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Revision of the ISN/RPS classification for lupus nephritis:
modified NIH activity and chronicity indices and clarification
of definitions
Journal: Kidney International
Manuscript ID KI-08-17-1259.R1
Article Type: Meeting Report
Date Submitted by the Author: 13-Nov-2017
Complete List of Authors: Bajema, Ingeborg; Leiden University Medical Center, Department of Pathology Wilhelmus, Suzanne; Leiden University Medical Center, Pathology Alpers, Charles Bruijn, Jan Colvin, Robert; Mass Gen Hosp, Pathology Cook, Terence; Imperial College London, Medicine D'Agati, Vivette; Columbia University, Pathology Ferrario, Franco; University of Milano-Bicocca, Surgery and Translational 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 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 Fogo, Agnes; Vanderbilt University, Pathology
Keywords: systemic lupus erythematosus, renal pathology
Subject Area: Renal Pathology
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Revision of the ISN/RPS classification for lupus nephritis: 1
clarification of definitions, and modified NIH activity and chronicity 2
indices 3
4
Ingeborg M. Bajema1, Suzanne Wilhelmus
1, Charles E. Alpers
2, Jan A. Bruijn
1, Robert B. 5
Colvin3, H. Terence Cook
4, Vivette D. D’Agati
5, Franco Ferrario
6, Mark Haas
7, J. Charles 6
Jennette8, Kensuke Joh
9, Cynthia C. Nast
7, Laure-Hélène Noël
10, Emilie C. Rijnink
1, Ian S.D. 7
Roberts11
, Surya V. Seshan12
, Sanjeev Sethi13
, Agnes B. Fogo14
8
Affiliations: see page 2 9
10
11
Corresponding author 12
Ingeborg M. Bajema, MD PhD 13
Department of Pathology, Leiden University Medical Center 14
PO Box 9600 15
2300 RC Leiden 16
The Netherlands 17
Telephone number: +31 71 526 6621 18
Fax number: + 31 71 526 6952 19
21
22
Running title: revision of lupus nephritis classification 23
Key words: lupus nephritis, renal biopsy, systemic lupus erythematosus 24
Word count abstract: 197 25
Word count text (excluding references, figures and tables): 3616 26
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Affiliations: 1
2 1Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands 3
4 2Department of Pathology, University of Washington, Seattle, WA, USA 5
6 3Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston 7
MA 02114, USA 8
9 4Department of Medicine, Imperial College, London, UK 10
11 5Department of Pathology and Cell Biology, Columbia University Medical Center, New York, 12
New York, USA 13
14 6Nephropathology Center, San Gerardo Hospital-Monza, Milan Bicocca University, Milan, 15
Italy 16
17 7Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los 18
Angeles, California USA 19
20 8Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel 21
Hill, Chapel Hill, NC, USA 22
23 9Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan 24
25 10
Department of Pathology, Necker Hospital, Paris, France 26
27 11
Department of Cellular Pathology, Oxford University Hospitals, Oxford, UK 28
29 12
Department of Pathology and laboratory Medicine, Weill Cornell University Medical 30
Center, New York, New York, USA 31
32 13
Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA 33
34 14
Dept. of Pathology, Vanderbilt University School of Medicine, MCN, USA 35
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ABSTRACT 1
We present a consensus report pertaining to the improved clarity of definitions and 2
classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 3
members from an international nephropathology working group in Leiden, 2016. Here we 4
report detailed recommendations on issues for which we can propose adjustments based on 5
existing evidence and current consensus opinion (phase 1). New definitions are provided for 6
mesangial hypercellularity and for cellular, fibrocellular and fibrous crescents. The term 7
endocapillary proliferation is eliminated and the definition of endocapillary hypercellularity 8
considered in some detail. We also eliminate the Class IV-S and IV-G subdivisions of Class IV 9
lupus nephritis. The active/chronic (A/C) designations for Class III/IV lesions are replaced by 10
a proposal for activity and chronicity indices which should be applied to all classes. In the 11
activity index, we include fibrinoid necrosis as a specific descriptor. We also make 12
recommendations on issues for which there are limited data at present, and that can best be 13
addressed in future studies (phase 2). We propose to proceed to these investigations, with 14
clinicopathologic studies and tests of inter-observer reproducibility to evaluate the 15
