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Classification of Lupus GlomerJ. Charles Je
Class I Class II Class III
rulonephritis: Five Years Laterennette, MD,
Class IV-G Class VClass IV-S
Who Classified L
“Original WHO COriginal WHO CBuffalo, NY, 1974;
“Modified WHO ISKDC, Paris, 1980 (Ch
“Modified WHO Churg
Lupus Nephritis?
Classification”Classificationor Geneva, 1975
Classification”hurg and Sobin, 1982)
Classification”1995
Appel, Silva, Pirani, et al,(“according to a classifica
Class I. Normal
( according to a classifica
Normal by LM, EM and IFClass II. Mesangial Changes
A. Minimal alterationsA. Minimal alterations (normal by LM, mesang
B. Mesangial GlomerulitisCl III F l d S t l PClass III. Focal and Segmental Pr
(<50% glomeruli involveClass IV. Diffuse Proliferative Glo
(>50% glomeruli involveClass V. Membranous Glomerulo
PurePureMixed Patterns (such as C
, Medicine 57:371-410, 1978ation proposed by the WHO”)ation proposed by the WHO )
gial deposits by IF and EM)s (mesangial hypercellularity)
lif ti Gl l h itiroliferative Glomerulonephritised)omerulonephritised)onephritis
Class III associated with Class V)
Post card sent from Ed Lewis twas at the 1980
to Mel Schwrtz while Ed Lewis ISKDC Meeting
Jacob Churg, 1982 (based on “WHO Morphologic Classifi
I. Normala. Nil (by all technb. Normal by LM,
II. Pure Mesangial Alterata. Mesangial wideb Moderate hyperb. Moderate hyper
III. Focal Segmental Gloma. Active necrotizib. Active and scle
S l i l ic. Sclerosing lesioIV. Diffuse Glomerulonep
a. Without segmeb., c., and d. like ab., c., and d. like a
V. Diffuse Membranous Ga. Pureb. Associated withc Associated withc. Associated withd. Associated with
VI. Advanced Sclerosing
modifications at the ISKDC): ication of Lupus Nephritis”
niques)but deposits by EM or IFions (Mesangiopathy)
ening/mild hypercellularityrcellularityrcellularity
merulonephritising lesions
erosing lesionsonshritisntal lesions
a., b. and c. abovea., b. and c. aboveGlomerulonephritis
h category IIh category IIIh category IIIh category IVGlomerulonephritis
Jacob ChWHO Morphologic Classificatio
I. NormalA. Nil (by all technB. Normal by LM,
II. Pure Mesangial AlteratA. Mesangial wideB M d hB. Moderate hype
III. Focal Segmental GlomA. Active necrotizB Active and scleB. Active and scleC. Sclerosing lesi
IV. Diffuse GlomerulonepA Without segmeA. Without segmeB., C., and D. like
V. Diffuse Membranous GA. PureB. Associated wit
VI. Advanced Sclerosing
urg, 1995: on of Lupus Nephritis (modified)
niques)but deposits by EM or IFions (Mesangiopathy)ening/mild hypercellularity
ll l ircellularitymerulonephritiszing lesionserosing lesions
50% cutoff between III and IVerosing lesions
onshritis
ental lesions
V-C and V-D deleted.
