Lupus Revision 2018

Kidney International
Revision of the ISN/RPS classification for lupus nephritis:

modified NIH activity and chronicity indices and clarification
of definitions
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Journal: Kidney International

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Manuscript ID KI-08-17-1259.R1
Article Type: Meeting Report

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Date Submitted by the Author: 13-Nov-2017
Complete List of Authors: Bajema, Ingeborg; Leiden University Medical Center, Department of
Pathology
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Wilhelmus, Suzanne; Leiden University Medical Center, Pathology

Alpers, Charles
Bruijn, Jan
Colvin, Robert; Mass Gen Hosp, Pathology
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Cook, Terence; Imperial College London, Medicine

D'Agati, Vivette; Columbia University, Pathology
Ferrario, Franco; University of Milano-Bicocca, Surgery and Translational
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Medicine
Haas, Mark; Cedars-Sinai Medical Center, Dept of Pathology and
Laboratory Medicine; Cedars-Sinai,
Jennette, Charles
Joh, Kensuke
Nast, Cynthia; Cedars-Sinai Medical Center, Pathology
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Noël, Laure-Hélène
Rijnink, Emilie; Leiden University Medical Center, Pathology
Roberts, Ian; Oxford University Hospital, Cellular Pathology
Seshan, MD, Surya V; Cornell University,New York, pathology
Sethi, Sanjeev; Mayo Clinic, Laboratory Medicine and Pathology
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Fogo, Agnes; Vanderbilt University, Pathology
Keywords: systemic lupus erythematosus, renal pathology
Subject Area: Renal Pathology
The International Society of Nephrology (http://www.isn-online.org/site/cms)