applications of the proposed definitions and to classify lupus nephritis lesions. 16
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On May 9-11th 2016, a Working Group for Lupus Nephritis Classification (the Group) met at 1
Leiden University Medical Center to reach a consensus on recently raised issues concerning 2
problems with definitions of lupus nephritis lesions.1 Prior to the meeting, those attending 3
received a questionnaire asking for anonymous suggestions for improving the definitions. 4
The responses served as a starting point for making adjustments to the definitions of lupus 5
nephritis lesions, a process that was further accomplished by group discussions and a multi-6
head microscopy session. The Group decided that consensus had to be reached for any 7
proposed changes and that recommendations should be divided in two types: Phase 1 8
recommendations are clarifying modifications for which we could propose adjustments 9
based on existing published evidence and mutual agreement. Phase 2 recommendations will 10
address issues that can best be validated or modified through an evidence-based process. 11
These include more problematic lesion definitions and adjustments to the lupus nephritis 12
classification. We now report on phase 1 recommendations, and provide a framework for 13
phase 2 issues. 14
Our immediate aim is to improve problematic definitions that form the basis of the 15
lupus nephritis classification and thereby increase the interobserver agreement between 16
nephropathologists worldwide who apply these definitions to classify lupus nephritis. Our 17
eventual goal is to improve the lupus nephritis classification using an evidence-based 18
approach, but refining the definitions for lesions is necessary because they form the 19
essential elements for the classification. Here we describe a plan to proceed in the near 20
future to gather data and, as indicated, modify the lupus nephritis classification. 21
Many renal lesions encountered in lupus nephritis also are present in other renal 22
diseases, providing a rationale for harmonizing definitions for lesions irrespective of the 23
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disease context. Depending on the setting, i.e. evaluation of renal biopsies in a clinical 1
setting or for research purposes, different guidelines may apply regarding biopsy 2
requirements. In a clinical setting, it is necessary to obtain as much information as possible 3
from the biopsy by evaluating all stains in all levels and sections and to apply a basic format 4
of the kidney biopsy report. As a general rule, 10 glomeruli for evaluation seem to be 5
appropriate. By studying definitions of frequently occurring lesions as currently formulated 6
(e.g., as in classification systems for IgA nephropathy2-4
and ANCA-associated 7
glomerulonephritis,5 as well as definitions created by the Neptune,
6 CureGN
7 and Banff
8 8
workgroups), we strove for uniform definitions but recognized that certain thresholds may 9
be different among diseases. For example, it remains to be determined (an evidence-based 10
phase 2 issue) which thresholds – for instance for mesangial hypercellularity – have clinical 11
and prognostic value in lupus nephritis, and whether these should be different from those 12
for another disease such as IgA nephropathy. Below, we discuss our modifications of 13
definitions by class. Glomerular, tubulointerstitial and vascular lesions are discussed 14
separately. At this stage, we mainly focus on lesions evaluable by light microscopy, although 15
we do take into account findings by immunofluorescence (IF) and electron microscopy (EM) 16
if they are helpful in the decision-making process. An overview of the alterations to the 17
ISN/RPS lesion definitions and classification9 that we propose is found in Table 1. 18
19
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Table 1. Phase 1 recommendations for lupus nephritis classification
1
2
Category Recommendation Comments on ISN/RPS guidelines
Class II Definition for mesangial hypercellularity adjusted: Cuttoff for mesangial hypercellularity unclear
Four or more nuclei fully surrounded by matrix in
the mesangial area not including the hilar region (A)
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
The term crescent is used for a lesion consisting of Extracapillary proliferation involving < 25% of the circumference
extracapillary hypercellularity, composed of a variable mixture of Bowman's capsule was original cutoff. There were no
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.