ental lesionsA., B. and C. above
Glomerulonephritis
h category IIGlomerulonephritis
Problems with the WHO Lup
•Different versions with no official
•Lack of precise definitions of term
•Never validated for reproducibilit
•Unnecessary subcategorization bUnnecessary subcategorization b
•No guidance for classifying borde
Conf sion abo t class III and cla•Confusion about class III and cla
•Uncertainty about how to classify
•Different approaches to classifyinmembranous lesions
C b d i ti f•Cumbersome designations for ac
pus Nephritis Classification
peer-reviewed version
ms and criteria for different classes
y
based on mesangial hypercellularitybased on mesangial hypercellularity
erline lesions
ass IVass IV
y segmental necrotizing lesions
ng mixed proliferative and
ti it d h i itctivity and chronicity
Outcome of Lu100100
80al, %
80
60Surv
iva
40
60
lity
of S n=
35
WHO 20
Prob
abi
24
36
2 4 6 80
P
Korbet, Lewis, Schwar
upus Nephritis
WHO Class IVWHO Class IV
“WHO Class III (>50%)”WHO Class III (>50%)
Class” Vc (>50%)” & Vd
8 1210 Years1614rtz, et al., Am J Kidney Dis 35:904-914, 2000
Outcome of Lu
M t100
, %
Most rena
80
60urvi
val
40
60
ity o
f S n=
35
WHO 20
40
roba
bili
24
36
2 4 6 80
Pr 36
Korbet, Lewis, Schwar2 4 6 80
upus Nephritis
l th l i t ld l ifal pathologists would classify all of these as class IV
WHO Class IV
“WHO Cl III (>50%)”“WHO Class III (>50%)”
Class” Vc (>50%)” & Vd
8 1210 Years1614rtz, et al., Am J Kidney Dis 35:904-914, 20008 1210 Years1614
ISN/RPS Working Group on Glomerulo
PATHOLOGISTS:Charles Alpers U S ACharles Alpers, U.S.A.Jan Bruijn, NetherlandsTerrence Cook, EnglandVivette D'Agati U S AVivette D Agati, U.S.A. Franco Ferrario, ItalyAgnes Fogo, U.S.A.Gary Hill ParisGary Hill, ParisPrue Hill, AustraliaCharles Jennette, U.S.A.Lai-Ming Looi MalaysiaLai Ming Looi, MalaysiaLuiz Moura, BrazilMichio Nagata, JapanMelvin Schwartz U S AMelvin Schwartz, U.S.A.Surya Seshan, U.S.A.Jan J. Weening, Netherlands
the Classification of Lupus onephritis
CLINICIANS:Gerald Appel U S A
p
Gerald Appel, U.S.A.James Balow, U.S.A.Ellen Ginzler, U.S.A.Lee Hebert U S ALee Hebert, U.S.A.Norella Kong, MalaysiaPhillipe Lesavre, FranceMichael Lockshin U S AMichael Lockshin, U.S.A.Hirofumi Makino, Japan
The Classification of GSystemic Lupus Eryth
Jan J. Weening, Vivette D. D’Agati,Seshan, Charles E. Alpers, Gerald B ij T C k F FBruijn, Terence Cook, Franco FerraGinzler, Lee Hebert, Gary Hill, PrueC. Kong, Philippe Lesavre, MichaelgMakino21, Luiz A. Moura, Michio NInternational Society of NephrologyWorking Group on the classificationWorking Group on the classification
Kidney Int 2004;65:521-530 and J A
Glomerulonephritis in phematosus Revisited
Melvin M. Schwartz, Surya V. B. Appel, James E. Balow, Jan A. i A B F Ell Mario, Agnes B. Fogo, Ellen M.
e Hill, J. Charles Jennette, Norella l Lockshin, Lai-Meng Looi, Hirofumi gagata, on behalf of the
y and Renal Pathology Society n of lupus nephritisn of lupus nephritis
Am Soc Nephrol, 2004;15:241-250
2004 ISN/RPS Consensus ConfeLupus Glomerp
Class I Minimal mesangial
Class II Mesangial proliferat
Class III Focal LGN (involvinClass III Focal LGN (involvin
Class IV Diffuse LGN (involv
Class IVS Predo
Class IVG PredoClass IVG Predo
Class V Membranous LGN
Class VI Advanced sclerotic
erence on the Classification of rulonephritisp
lupus glomerulonephritis (LGN)
tive LGN
ng < 50% of glomeruli)ng < 50% of glomeruli)
ving 50% or > glomeruli)
ominantly segmental
ominantly globalominantly global
LGN (> 90% sclerotic glomeruli)
Class I Class II Class III
ISN/RPS Classification of
Class IV-G Class VClass IV-S
f Lupus Glomerulonephritis
Class I Minimal mesangial lupus glomerulo
ISN/RPS Classification of
Class I Minimal mesangial lupus glomerulomicroscopy, but mesangial immune deposits b
Mesangial stfor IgG
Normal histology
onephritis. Normal glomeruli by light
f Lupus Glomerulonephritis
onephritis. Normal glomeruli by light by immunofluorescence.