Page 1 of 25 Kidney International
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3 1 Revision of the ISN/RPS classification for lupus nephritis:
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2 clarification of definitions, and modified NIH activity and chronicity
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13 5 Ingeborg M. Bajema1, Suzanne Wilhelmus1, Charles E. Alpers2, Jan A. Bruijn1, Robert B.
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15 6 Colvin3, H. Terence Cook4, Vivette D. D’Agati5, Franco Ferrario6, Mark Haas7, J. Charles
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Jennette8, Kensuke Joh9, Cynthia C. Nast7, Laure-Hélène Noël10, Emilie C. Rijnink1, Ian S.D.
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18 8 Roberts11, Surya V. Seshan12, Sanjeev Sethi13, Agnes B. Fogo14
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21 9 Affiliations: see page 2
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12 Corresponding author
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28 13 Ingeborg M. Bajema, MD PhD
29 14 Department of Pathology, Leiden University Medical Center
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15 PO Box 9600
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32 16 2300 RC Leiden
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33 17 The Netherlands
34 18 Telephone number: +31 71 526 6621
35 19 Fax number: + 31 71 526 6952
36 20 i.bajema@lumc.nl
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23 Running title: revision of lupus nephritis classification
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44 24 Key words: lupus nephritis, renal biopsy, systemic lupus erythematosus
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46 25 Word count abstract: 197
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48 26 Word count text (excluding references, figures and tables): 3616
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60 The International Society of Nephrology (http://www.isn-online.org/site/cms)
Kidney International Page 2 of 25
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3 1 Affiliations:
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Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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5 Department of Pathology, University of Washington, Seattle, WA, USA
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10 7 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston
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Department of Medicine, Imperial College, London, UK
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12 Department of Pathology and Cell Biology, Columbia University Medical Center, New York,
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19 15 Nephropathology Center, San Gerardo Hospital-Monza, Milan Bicocca University, Milan,
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20 16 Italy
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Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los
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19 Angeles, California USA
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26 21 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel
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Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
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26 Department of Pathology, Necker Hospital, Paris, France
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34 28 Department of Cellular Pathology, Oxford University Hospitals, Oxford, UK
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Department of Pathology and laboratory Medicine, Weill Cornell University Medical
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42 35 Dept. of Pathology, Vanderbilt University School of Medicine, MCN, USA
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3 1 ABSTRACT
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6 2 We present a consensus report pertaining to the improved clarity of definitions and
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8 3 classification of glomerular lesions in lupus nephritis that derived from a meeting of 18
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4 members from an international nephropathology working group in Leiden, 2016. Here we
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13 5 report detailed recommendations on issues for which we can propose adjustments based on
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15 6 existing evidence and current consensus opinion (phase 1). New definitions are provided for
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7 mesangial hypercellularity and for cellular, fibrocellular and fibrous crescents. The term
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20 8 endocapillary proliferation is eliminated and the definition of endocapillary hypercellularity
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22 9 considered in some detail. We also eliminate the Class IV-S and IV-G subdivisions of Class IV
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24 10 lupus nephritis. The active/chronic (A/C) designations for Class III/IV lesions are replaced by
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27 11 a proposal for activity and chronicity indices which should be applied to all classes. In the
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29 12 activity index, we include fibrinoid necrosis as a specific descriptor. We also make
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31 13 recommendations on issues for which there are limited data at present, and that can best be
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14 addressed in future studies (phase 2). We propose to proceed to these investigations, with
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36 15 clinicopathologic studies and tests of inter-observer reproducibility to evaluate the
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3 1 On May 9-11th 2016, a Working Group for Lupus Nephritis Classification (the Group) met at
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5 2 Leiden University Medical Center to reach a consensus on recently raised issues concerning
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3 problems with definitions of lupus nephritis lesions.1 Prior to the meeting, those attending
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10 4 received a questionnaire asking for anonymous suggestions for improving the definitions.
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12 5 The responses served as a starting point for making adjustments to the definitions of lupus
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14 6 nephritis lesions, a process that was further accomplished by group discussions and a multi-
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17 7 head microscopy session. The Group decided that consensus had to be reached for any
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19 8 proposed changes and that recommendations should be divided in two types: Phase 1
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21 9 recommendations are clarifying modifications for which we could propose adjustments
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10 based on existing published evidence and mutual agreement. Phase 2 recommendations will
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26 11 address issues that can best be validated or modified through an evidence-based process.
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28 12 These include more problematic lesion definitions and adjustments to the lupus nephritis
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13 classification. We now report on phase 1 recommendations, and provide a framework for
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36 15 Our immediate aim is to improve problematic definitions that form the basis of the
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40 17 nephropathologists worldwide who apply these definitions to classify lupus nephritis. Our
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43 18 eventual goal is to improve the lupus nephritis classification using an evidence-based
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45 19 approach, but refining the definitions for lesions is necessary because they form the
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47 20 essential elements for the classification. Here we describe a plan to proceed in the near
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21 future to gather data and, as indicated, modify the lupus nephritis classification.
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53 22 Many renal lesions encountered in lupus nephritis also are present in other renal
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55 23 diseases, providing a rationale for harmonizing definitions for lesions irrespective of the
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3 1 disease context. Depending on the setting, i.e. evaluation of renal biopsies in a clinical
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5 2 setting or for research purposes, different guidelines may apply regarding biopsy
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3 requirements. In a clinical setting, it is necessary to obtain as much information as possible
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10 4 from the biopsy by evaluating all stains in all levels and sections and to apply a basic format
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12 5 of the kidney biopsy report. As a general rule, 10 glomeruli for evaluation seem to be
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14 6 appropriate. By studying definitions of frequently occurring lesions as currently formulated
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17 7 (e.g., as in classification systems for IgA nephropathy2-4 and ANCA-associated
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19 8 glomerulonephritis,5 as well as definitions created by the Neptune,6 CureGN7 and Banff8
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21 9 workgroups), we strove for uniform definitions but recognized that certain thresholds may
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10 be different among diseases. For example, it remains to be determined (an evidence-based
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26 11 phase 2 issue) which thresholds – for instance for mesangial hypercellularity – have clinical
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28 12 and prognostic value in lupus nephritis, and whether these should be different from those
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13 for another disease such as IgA nephropathy. Below, we discuss our modifications of
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35 15 separately. At this stage, we mainly focus on lesions evaluable by light microscopy, although
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37 16 we do take into account findings by immunofluorescence (IF) and electron microscopy (EM)
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40 17 if they are helpful in the decision-making process. An overview of the alterations to the
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42 18 ISN/RPS lesion definitions and classification9 that we propose is found in Table 1.

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3 Table 1. Phase 1 recommendations for lupus nephritis classification
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7 Category Recommendation Comments on ISN/RPS guidelines
8 Class II Definition for mesangial hypercellularity adjusted: Cuttoff for mesangial hypercellularity unclear
9 Four or more nuclei fully surrounded by matrix in
10 the mesangial area not including the hilar region (A)
11 Class III and IV The term endocapillary proliferation is replaced by Definition for endocapillary proliferation unclear;
endocapillary hypercellularity (B) the term proliferation was considered imprecise
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13 The term crescent is used for a lesion consisting of
extracapillary hypercellularity, composed of a variable mixture
Extracapillary proliferation involving < 25% of the circumference
of Bowman's capsule was original cutoff. There were no
14 of cells. Fibrin and fibrous matrix may be present; 10% or more definitions for fibrous or fibrocellular crescents
of the circumference of Bowman's capsule should be involved.
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16 Cellular crescent: more than 75% cells and fibrin
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and less than 25% fibrous matrix (C)
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Fibrous crescent: more than 75% fibrous matrix
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Fibrocellular crescent: 25-75% cells and fibrin
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21 Adhesion: an area of isolated continuity of extracellular matrix There was no definition for an adhesion
22 material between the tuft and capsule even when the underlying
segment does not have overt sclerosis (F)
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Fibrinoid necrosis: fibrin associated with glomerular basement membrane There was no definition for fibrinoid necrosis
24 disruption and/or lysis of the mesangial matrix; this lesion does not
25 require the presence of karyorrhexis
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Elimination of segmental and global subdivions of class IV Definitions for segmental and global were unclear;
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interobserver variability was large; clinical significance uncertain
28 Modification of the NIH lupus nephritis activity and chronicity scoring