Cellular crescent: more than 75% cells and fibrin
and less than 25% fibrous matrix (C)
Fibrous crescent: more than 75% fibrous matrix
and less than 25% cells and fibrin (D)
Fibrocellular crescent: 25-75% cells and fibrin
and the remainder fibrous matrix (E)
Adhesion: an area of isolated continuity of extracellular matrix There was no definition for an adhesion
material between the tuft and capsule even when the underlying
segment does not have overt sclerosis (F)
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
require the presence of karyorrhexis
Elimination of segmental and global subdivions of class IV Definitions for segmental and global were unclear;
interobserver variability was large; clinical significance uncertain
Modification of the NIH lupus nephritis activity and chronicity scoring Designation of activity/chronicity through A, C and A/C
system (Table 2) to be used instead of the currently used A, C considered too broad and nonspecific; preference for a
and A/C parameters semiquantitative approach to describe active and chronic lesions
Tubulointerstitial lesions Indicate whether interstitial inflammation occurs in presence or Lack of cut-off values for reporting the severity of
absence of interstitial fibrosis tubulointerstitial lesions
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Glomerular lesions, Class I – VI: 1
Class I and II 2
An important question was the threshold between class I and class II. We questioned 3
whether the current cutoff for mesangial hypercellularity implies that hypercellularity in 4
merely one mesangial area in one glomerulus in the entire biopsy would suffice. We agreed 5
that mesangial hypercellularity in one area in one glomerulus seems rather low. The 6
appropriate threshold will be investigated in phase 2. In the meantime, we propose 7
increasing the threshold of mesangial hypercellularity from 3 cells/mesangial area to 4 cells, 8
not including the hilar region, in line with the Oxford classification of IgA nephropathy2-4
and 9
specify that mesangial cell nuclei be fully surrounded by matrix. An evidence-based 10
approach to define an appropriate threshold was judged to be necessary. Whether and to 11
what extent mesangial matrix expansion should be incorporated in the definition together 12
with this cell number cut-off level, also needs to be investigated in an evidence-based 13
approach. Of note, only peripheral mesangial areas should be assessed for cellularity, with 14
central and perihilar areas excluded, as described for IgA nephropathy. Importantly, we 15
discussed whether or not hypercellularity within the mesangial zone caused by 16
monocytes/macrophages, lymphocytes, or neutrophils should be considered as mesangial 17
hypercellularity or as endocapillary hypercellularity. This topic will be discussed in more 18
detail below. 19
Class III and IV 20
A substantial amount of discussion centered on Class III and IV lesions. We agreed, as 21
previously noted, that the definitions of endocapillary ‘’proliferation’’ are unclear and 22
inconsistent,1 with issues raised about the types and numbers of cells involved in 23
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endocapillary lesions, the definition of lumen reduction, and the specific contribution of 1
endothelial cells. The Group decided that the term ‘’endocapillary proliferation’’ is a 2
misnomer, which should be abandoned and replaced by the term “endocapillary 3
hypercellularity” because most of the hypercellularity in glomerular capillaries in lupus 4
nephritis is caused by influx of inflammatory cells rather than by actual cell proliferation. 5
Phase 2 will address if there should be, for instance, an overall glomerular inflammation 6
score. 7
Endocapillary Hypercellularity 8
Hypercellularity in lupus nephritis may be due to increase in cells in mesangial, endocapillary 9
and/or extracapillary locations. With regard to mesangial hypercellularity, it could be argued 10
that this should be named mesangial hyperplasia in lesions purely consisting of an 11
abundance of mesangial cells (Figure 1), representing lupus nephritis class II lesions. It is 12
unknown if the presence of inflammatory cells in the mesangium indicates a more active 13
lesion; the cut-off values for mesangial hypercellularity and significance of mesangial 14
inflammation remain to be determined in phase 2. Likewise, the cut-off levels for number of 15
inflammatory cells, extent of capillary luminal narrowing and role of endothelial cell swelling 16
need to be defined in a phase 2 exercise. Figure 1 shows ultrastructural features of a single 17
glomerular capillary affected by lupus glomerulonephritis. Inflammatory cells can be in the 18
capillary lumen, beneath endothelial cells in capillary walls, and in the mesangial 19
extracellular compartment. It has to be decided in phase 2 whether endocapillary 20
hypercellularity should encompass all glomerular hypercellularity internal to the capillary 21
wall glomerular basement membrane (GBM) and paramesangial GBM (excluding pure 22
mesangial hyperplasia), or whether it should be restricted to an increase of cells within 23
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capillary lumens. Endothelial cell swelling alone was considered insufficient for a lesion to be 1
regarded as representing endocapillary hypercellularity. If endothelial cell swelling is 2
encountered in the absence of inflammatory cells, TMA should be considered, taking into 3
account the number and extent of swollen endothelial cells and whether or not this is 4
