part in the Banff schema of renal allograft biopsy reporting.4Solez K. Axelsen R.A. Benediktssen H. et al.International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology.Kidney Int. 1993; 44: 411-422Abstract Full Text PDF PubMed Scopus (1289) Google Scholar Recently, a group of pathologists and nephrologists revisited the classification and reporting of glomerulonephritis.1Sethi S. Haas M. Markowitz G.S. D’Agati V.D. et al.Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.J Am Soc Nephrol. 2016; 27: 1278-1287Crossref PubMed Scopus (143) Google Scholar For chronicity, it was decided to list the chronic changes present on the biopsy specimen as an additional finding, including the percentage of glomeruli that are globally sclerosed, the estimated percentage of IFTA, and the severity of arteriosclerosis. However, merely enumerating the percentages of chronic changes in these renal compartments often does not provide context of the overall severity of the chronic changes present on the kidney biopsy specimen. Pathologists generally grade the chronic changes reliably with a higher degree of interobserver agreement than for acute lesions such as mesangial and endocapillary hypercellularity.5Roberts I.S. Cook H. Troyanov S. Alpers C.E. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar Studies have shown that pathologist “eyeball” assessment of fibrosis shows remarkably excellent correlation with morphometric techniques for assessing IFTA.6Farris A.B. Adams C.D. Brousaides N. et al.Morphometric and visual evaluation of fibrosis in renal biopsies.J Am Soc Nephrol. 2011; 22: 176-186Crossref PubMed Scopus (164) Google Scholar Scoring and subsequent grading of the chronic changes are proposed as follows: global and segmental GS is scored from 0 to 3, TA from 0 to 3, IF from 0 to 3, and arteriosclerosis from 0 to 1 (Table 1). The scores are then added (total renal chronicity score) to grade the overall severity of the chronic lesions into minimal (0–1 total score), mild (2–4 total score), moderate (5–7 total score), and severe (≥8 total score) (Table 2). Lesser weight is attached to arteriosclerosis compared with GS and IFTA because both GS and IFTA have been found to be predictors of poor renal outcomes in multiple studies of different glomerular diseases, whereas such prediction is much less consistently found with arteriosclerosis. Hyaline arteriolosclerosis is not included in the scoring of chronic changes. We propose that the grade of the chronic changes should be reported as a separate entity in the diagnosis. Thus, based on the Mayo Clinic/RPS consensus report,1Sethi S. Haas M. Markowitz G.S. D’Agati V.D. et al.Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.J Am Soc Nephrol. 2016; 27: 1278-1287Crossref PubMed Scopus (143) Google Scholar the diagnosis would include primary diagnosis, pattern of injury, additional findings, secondary diagnosis, and chronicity grade. Disease entities with scoring systems that already include semiquantitative measures of chronicity such as IgA nephropathy (S and T scores of the Oxford Classification)5Roberts I.S. Cook H. Troyanov S. Alpers C.E. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar and lupus nephritis (National Institutes of Health chronicity index)7Austin 3rd, H.A. Muenz L.R. Joyce K.M. et al.Prognostic factors in lupus nephritis. Contribution of renal histologic data.Am J Med. 1983; 75: 382-391Abstract Full Text PDF PubMed Scopus (562) Google Scholar do not need a separate chronicity grade when these scoring systems are used.Table 1Scoring of the chronic lesions in individual renal tissue compartmentsTissue compartmentaGS score includes the percentage of glomeruli with global and segmental sclerosis and ischemic glomeruli; IF and TA score includes the percentage of renal cortex involved by interstitial fibrosis and tubular atrophy, respectively; CV score includes the severity of arteriosclerosis determined by the extent of thickening of the intima.Score0123Glomerulosclerosis (GS score) 50%Interstitial fibrosis (IF score) 50%Tubular atrophy (TA score) 50%Arteriosclerosis (CV score)Intimal thickening < thickness of mediaIntimal thickening ≥ thickness of mediaa GS score includes the percentage of glomeruli with global and segmental sclerosis and ischemic glomeruli; IF and TA score includes the percentage of renal cortex involved by interstitial fibrosis and tubular atrophy, respectively; CV score includes the severity of arteriosclerosis determined by the extent of thickening of the intima. Open table in a new tab Table 2Grades of chronic changes based on total renal chronicity score (0–10)GradeTotal renal chronicity scoreaTotal chronicity score is the sum of individual chronicity scores for each renal tissue compartment as shown in Table 1.Minimal chronic changes0–1Mild chronic changes2–4Moderate chronic changes5–7Severe chronic changes≥8a Total chronicity score is the sum of individual chronicity scores for each renal tissue compartment as shown in Table 1. Open table in a new tab Three concerns need to be addressed when assessing the chronic changes. First, an adequate cortical sample should be present to score and grade chronic changes. We suggest, in accordance with the Banff recommendations, that an adequate representation of the renal cortex is based on the presence of a minimum of 10 glomeruli and 2 arteries.8Racusen L.C. Solez K. Colvin R.B. et al.The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55: 713-723Abstract Full Text Full Text PDF PubMed Scopus (2771) Google Scholar It is also important to point out that subcapsular cortex often is not representative of the total renal cortex and may disproportionately show a higher extent of chronic changes. A comment on whether the biopsy specimen is adequate for interpreting the extent of chronic changes should be included. Second, chronic changes occur with healthy aging. The 95th percentile for global GS among healthy adults (living kidney donors) older than 50 years of age exceeds 10%.9Rule A.D. Amer H. Cornell L.D. et al.The association between age and nephrosclerosis on renal biopsy among healthy adults.Ann Intern Med. 2010; 152: 561-567Crossref PubMed Scopus (329) Google Scholar Whether age-related chronic changes contribute to prognosis or only disease-related chronic changes matter is unclear. Third, preexisting chronic changes may be present due to causes other than the primary diagnosis, such as hypertension and diabetes. Thus, it may sometimes be difficult to ascribe the chronic changes to the primary disease or due to coexisting comorbidities. However, it should be recognized that the chronic changes, regardless of whether due to the primary disease or comorbidities, are in themselves strong predictors of renal outcome. Therefore, it is reasonable to list chronic changes as a separate finding due to their likely clinical importance. We emphasize that scoring and grading the chronic changes are not a classification, but rather a systematic and semiquantitative approach to assessing and reporting the chronic lesions. Chronic changes are not disease specific and may have variable prognostic and therapeutic implications in different renal diseases. Evidence-based outcome studies are needed to determine whether the proposed scoring is universally valid or is disease specific. In summary, we propose a simple approach to score and grade chronic changes on the kidney biopsy specimen. We suggest that in addition to providing an assessment of the degree of GS, TA, IF, and arteriosclerosis, an overall chronicity grade be included in the kidney biopsy report. The chronicity grade should be part of the diagnosis. A benefit of a consistent grading scale is to provide uniformity in assessing treatment responses and outcomes, especially for patients enrolled in clinical trials or observational studies. Future studies should examine the prognostic value of this simple scoring and grading system to determine the relative significance of each of the variables on outcome and allow refinement of the system. All the authors declared no competing interests.