system (Table 2) to be used instead of the currently used A, C
Designation of activity/chronicity through A, C and A/C
considered too broad and nonspecific; preference for a
29 and A/C parameters semiquantitative approach to describe active and chronic lesions
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30 Tubulointerstitial lesions Indicate whether interstitial inflammation occurs in presence or Lack of cut-off values for reporting the severity of
31 absence of interstitial fibrosis tubulointerstitial lesions
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3 1 Glomerular lesions, Class I – VI:
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6 2 Class I and II
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9 3 An important question was the threshold between class I and class II. We questioned
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14 5 merely one mesangial area in one glomerulus in the entire biopsy would suffice. We agreed
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16 6 that mesangial hypercellularity in one area in one glomerulus seems rather low. The
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18 7 appropriate threshold will be investigated in phase 2. In the meantime, we propose
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8 increasing the threshold of mesangial hypercellularity from 3 cells/mesangial area to 4 cells,
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23 9 not including the hilar region, in line with the Oxford classification of IgA nephropathy2-4 and
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25 10 specify that mesangial cell nuclei be fully surrounded by matrix. An evidence-based
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27 11 approach to define an appropriate threshold was judged to be necessary. Whether and to

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30 12 what extent mesangial matrix expansion should be incorporated in the definition together
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32 13 with this cell number cut-off level, also needs to be investigated in an evidence-based
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34 14 approach. Of note, only peripheral mesangial areas should be assessed for cellularity, with
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37 15 central and perihilar areas excluded, as described for IgA nephropathy. Importantly, we
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39 16 discussed whether or not hypercellularity within the mesangial zone caused by
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18 hypercellularity or as endocapillary hypercellularity. This topic will be discussed in more
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49 20 Class III and IV
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52 21 A substantial amount of discussion centered on Class III and IV lesions. We agreed, as
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3 1 endocapillary lesions, the definition of lumen reduction, and the specific contribution of
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10 4 hypercellularity” because most of the hypercellularity in glomerular capillaries in lupus
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20 8 Endocapillary Hypercellularity
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27 11 that this should be named mesangial hyperplasia in lesions purely consisting of an