accompanied by subendothelial expansion or thrombosis. Relevant thresholds for this 5
situation should be defined more precisely in phase 2. Hypercellularity external to the GBM 6
is extracapillary hypercellularity. 7
Membranoproliferative glomerulonephritis (MPGN) pattern 8
We discussed the value of using the term ‘MPGN pattern’ in relation to the modifications of 9
definitions for lesions within class III and IV lupus nephritis. The group concluded that an 10
MPGN pattern of injury is subsumed in class III/IV lupus nephritis as a form of endocapillary 11
injury. We agreed with the ISN/RPS approach of considering subendothelial deposits that 12
can be seen by light microscopy (i.e. wire loops) and hyaline masses within capillary lumens 13
caused by immune complexes (i.e. hyaline thrombi) as lesions indicative of class III/IV. 14
Determination of the clinical significance of the MPGN pattern and whether or not acute and 15
chronic variants should be distinguished, is a phase 2 exercise. 16
Crescents 17
The term crescent is used for a lesion consisting of extracapillary hypercellularity, composed 18
of a variable mixture of cells. Because some crescents may have predominantly epithelial 19
proliferation, whereas others consist predominantly of monocytes/macrophages, the Group 20
chose the description of a ‘variable mixture of cells’. Fibrin and fibrous matrix may also be 21
present. The ISN/RPS criterion of a crescent involving 25% or more of the glomerular 22
capsular circumference was discussed. It was decided that this threshold should be 10% or 23
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more in accord with evidence from the Oxford Classification of IgA nephropathy and 1
standard approaches used in clinical reporting of renal biopsy lesions. Crescents should be 2
composed of more than 2 cell layers in order to distinguish them from apposition of the 3
single layers of hypertrophied visceral and parietal cells. We propose definitions for the 4
distinction of cellular, fibrous and fibrocellular crescents, which were lacking in the ISN/RPS 5
lupus nephritis classification (Table 1). Some glomeruli may have more than one type of 6
crescent. In line with conventional nephropathology practice, extracapillary hypercellularity 7
attributable to concurrent collapsing glomerulopathy lesions should not be designated as 8
crescents. We propose to preserve the term ‘adhesion’ for a lesion characterized by an area 9
of isolated continuity of extracellular matrix material between the tuft and capsule even 10
when the underlying segment does not have overt sclerosis. This is a lesion that is distinct 11
from both crescents and segmental sclerosis, although this differs from the Oxford 12
classification of IgA nephropathy in which such lesions are considered manifestations of 13
segmental sclerosis. How to deal with a lesion characterized by cellular continuity between 14
the tuft and Bowman’s capsule, which is not extensive enough to be called a crescent, needs 15
to be further discussed based on evidence acquired in phase 2. 16
Global/segmental 17
We previously discussed problematic issues concerning the distinction between segmental 18
and global lesions in class III and IV.10
As recently demonstrated in a meta-analysis by Haring 19
et al,11
the clinical importance of distinguishing between segmental and global lesions in 20
class IV as defined by the ISN/RPS Classification System has been questioned. A caveat is that 21
there is poor interobserver agreement among nephropathologists worldwide in determining 22
whether a glomerular lesion in lupus nephritis is segmental or global.10
The latter, in 23
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combination with the uncertainty of how to evaluate the combination of intra- and 1
extracapillary lesions into a segmental/global division, may have added greatly to the 2
variability in outcomes of studies addressing the clinical impact of segmental and global 3
lesions. The ISN/RPS approach to subclassifying class IV did not use segmental necrosis as a 4
defining feature of a segmental variant of lupus nephritis, which may have reduced 5
reproducibility and precluded recognition of a pathophysiologically distinct variant of lupus 6
nephritis. Therefore, for phase 1, based on the lack of reproducibility and weak evidence of 7
clinical significance, we propose to eliminate the S and G subdivisions of Class IV. We believe 8
that the distinction between segmental and global lesions should be retained in the 9
microscopic description, as such distinctions still may prove to have clinical value with 10
further study using the modified classification of lupus nephritis. As noted below, segmental 11
fibrinoid necrosis as well as segmental endocapillary hypercellularity will be evaluated. 12
Fibrinoid Necrosis 13
It was emphasized during the meeting that another potentially important feature not taken 14
into consideration in the ISN/RPS identification of segmental lesions is the occurrence in 15
lupus nephritis of fibrinoid necrosis. This is usually segmental and resembles lesions caused 16
by anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Conceptually, 17
segmental endocapillary lesions may be merely a distribution variant of global endocapillary 18
hypercellularity caused by the same pathogenic mechanisms, whereas segmental fibrinoid 19
necrosis may be a pathogenetically distinct lesion. Therefore, for classes III and IV, we 20
recommend noting the presence of fibrinoid necrosis. In phase 1, we propose to adjust the 21
definition for fibrinoid necrosis in lupus nephritis as follows: fibrin associated with GBM 22
disruption and/or lysis of the mesangial matrix; this lesion does not require the presence of 23
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karyorrhexis. Furthermore, karyorrhexis is defined as the presence of apoptotic, pyknotic 1
and fragmented nuclei – a definition used uniformly in other classification systems. In phase 2
2, we propose that the clinical significance of fibrinoid necrosis should be reevaluated in 3
addition to assessing the coexistence of necrotizing lesions with crescents. Whether these 4
lesions have “pauci-immune” features by IF and/or co-existent ANCA serology12
requires 5
further study. The Group concluded that phase 2 studies should determine and compare the 6
clinical and pathogenic significance of karyorrhexis alone, which is common in class III and IV 7
lupus nephritis, versus fibrinoid necrosis, which is less common. 8
Activity and Chronicity Assessment 9
For a critical re-evaluation of activity and chronicity, we turned to the paper by Austin et al13
10
on which the currently widely used NIH activity and chronicity index in lupus nephritis was 11
based. This system can be used to report the extent of overall activity and chronicity in a 12
semiquantitative way. It should be emphasized that this system has a number of limitations: 13
the cut-offs for the scores 0-3 are arbitrary and the scoring system was not developed using 14
an evidence- based approach. Therefore, in phase 2, we will use an evidence- based 15
approach without prior assumptions to modify these indices. We propose in phase 2 that the 16
evaluation for active and chronic lesions in lupus nephritis should be refined to improve 17
interobserver reproducibility and to validate prognostic value. In the meantime, we advocate 18
the usage of these indices, but modified as indicated below, for all classes in a modified 19
classification for lupus nephritis, thereby not restricting them to class III and IV. The modified 20
NIH activity and chronicity scoring system provides more information than the shorthand A, 21
C and A/C parameters currently used. We decided it is important to retain total scores of 24 22
in the activity index and 12 in the chronicity index, in particular for comparing the scores 23
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recorded for earlier renal biopsy samples from the same patient using the original NIH 1
scoring system. We therefore continue to accord double weight to the presence of fibrinoid 2
necrosis and cellular/fibrocellular crescents; results from our phase 2 study will be used to 3
find out whether this approach is valid. 4
In the modified NIH activity index, we have made the following modifications: 5
because in the original description of the combined karyorrhexis/fibrinoid necrosis category, 6
the emphasis was on the presence of fibrinoid necrosis,13
we now have modified this into a 7
stand-alone category of fibrinoid necrosis whereas we link the presence of karyorrhexis to 8
neutrophil infiltration. Because most karyorrhexis represents apoptotic cell death of 9
neutrophils, and because the original description for ‘leukocyte infiltration’ refers to the 10
presence of neutrophils only, we have changed the name and description of this category to 11
indicate the presence of neutrophils and/or karyorrhexis. In the original description of the 12
category ‘cellular crescents’, it was unclear to what extent fibrocellular crescents should be 13
included. Whereas fibrous crescents are part of the chronicity Index, we have now included 14
fibrocellular crescents in the activity index (see our proposal for definitions in Table 1). We 15
refer to our considerations about the definition for endocapillary hypercellularity above: in 16
the original description of Austin et al,13
only monocytes were taken into account in this 17
category with respect to inflammatory cells leading to hypercellularity. We have to 18
investigate in phase 2 how to approach the presence of inflammatory cells in endocapillary 19
hypercellularity in more detail. For the moment, we find it important to specifically score 20
neutrophils as a separate entity. Also the composition of the interstitial infiltrate as well as 21
its presence in areas affected by interstitial fibrosis and tubular atrophy (IFTA) should be 22
studied in further detail in phase 2. 23
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Table 2. Modified NIH lupus nephritis activity and chronicity scoring system proposal 1
Modified NIH Activity Index Definition Score
Endocapillary Hypercellularity Endocapillary hypercellularity in <25% (1+), 25-50% (2+), or
>50 (3+) of glomeruli.
0-3
Neutrophils/Karyorrhexis
Neutrophils and/or karyorrhexis in <25% (1+), 25-50% (2+), or
>50 (3+) of glomeruli.
0-3
Fibrinoid Necrosis FFibrinoid necrosis in <25% (1+), 25-50% (2+), or >50 (3+) of
glomeruli.
(0-3) x 2
Hyaline Deposits Wire loop lesions and/or hyaline thrombi in <25% (1+), 25-50%
(2+), or >50 (3+) of glomeruli.
0-3
Cellular/Fibrocellular Crescents Cellular and/or fibrocellular crescents in <25% (1+), 25-50%
(2+), or >50 (3+) of glomeruli.
(0-3) x 2
Interstitial Inflammation Interstitial leukocytes in <25% (1+), 25-50% (2+), or >50 (3+) in
the cortex.
0-3
Total 0-24
Modified NIH Chronicity Index Definition Score
Total Glomerulosclerosis Score Global and/or segmental sclerosis in <25% (1+), 25-50% (2+),
or >50 (3+) of glomeruli.
0-3
Fibrous Crescents Fibrous crescents in <25% (1+), 25-50% (2+), or >50 (3+) of
glomeruli.
0-3
Tubular Atrophy Tubular atrophy in <25% (1+), 25-50% (2+), or >50 (3+) of the
cortical tubules.