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34 14 lesion; the cut-off values for mesangial hypercellularity and significance of mesangial
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37 15 inflammation remain to be determined in phase 2. Likewise, the cut-off levels for number of
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41 17 need to be defined in a phase 2 exercise. Figure 1 shows ultrastructural features of a single
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18 glomerular capillary affected by lupus glomerulonephritis. Inflammatory cells can be in the
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46 19 capillary lumen, beneath endothelial cells in capillary walls, and in the mesangial
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48 20 extracellular compartment. It has to be decided in phase 2 whether endocapillary
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50 21 hypercellularity should encompass all glomerular hypercellularity internal to the capillary
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53 22 wall glomerular basement membrane (GBM) and paramesangial GBM (excluding pure
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3 1 capillary lumens. Endothelial cell swelling alone was considered insufficient for a lesion to be
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3 encountered in the absence of inflammatory cells, TMA should be considered, taking into
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20 8 Membranoproliferative glomerulonephritis (MPGN) pattern
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23 9 We discussed the value of using the term ‘MPGN pattern’ in relation to the modifications of
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25 10 definitions for lesions within class III and IV lupus nephritis. The group concluded that an
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27 11 MPGN pattern of injury is subsumed in class III/IV lupus nephritis as a form of endocapillary
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34 14 caused by immune complexes (i.e. hyaline thrombi) as lesions indicative of class III/IV.
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37 15 Determination of the clinical significance of the MPGN pattern and whether or not acute and
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42 17 Crescents
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45 18 The term crescent is used for a lesion consisting of extracapillary hypercellularity, composed
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47 19 of a variable mixture of cells. Because some crescents may have predominantly epithelial
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50 20 proliferation, whereas others consist predominantly of monocytes/macrophages, the Group
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52 21 chose the description of a ‘variable mixture of cells’. Fibrin and fibrous matrix may also be
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54 22 present. The ISN/RPS criterion of a crescent involving 25% or more of the glomerular
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3 1 more in accord with evidence from the Oxford Classification of IgA nephropathy and
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5 2 standard approaches used in clinical reporting of renal biopsy lesions. Crescents should be
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3 composed of more than 2 cell layers in order to distinguish them from apposition of the
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10 4 single layers of hypertrophied visceral and parietal cells. We propose definitions for the
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12 5 distinction of cellular, fibrous and fibrocellular crescents, which were lacking in the ISN/RPS
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14 6 lupus nephritis classification (Table 1). Some glomeruli may have more than one type of
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21 9 crescents. We propose to preserve the term ‘adhesion’ for a lesion characterized by an area
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10 of isolated continuity of extracellular matrix material between the tuft and capsule even
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28 12 from both crescents and segmental sclerosis, although this differs from the Oxford
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13 classification of IgA nephropathy in which such lesions are considered manifestations of
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35 15 the tuft and Bowman’s capsule, which is not extensive enough to be called a crescent, needs
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46 19 and global lesions in class III and IV.10 As recently demonstrated in a meta-analysis by Haring
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48 20 et al,11 the clinical importance of distinguishing between segmental and global lesions in
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50 21 class IV as defined by the ISN/RPS Classification System has been questioned. A caveat is that
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3 1 combination with the uncertainty of how to evaluate the combination of intra- and
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5 2 extracapillary lesions into a segmental/global division, may have added greatly to the
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3 variability in outcomes of studies addressing the clinical impact of segmental and global
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10 4 lesions. The ISN/RPS approach to subclassifying class IV did not use segmental necrosis as a
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12 5 defining feature of a segmental variant of lupus nephritis, which may have reduced
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21 9 that the distinction between segmental and global lesions should be retained in the
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10 microscopic description, as such distinctions still may prove to have clinical value with
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26 11 further study using the modified classification of lupus nephritis. As noted below, segmental
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28 12 fibrinoid necrosis as well as segmental endocapillary hypercellularity will be evaluated.
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31 13 Fibrinoid Necrosis
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34 14 It was emphasized during the meeting that another potentially important feature not taken
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37 15 into consideration in the ISN/RPS identification of segmental lesions is the occurrence in
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39 16 lupus nephritis of fibrinoid necrosis. This is usually segmental and resembles lesions caused
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18 segmental endocapillary lesions may be merely a distribution variant of global endocapillary
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46 19 hypercellularity caused by the same pathogenic mechanisms, whereas segmental fibrinoid
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48 20 necrosis may be a pathogenetically distinct lesion. Therefore, for classes III and IV, we
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50 21 recommend noting the presence of fibrinoid necrosis. In phase 1, we propose to adjust the
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3 1 karyorrhexis. Furthermore, karyorrhexis is defined as the presence of apoptotic, pyknotic
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5 2 and fragmented nuclei – a definition used uniformly in other classification systems. In phase
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3 2, we propose that the clinical significance of fibrinoid necrosis should be reevaluated in
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10 4 addition to assessing the coexistence of necrotizing lesions with crescents. Whether these
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12 5 lesions have “pauci-immune” features by IF and/or co-existent ANCA serology12 requires
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14 6 further study. The Group concluded that phase 2 studies should determine and compare the
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19 8 lupus nephritis, versus fibrinoid necrosis, which is less common.
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22 9 Activity and Chronicity Assessment
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25 10 For a critical re-evaluation of activity and chronicity, we turned to the paper by Austin et al13
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27 11 on which the currently widely used NIH activity and chronicity index in lupus nephritis was
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34 14 the cut-offs for the scores 0-3 are arbitrary and the scoring system was not developed using
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37 15 an evidence- based approach. Therefore, in phase 2, we will use an evidence- based
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39 16 approach without prior assumptions to modify these indices. We propose in phase 2 that the
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18 interobserver reproducibility and to validate prognostic value. In the meantime, we advocate
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46 19 the usage of these indices, but modified as indicated below, for all classes in a modified
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48 20 classification for lupus nephritis, thereby not restricting them to class III and IV. The modified
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50 21 NIH activity and chronicity scoring system provides more information than the shorthand A,
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53 22 C and A/C parameters currently used. We decided it is important to retain total scores of 24
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3 1 recorded for earlier renal biopsy samples from the same patient using the original NIH
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10 4 find out whether this approach is valid.
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13 5 In the modified NIH activity index, we have made the following modifications:
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20 8 stand-alone category of fibrinoid necrosis whereas we link the presence of karyorrhexis to
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22 9 neutrophil infiltration. Because most karyorrhexis represents apoptotic cell death of
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27 11 presence of neutrophils only, we have changed the name and description of this category to
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29 12 indicate the presence of neutrophils and/or karyorrhexis. In the original description of the
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31 13 category ‘cellular crescents’, it was unclear to what extent fibrocellular crescents should be
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14 included. Whereas fibrous crescents are part of the chronicity Index, we have now included
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36 15 fibrocellular crescents in the activity index (see our proposal for definitions in Table 1). We
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40 17 the original description of Austin et al,13 only monocytes were taken into account in this
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43 18 category with respect to inflammatory cells leading to hypercellularity. We have to
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45 19 investigate in phase 2 how to approach the presence of inflammatory cells in endocapillary
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47 20 hypercellularity in more detail. For the moment, we find it important to specifically score
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21 neutrophils as a separate entity. Also the composition of the interstitial infiltrate as well as
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52 22 its presence in areas affected by interstitial fibrosis and tubular atrophy (IFTA) should be
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3 1 Table 2. Modified NIH lupus nephritis activity and chronicity scoring system proposal
4
5 Modified NIH Activity Index Definition Score
6
7 Endocapillary Hypercellularity Endocapillary hypercellularity in <25% (1+), 25-50% (2+), or 0-3
8
9 >50 (3+) of glomeruli.
10
11 Neutrophils/Karyorrhexis Neutrophils and/or karyorrhexis in <25% (1+), 25-50% (2+), or 0-3
12
13 >50 (3+) of glomeruli.
14
15 Fibrinoid Necrosis FFibrinoid necrosis in <25% (1+), 25-50% (2+), or >50 (3+) of (0-3) x 2
16
Fo
17 glomeruli.
18
19 Hyaline Deposits Wire loop lesions and/or hyaline thrombi in <25% (1+), 25-50% 0-3
rP
20
21 (2+), or >50 (3+) of glomeruli.
22
23 Cellular/Fibrocellular Crescents Cellular and/or fibrocellular crescents in <25% (1+), 25-50% (0-3) x 2
ee
24
(2+), or >50 (3+) of glomeruli.
25
26
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Interstitial Inflammation Interstitial leukocytes in <25% (1+), 25-50% (2+), or >50 (3+) in 0-3
27
28
the cortex.
29
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30 Total 0-24
31
32
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33
34 Modified NIH Chronicity Index Definition Score
35
36 Total Glomerulosclerosis Score Global and/or segmental sclerosis in <25% (1+), 25-50% (2+), 0-3
37
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38 or >50 (3+) of glomeruli.