0-3
Interstitial Fibrosis Interstitial fibrosis in <25% (1+), 25-50% (2+), or >50 (3+) in the
cortex.
0-3
Total 0-12
2
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Global and segmental glomerulosclerosis 1
We previously mentioned difficulties in the attribution of global glomerulosclerosis to either 2
lupus nephritis or another cause,1 an issue related to the classification of lesions into class 3
III/IV, which requires deciding if global sclerosis is the sequel of an active class III/IV lesion. It 4
was discussed that some globally sclerotic glomeruli show features that indicate lupus 5
nephritis was the cause of the global sclerosis, for example fragmented tuft with 6
surrounding fibrosis, and extensive disruption of Bowman’s capsule. Moreover, residual 7
deposits other than IgM and C3 found by IF in globally sclerotic glomeruli should also be 8
considered evidence that the lesion is the result of lupus nephritis. Globally sclerotic 9
glomeruli should not be considered in the evaluation of lupus chronicity if they have a typical 10
pattern of arterionephrosclerosis, e.g. subcapsular clusters of glomeruli with ischemic tuft 11
collapse surrounded by collagen in Bowman’s space. Incorporating globally sclerotic 12
glomeruli that resulted from non-lupus injury in a chronicity index would overestimate the 13
lupus nephritis chronicity and severity, but still may correlate with outcome. This issue 14
should be addressed by phase 2 studies. It should be emphasized that in lupus nephritis the 15
term global sclerosis is used for those glomeruli that are completely sclerotic, and that any 16
other form of glomerulosclerosis should be regarded as segmental sclerosis. As mentioned 17
previously, it is difficult to reliably differentiate segmental sclerosis as a consequence of class 18
III/IV lupus nephritis from segmental sclerosis due to other causes (e.g., post-adaptive 19
segmental sclerosis). Still, only the former should be designated as lesions of class III/IV, 20
employing the same features noted above to differentiate segmental sclerosis due to prior 21
active lupus nephritis from that due to other causes. Within the chronicity index, segmental 22
and global glomerulosclerosis are considered together. 23
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Class V 1
Two issues were addressed in Class V. First, we considered whether or not to distinguish 2
Class V with and without mesangial hypercellularity and agreed this decision should be 3
evidence based (phase 2). Second, phase 2 studies should determine the allowable extent of 4
non-wire-loop subendothelial deposits within class V, above which one would have to 5
classify as III + V. 6
Class VI 7
We recognize that the RPS/ISN category VI is rarely seen in renal biopsy specimens, and 8
propose that this class be re-evaluated in phase 2, especially in view of our discussion above 9
on the recognizability of globally sclerotic glomeruli resulting from preceding lupus nephritis 10
active lesions versus nonspecific global sclerosis associated with other factors (e.g., aging, 11
hypertension or healed TMA lesions). Class VI will either need to be eliminated, or some 12
fraction of globally sclerotic glomeruli designated as the cut-off between chronic class IV and 13
class VI. 14
Tubulointerstitial lesions 15
We previously indicated the lack of cut-off values in the ISN/RPS classification for reporting 16
of severity of tubulointerstitial lesions.1 This deficiency will be addressed by the 17
development of a valid activity and chronicity index that scores the severity of 18
tubulointerstitial injury. We propose that in phase 2 we gather data on IFTA, and interstitial 19
infiltrates in a semi-quantitative fashion, rounding fibrosis to nearest 10%, with minimal 20
fibrosis stated as 5%. These values then can be translated into reproducible scoring 21
categories (e.g. on a scale of 0-3+) based on cut-off values to be evaluated for prognostic 22
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significance as currently done for the Banff and Oxford classifications. We advocate at this 1
time, as a phase 1 recommendation, to indicate in biopsy reports whether interstitial 2
inflammation occurs in the presence or absence of interstitial fibrosis. For the present, 3
interstitial inflammation remains part of the activity index as proposed above, while 4
interstitial fibrosis and tubular atrophy remain as separate entities within the chronicity 5
index. It has to be determined in phase 2 whether interstitial fibrosis and tubular atrophy 6
should be considered separately or combined into one parameter (as in the Oxford 7
classification for IgA nephropathy) and whether making a distinction between interstitial 8
inflammation in areas with or without interstitial fibrosis has clinical significance. 9
Vascular lesions 10
Currently, the ISN/RPS lupus classification does not evaluate vascular lesions. We believe it is 11
important to have a standardized approach and terminology to distinguish ordinary 12
arterial/arteriolar sclerosis from lupus-related lesions such as vasculopathy associated with 13
immune complex deposition, vasculitis, and TMA. In phase 2, a grading system for vascular 14
lesions could be used following the Banff classification, and the definitions of the Cure GN 15
group for evaluating hyalinosis. Definitions for TMA and vasculitis in lupus nephritis still have 16
to be created, as they can occur in an isolated manner with or without associated specific 17
serologic findings (ANCA, APA, etc.) or coexist with immune complex-mediated lupus 18
glomerular lesions. We propose that lupus vasculopathy be defined as luminal narrowing of 19
arterioles or terminal interlobular arteries by intramural immune deposits, typically admixed 20
with fibrinoid changes, without inflammation of the vessel wall. The immunoglobulin and 21
complement composition of the deposits is confirmed by IF.14-16
Future studies will 22
determine any impact of such lesions on prognosis and response to treatment. 23
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Summary and Future Directions 1
In our efforts to work towards a more effective, more reproducible and more valuable 2
classification for lupus nephritis, we have proposed improvements in the definitions of lupus 3
nephritis lesions, which could impact treatment and prognosis. We have also proposed two 4
important alterations in the classification system, namely to abandon the segmental/global 5
designations in class IV, and to replace the A/C/AC designations of class III and IV by use of 6
modified NIH lupus nephritis activity and chronicity scoring indices. Our proposed 7
modifications are based on published evidence, expert experience and mutual agreement; 8
we regard this as a phase 1 venture. The new definitions for lesions in lupus nephritis and 9
the modifications to the classification system address some of the disagreement that 10
currently exists among nephropathologists world-wide in classifying lupus nephritis 11
according to the ISN/RPS lupus nephritis classification. 12
We would like to emphasize that many of the proposed changes involve descriptions of 13
lesions that in other settings, such as the Oxford classification of IgA nephropathy, have 14
proved challenging even for experienced pathologists to reliably reproduce. We will proceed 15
to a phase 2 evidence-based approach using clinicopathologic studies and tests of inter-16
observer reproducibility to evaluate and validate the value of the newly proposed definitions 17
and adjustments to the classification system and include tubulointerstitial and vascular 18
lesions. This will entail a process similar to that used to develop the Oxford classification for 19
IgA nephropathy, i.e. scoring of individual lesions by multiple pathologists in lupus nephritis 20
biopsies obtained from patients for whom clinical outcomes are available. Once these data 21
become available, it will be possible to modify the currently used cut-off points to optimize 22
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the classes of lupus nephritis and to develop and validate reproducible activity and 1
chronicity indices that are of clinical utility. 2
3
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References 1
1. Wilhelmus S, Alpers CE, Cook HT, Ferrario F, Fogo AB, Haas M, Joh K, Noël LH, Seshan SV, Bruijn JA, 2
Bajema IM: The Revisited Classification of GN in SLE at 10 Years: Time to Re-Evaluate Histopathologic 3
Lesions. J Am Soc Nephrol 26: 2938-2946, 2015 4
2. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, 5
Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, 6
Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator S, Emma F, Ferrario F, Fervenza 7
FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, 8
Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, 9
Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H: The Oxford 10
classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney 11
Int 76: 534-545, 2009 12
3. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, 13
Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, 14
Cattran DC, Coppo R, D'Agati V, D'Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza 15
FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, 16
Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, 17
Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H: The Oxford 18
classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int 19
76: 546-556, 2009 20
4. Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, Liu ZH, Roberts IS, Yuzawa Y, Zhang 21
H, Feehally J: Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy 22
Classification Working Group. Kidney Int 91:1014-1021, 2017 23
5. Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD, 24
Waldherr R, Bruijn JA, Bajema IM: Histopathologic classification of ANCA-associated 25
glomerulonephritis. J Am Soc Nephrol 21: 1628-1636, 2010 26
6. Barisoni L, Troost J, Nast C, Bagnasco S, Avila-Casado C, Hodgin J, Palmer M, Rosenberg A, Gasim A, 27
Liensziewski C, Merlino L, Chang A, Meehan S, Gaut J, Song P, Holzman L, Gibson D, Kretzler M, 28
Gillespie B, Hewitt S: Reproducibility of the NEPTUNE descriptor-based scoring system on whole slide 29
images and histologic and ultrastructural digital images. Modern Pathol 29: 671-684, 2016 30
7. NIH/NIDDK Cure Glomerulonephropathy Network (CureGN) Pathology Scoring System Definitions, 31
provided by JC Jennette, CureGN Core Scoring Committeee Chair. 32
8. Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin 33