39
40 Fibrous Crescents Fibrous crescents in <25% (1+), 25-50% (2+), or >50 (3+) of 0-3
41
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42 glomeruli.
43
44 Tubular Atrophy Tubular atrophy in <25% (1+), 25-50% (2+), or >50 (3+) of the 0-3
45
46 cortical tubules.
47
48 Interstitial Fibrosis Interstitial fibrosis in <25% (1+), 25-50% (2+), or >50 (3+) in the 0-3
49
50 cortex.
51
52 Total 0-12
53
54 2
55
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58 14
59
1
2
3 1 Global and segmental glomerulosclerosis
4
5
6 2 We previously mentioned difficulties in the attribution of global glomerulosclerosis to either
7
8 3 lupus nephritis or another cause,1 an issue related to the classification of lesions into class
9
10
11
4 III/IV, which requires deciding if global sclerosis is the sequel of an active class III/IV lesion. It
12
13 5 was discussed that some globally sclerotic glomeruli show features that indicate lupus
14
15 6 nephritis was the cause of the global sclerosis, for example fragmented tuft with
16
Fo
17
7 surrounding fibrosis, and extensive disruption of Bowman’s capsule. Moreover, residual
18
19
rP
20 8 deposits other than IgM and C3 found by IF in globally sclerotic glomeruli should also be
21
22 9 considered evidence that the lesion is the result of lupus nephritis. Globally sclerotic
23
ee
24 10 glomeruli should not be considered in the evaluation of lupus chronicity if they have a typical
25
26
rR
27 11 pattern of arterionephrosclerosis, e.g. subcapsular clusters of glomeruli with ischemic tuft

28
29 12 collapse surrounded by collagen in Bowman’s space. Incorporating globally sclerotic
ev
30
31 13 glomeruli that resulted from non-lupus injury in a chronicity index would overestimate the
32
iew
33
14 lupus nephritis chronicity and severity, but still may correlate with outcome. This issue
34
35
36 15 should be addressed by phase 2 studies. It should be emphasized that in lupus nephritis the
37
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38 16 term global sclerosis is used for those glomeruli that are completely sclerotic, and that any
39
40 17 other form of glomerulosclerosis should be regarded as segmental sclerosis. As mentioned
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43 18 previously, it is difficult to reliably differentiate segmental sclerosis as a consequence of class
44
45 19 III/IV lupus nephritis from segmental sclerosis due to other causes (e.g., post-adaptive
46
47 20 segmental sclerosis). Still, only the former should be designated as lesions of class III/IV,
48
49
50
21 employing the same features noted above to differentiate segmental sclerosis due to prior
51
52 22 active lupus nephritis from that due to other causes. Within the chronicity index, segmental
53
54 23 and global glomerulosclerosis are considered together.
55
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58 15
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1
2
3 1 Class V
4
5
6 2 Two issues were addressed in Class V. First, we considered whether or not to distinguish
7
8 3 Class V with and without mesangial hypercellularity and agreed this decision should be
9
10
11
4 evidence based (phase 2). Second, phase 2 studies should determine the allowable extent of
12
13 5 non-wire-loop subendothelial deposits within class V, above which one would have to
14
15 6 classify as III + V.
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18 7 Class VI
19
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20
21 8 We recognize that the RPS/ISN category VI is rarely seen in renal biopsy specimens, and
22
23
ee
24 9 propose that this class be re-evaluated in phase 2, especially in view of our discussion above
25
26 10 on the recognizability of globally sclerotic glomeruli resulting from preceding lupus nephritis
rR
27
28 11 active lesions versus nonspecific global sclerosis associated with other factors (e.g., aging,
29
ev
30
12 hypertension or healed TMA lesions). Class VI will either need to be eliminated, or some
31
32
iew
33 13 fraction of globally sclerotic glomeruli designated as the cut-off between chronic class IV and
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35 14 class VI.
36
37
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38 15 Tubulointerstitial lesions
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41 16 We previously indicated the lack of cut-off values in the ISN/RPS classification for reporting
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17 of severity of tubulointerstitial lesions.1 This deficiency will be addressed by the
44
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46 18 development of a valid activity and chronicity index that scores the severity of
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48 19 tubulointerstitial injury. We propose that in phase 2 we gather data on IFTA, and interstitial
49
50
20 infiltrates in a semi-quantitative fashion, rounding fibrosis to nearest 10%, with minimal
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53 21 fibrosis stated as 5%. These values then can be translated into reproducible scoring
54
55 22 categories (e.g. on a scale of 0-3+) based on cut-off values to be evaluated for prognostic
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58 16
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1
2
3 1 significance as currently done for the Banff and Oxford classifications. We advocate at this
4
5 2 time, as a phase 1 recommendation, to indicate in biopsy reports whether interstitial
6
7
3 inflammation occurs in the presence or absence of interstitial fibrosis. For the present,
8
9
10 4 interstitial inflammation remains part of the activity index as proposed above, while
11
12 5 interstitial fibrosis and tubular atrophy remain as separate entities within the chronicity
13
14 6 index. It has to be determined in phase 2 whether interstitial fibrosis and tubular atrophy
15
16
Fo
17 7 should be considered separately or combined into one parameter (as in the Oxford
18
19 8 classification for IgA nephropathy) and whether making a distinction between interstitial
rP
20
21 9 inflammation in areas with or without interstitial fibrosis has clinical significance.
22
23
ee
24 10 Vascular lesions
25
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27 11 Currently, the ISN/RPS lupus classification does not evaluate vascular lesions. We believe it is
28
29
ev
30 12 important to have a standardized approach and terminology to distinguish ordinary

31
32 13 arterial/arteriolar sclerosis from lupus-related lesions such as vasculopathy associated with
iew
33
34 14 immune complex deposition, vasculitis, and TMA. In phase 2, a grading system for vascular
35
36
37 15 lesions could be used following the Banff classification, and the definitions of the Cure GN
On
38
39 16 group for evaluating hyalinosis. Definitions for TMA and vasculitis in lupus nephritis still have
40
41 17 to be created, as they can occur in an isolated manner with or without associated specific
ly
42
43
18 serologic findings (ANCA, APA, etc.) or coexist with immune complex-mediated lupus
44
45
46 19 glomerular lesions. We propose that lupus vasculopathy be defined as luminal narrowing of
47
48 20 arterioles or terminal interlobular arteries by intramural immune deposits, typically admixed
49
50 21 with fibrinoid changes, without inflammation of the vessel wall. The immunoglobulin and
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53 22 complement composition of the deposits is confirmed by IF.14-16 Future studies will
54
55 23 determine any impact of such lesions on prognosis and response to treatment.
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58 17
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1
2
3 1 Summary and Future Directions
4
5
6 2 In our efforts to work towards a more effective, more reproducible and more valuable
7
8 3 classification for lupus nephritis, we have proposed improvements in the definitions of lupus
9
10
11
4 nephritis lesions, which could impact treatment and prognosis. We have also proposed two
12
13 5 important alterations in the classification system, namely to abandon the segmental/global
14
15 6 designations in class IV, and to replace the A/C/AC designations of class III and IV by use of
16
Fo
17
7 modified NIH lupus nephritis activity and chronicity scoring indices. Our proposed
18
19
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20 8 modifications are based on published evidence, expert experience and mutual agreement;
21
22 9 we regard this as a phase 1 venture. The new definitions for lesions in lupus nephritis and
23
ee
24 10 the modifications to the classification system address some of the disagreement that
25
26
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27 11 currently exists among nephropathologists world-wide in classifying lupus nephritis