E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW, 34
Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant 35
M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, 36
Mengel M: The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and 37
Prospects for Adopting Molecular Pathology. Am J Transplant 17: 28-41, 2017 38
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9. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, 1
Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, 2
Looi LM, Makino H, Moura LA, Nagata M: The classification of glomerulonephritis in systemic lupus 3
erythematosus revisited. J Am SocNephrol 15: 241-250, 2004 4
10. Wilhelmus S, Cook HT, Noël LH, Ferrario F, Wolterbeek R, Bruijn JA, Bajema IM: Interobserver 5
agreement on histopathological lesions in class III or IV lupus nephritis. Clin J Am Soc Nephrol 10: 47-6
53, 2015 7
11. Haring CM, Rietveld A, vanden Brand JA, Berden JH: Segmental and global subclasses of class IV 8
lupus nephritis have similar renal outcomes. J Am Soc Nephrol 15: 241-250, 2004 9
12. Nasr SH, D'Agati VD, Park HR, Sterman PL, Goyzueta JD, Dressler RM, Hazlett SM, Pursell RN, 10
Caputo C, Markowitz GS: Necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic 11
antibody seropositivity. Clin J Am Soc Nephrol 3: 682-690, 2008 12
13. Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE: Diffuse proliferative lupus 13
nephritis: Identification of specific pathologic features affecting renal outcome. Kidney Int 25: 689–14
695, 1984 15
14. Bhathena DB, Sobel BJ, Migdal SD: Noninflammatory renal microangiopathy of systemic lupus 16
erythematosus ('lupus vasculitis'). Am J Nephrol 1: 144-159, 1981 17
15. Appel GB, Pirani CL, D'Agati V: Renal vascular complications of systemic lupus erythematosus. J 18
Am Soc Nephrol 4: 1499-1515, 1994 19
16. Wu LH, Yu F, Tan Y, Qu Z, Chen MH, Wang SX, Liu G, Zhao MH: Inclusion of renal vascular lesions 20
in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions. 21
Kidney Int 83: 715-723, 2013 22
23
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ACKNOWLEDGMENTS 1
Boehringer Ingelheim gave financial support (Contract No.: 43074068) for the organization 2
of the meeting of this Workgroup in Leiden, the Netherlands, May 2016. 3
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Figure 1 as TIFF file Legend: Drawings depicting the ultrastructural features of a single glomerular capillary affected by lupus
glomerulonephritis: Class I with mesangial immune deposits (black) but no mesangial cell (red)
hypercellularity or influx of leukocytes; Class II with mesangial immune deposits and mesangial cell 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
by LM and mesangial but no capillary influx of leukocytes (dark green neutrophils and light green monocytes/macrophages); Class III/IV + V with influx of leukocytes and numerous subepithelial immune deposits in addition to subendothelial deposits; and Class V with numerous subepithelial immune deposits but no influx of leukocytes (podocyte = outer green cell, endothelial cell = yellow cell, mesangial cell = red
cell, neutrophil = green cell with segmented nucleus, monocyte/macrophage = light green cell)
216x149mm (120 x 120 DPI)
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Category Recommendation Comments on ISN/RPS guidelines
Class II Definition for mesangial hypercellularity adjusted: Cuttoff for mesangial hypercellularity unclear
Four or more nuclei fully surrounded by matrix in
the mesangial area not including the hilar region (A)
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
The term crescent is used for a lesion consisting of Extracapillary proliferation involving < 25% of the circumference
extracapillary hypercellularity, composed of a variable mixture of Bowman's capsule was original cutoff. There were no
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.
Cellular crescent: more than 75% cells and fibrin
and less than 25% fibrous matrix (C)
Fibrous crescent: more than 75% fibrous matrix
and less than 25% cells and fibrin (D)
Fibrocellular crescent: 25-75% cells and fibrin
and the remainder fibrous matrix (E)
Adhesion: an area of isolated continuity of extracellular matrix There was no definition for an adhesion
material between the tuft and capsule even when the underlying
segment does not have overt sclerosis (F)
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
require the presence of karyorrhexis
Elimination of segmental and global subdivions of class IV Definitions for segmental and global were unclear;
interobserver variability was large; clinical significance uncertain
Modification of the NIH lupus nephritis activity and chronicity scoring Designation of activity/chronicity through A, C and A/C
system (Table 2) to be used instead of the currently used A, C considered too broad and nonspecific; preference for a
and A/C parameters semiquantitative approach to describe active and chronic lesions
Tubulointerstitial lesions Indicate whether interstitial inflammation occurs in presence or Lack of cut-off values for reporting the severity of
absence of interstitial fibrosis tubulointerstitial lesions
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A B C
D E F
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