28
29 12 according to the ISN/RPS lupus nephritis classification.
ev
30
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32 13 We would like to emphasize that many of the proposed changes involve descriptions of
iew
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34 14 lesions that in other settings, such as the Oxford classification of IgA nephropathy, have
35
36
37 15 proved challenging even for experienced pathologists to reliably reproduce. We will proceed
On
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39 16 to a phase 2 evidence-based approach using clinicopathologic studies and tests of inter-
40
41 17 observer reproducibility to evaluate and validate the value of the newly proposed definitions
ly
42
43
18 and adjustments to the classification system and include tubulointerstitial and vascular
44
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46 19 lesions. This will entail a process similar to that used to develop the Oxford classification for
47
48 20 IgA nephropathy, i.e. scoring of individual lesions by multiple pathologists in lupus nephritis
49
50 21 biopsies obtained from patients for whom clinical outcomes are available. Once these data
51
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53 22 become available, it will be possible to modify the currently used cut-off points to optimize
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58 18
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1
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3 1 the classes of lupus nephritis and to develop and validate reproducible activity and
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5 2 chronicity indices that are of clinical utility.
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3 1 References
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5 2 1. Wilhelmus S, Alpers CE, Cook HT, Ferrario F, Fogo AB, Haas M, Joh K, Noël LH, Seshan SV, Bruijn JA,
6 3 Bajema IM: The Revisited Classification of GN in SLE at 10 Years: Time to Re-Evaluate Histopathologic
7 4 Lesions. J Am Soc Nephrol 26: 2938-2946, 2015
8
9 5 2. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society,
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6 Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J,
11
12 7 Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator S, Emma F, Ferrario F, Fervenza
13 8 FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI,
14 9 Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B,
15 10 Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H: The Oxford
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11 classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney
18 12 Int 76: 534-545, 2009
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20 13 3. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society,
21 14 Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA,
22 15 Cattran DC, Coppo R, D'Agati V, D'Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza
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16 FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI,
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25 17 Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S,
26 18 Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H: The Oxford
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27 19 classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int
28 20 76: 546-556, 2009
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30 21 4. Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, Liu ZH, Roberts IS, Yuzawa Y, Zhang
31
22 H, Feehally J: Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy
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33 23 Classification Working Group. Kidney Int 91:1014-1021, 2017

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35 24 5. Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD,
36 25 Waldherr R, Bruijn JA, Bajema IM: Histopathologic classification of ANCA-associated
37 26 glomerulonephritis. J Am Soc Nephrol 21: 1628-1636, 2010
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39 27 6. Barisoni L, Troost J, Nast C, Bagnasco S, Avila-Casado C, Hodgin J, Palmer M, Rosenberg A, Gasim A,
40 28 Liensziewski C, Merlino L, Chang A, Meehan S, Gaut J, Song P, Holzman L, Gibson D, Kretzler M,
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29 Gillespie B, Hewitt S: Reproducibility of the NEPTUNE descriptor-based scoring system on whole slide
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43 30 images and histologic and ultrastructural digital images. Modern Pathol 29: 671-684, 2016
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45 31 7. NIH/NIDDK Cure Glomerulonephropathy Network (CureGN) Pathology Scoring System Definitions,
46 32 provided by JC Jennette, CureGN Core Scoring Committeee Chair.
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48 33 8. Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin
49 34 E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW,
50 35 Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant
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36 M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A,
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53 37 Mengel M: The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and
54 38 Prospects for Adopting Molecular Pathology. Am J Transplant 17: 28-41, 2017
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3 1 9. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T,
4 2 Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M,
5 3 Looi LM, Makino H, Moura LA, Nagata M: The classification of glomerulonephritis in systemic lupus
6
4 erythematosus revisited. J Am SocNephrol 15: 241-250, 2004
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5 10. Wilhelmus S, Cook HT, Noël LH, Ferrario F, Wolterbeek R, Bruijn JA, Bajema IM: Interobserver
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10 6 agreement on histopathological lesions in class III or IV lupus nephritis. Clin J Am Soc Nephrol 10: 47-
11 7 53, 2015
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13 8 11. Haring CM, Rietveld A, vanden Brand JA, Berden JH: Segmental and global subclasses of class IV
14 9 lupus nephritis have similar renal outcomes. J Am Soc Nephrol 15: 241-250, 2004
15
16 10 12. Nasr SH, D'Agati VD, Park HR, Sterman PL, Goyzueta JD, Dressler RM, Hazlett SM, Pursell RN,
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17 11 Caputo C, Markowitz GS: Necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic
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12 antibody seropositivity. Clin J Am Soc Nephrol 3: 682-690, 2008
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13 13. Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE: Diffuse proliferative lupus
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22 14 nephritis: Identification of specific pathologic features affecting renal outcome. Kidney Int 25: 689–
23 15 695, 1984
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25 16 14. Bhathena DB, Sobel BJ, Migdal SD: Noninflammatory renal microangiopathy of systemic lupus
26
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17 erythematosus ('lupus vasculitis'). Am J Nephrol 1: 144-159, 1981

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28 18 15. Appel GB, Pirani CL, D'Agati V: Renal vascular complications of systemic lupus erythematosus. J
29 19 Am Soc Nephrol 4: 1499-1515, 1994
ev
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31 20 16. Wu LH, Yu F, Tan Y, Qu Z, Chen MH, Wang SX, Liu G, Zhao MH: Inclusion of renal vascular lesions
32
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21 in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions.
33
34 22 Kidney Int 83: 715-723, 2013
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36 23
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3 1 ACKNOWLEDGMENTS
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5 2 Boehringer Ingelheim gave financial support (Contract No.: 43074068) for the organization
6 3 of the meeting of this Workgroup in Leiden, the Netherlands, May 2016.
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29 Figure 1 as TIFF file
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30 Legend: Drawings depicting the ultrastructural features of a single glomerular capillary affected by lupus
31 glomerulonephritis: Class I with mesangial immune deposits (black) but no mesangial cell (red)
32 hypercellularity or influx of leukocytes; Class II with mesangial immune deposits and mesangial cell
iew
33 hypercellularity but no influx of leukocytes; and Class III/IV (upper right) with mesangial and capillary influx
of leukocytes; Class III/IV (lower right) with subendothelial capillary wall immune deposits that can be seen
34
by LM and mesangial but no capillary influx of leukocytes (dark green neutrophils and light green
35 monocytes/macrophages); Class III/IV + V with influx of leukocytes and numerous subepithelial immune
36 deposits in addition to subendothelial deposits; and Class V with numerous subepithelial immune deposits
37 but no influx of leukocytes (podocyte = outer green cell, endothelial cell = yellow cell, mesangial cell = red
On
38 cell, neutrophil = green cell with segmented nucleus, monocyte/macrophage = light green cell)
39
216x149mm (120 x 120 DPI)
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2 Category Recommendation Comments on ISN/RPS guidelines
3
4 Class II Definition for mesangial hypercellularity adjusted: Cuttoff for mesangial hypercellularity unclear
Four or more nuclei fully surrounded by matrix in
5 the mesangial area not including the hilar region (A)
6
Class III and IV The term endocapillary proliferation is replaced by Definition for endocapillary proliferation unclear;
7 endocapillary hypercellularity (B) the term proliferation was considered imprecise
8
Fo
The term crescent is used for a lesion consisting of Extracapillary proliferation involving < 25% of the circumference
9 extracapillary hypercellularity, composed of a variable mixture of Bowman's capsule was original cutoff. There were no
10 of cells. Fibrin and fibrous matrix may be present; 10% or more definitions for fibrous or fibrocellular crescents
of the circumference of Bowman's capsule should be involved.
11
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12 Cellular crescent: more than 75% cells and fibrin
13 and less than 25% fibrous matrix (C)
ee
14 Fibrous crescent: more than 75% fibrous matrix
15 and less than 25% cells and fibrin (D)
16
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Fibrocellular crescent: 25-75% cells and fibrin
17 and the remainder fibrous matrix (E)
18 Adhesion: an area of isolated continuity of extracellular matrix There was no definition for an adhesion
ev
19 material between the tuft and capsule even when the underlying
segment does not have overt sclerosis (F)
20
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21 Fibrinoid necrosis: fibrin associated with glomerular basement membrane There was no definition for fibrinoid necrosis
disruption and/or lysis of the mesangial matrix; this lesion does not
22 require the presence of karyorrhexis
23
Elimination of segmental and global subdivions of class IV Definitions for segmental and global were unclear;
24 interobserver variability was large; clinical significance uncertain
On
25
Modification of the NIH lupus nephritis activity and chronicity scoring Designation of activity/chronicity through A, C and A/C
26 system (Table 2) to be used instead of the currently used A, C considered too broad and nonspecific; preference for a
27 and A/C parameters semiquantitative approach to describe active and chronic lesions
ly
28 Tubulointerstitial lesions Indicate whether interstitial inflammation occurs in presence or Lack of cut-off values for reporting the severity of
29 absence of interstitial fibrosis tubulointerstitial lesions
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Kidney International

Revision of the ISN/RPS classification for lupus nephritis:

Journal: Kidney International

Article Type: Meeting Report

Date Submitted by the Author: 13-Nov-2017

Wilhelmus, Suzanne; Leiden University Medical Center, Pathology

Cook, Terence; Imperial College London, Medicine

Fogo, Agnes; Vanderbilt University, Pathology

Keywords: systemic lupus erythematosus, renal pathology

Subject Area: Renal Pathology

The International Society of Nephrology (http://www.isn-online.org/site/cms)

27 22 Hill, Chapel Hill, NC, USA

38 16 applications of the proposed definitions and to classify lupus nephritis lesions.

33 14 definitions by class. Glomerular, tubulointerstitial and vascular lesions are discussed

42 18 ISN/RPS lesion definitions and classification9 that we propose is found in Table 1.

10 the mesangial area not including the hilar region (A)

28 Modification of the NIH lupus nephritis activity and chronicity scoring

27 11 approach to define an appropriate threshold was judged to be necessary. Whether and to

27 11 that this should be named mesangial hyperplasia in lesions purely consisting of an

38 or >50 (3+) of glomeruli.

27 11 pattern of arterionephrosclerosis, e.g. subcapsular clusters of glomeruli with ischemic tuft

30 12 important to have a standardized approach and terminology to distinguish ordinary

27 11 currently exists among nephropathologists world-wide in classifying lupus nephritis

33 23 Classification Working Group. Kidney Int 91:1014-1021, 2017

17 erythematosus ('lupus vasculitis'). Am J Nephrol 1: 144-159, 1981

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