taining Mesangial electron dense immunedense immune complex deposits
Class II Mesangial proliferative lupus glomhypercellularity of any degree or mesangial m
ISN/RPS Classification of
hypercellularity of any degree or mesangial mmesangial immune deposits.
There may be a few isolated subepithelial or simmunofluorescence or electron microscopyimmunofluorescence or electron microscopy,
Segmental gmesangial hypercellularity
Mesangial staifor IgG
merulonephritis. Purely mesangial matrix expansion by light microscopy with
f Lupus Glomerulonephritis
matrix expansion by light microscopy, with
subendothelial deposits visible by but not by light microscopybut not by light microscopy.
Mesangial electronining
Mesangial electron dense immune complex deposits
Class III Focal lupus glomerulonephritis. Aglobal endo or extracapillary glomerulonephr
ISN/RPS Classification of
global endo- or extracapillary glomerulonephrtypically with focal subendothelial immune dealterations. Class III (A): Active lesions: focal(A/C): Active and chronic lesions: focal prolifeClass III (C): Chronic inactive lesions with glonephritis.
S t l Sli htSegmental endocapillary hypercellularity
Slight extracapillary hypercellularity
Band-likwall stai
Active or inactive focal, segmental or ritis involving <50% of all glomeruli
Lupus Glomerulonephritis
ritis involving <50% of all glomeruli, posits, with or without mesangial proliferative lupus nephritis. Class III
erative and sclerosing lupus nephritis. omerular scars: focal sclerosing lupus
Subendothelialke capillary ning
Subendothelial electron dense immune complex deposits
Class IV Diffuse lupus glomerulonephritis. Aendo- or extracapillary glomerulonephritis involvdiffuse subendothelial immune deposits, with ordivided into diffuse segmental (IV-S) lupus nephsegmental lesions, and diffuse global (IV-G) lupglomeruli have global lesions. IV-S and IV-G areand chronic lesions and (C): chronic inactive leand chronic lesions, and (C): chronic inactive le
Global injury (IV-G)
Segmental injury (IV-S)Less immunoglo
Active or inactive diffuse, segmental or global ving 50% or more of all glomeruli, typically with r without mesangial alterations. This class is hritis when 50% of the involved glomeruli have us nephritis when 50% of the involved e divided into (A): active lesions, (A/C): active sions with scarssions with scars.
Extensive subendothelial electron dense immune complex depositsdeposits
Minor electron subendothelial dense immune complexcomplex deposits
bulin
Class V Membranous lupus glomerulonepimmune deposits or their morphologic sequela
ISN/RPS Classification of
immune deposits or their morphologic sequelaimmunofluorescence or electron microscopy,
A diagnosis of both Class III & Class V or Clacombined lesionscombined lesions.
Thick capillary wall Segmental mesangial hypercellularity
Globacapillastainin
hritis. Global or segmental subepithelial ae by light microscopy and by
Lupus Glomerulonephritis
ae by light microscopy and by with or without mesangial alterations.
ss IV & Class V is given when there are
SubepithelialSubepithelial immune complex deposits
al granular ary wall ng for IgG
ISN/RPS Classification of
Class VI Advanced sclerosis lupus glomerglobally sclerosed without residual activity. (IS
f Lupus Glomerulonephritis
rulonephritis. 90% or more of glomeruli SN/RPS 2004)
Appel et al.78
N l i b LM Cl I ClNo lesion by LM, IF or EM
Class I Cla
Mesangial Class II A Cladeposits but no hypercellularityMesangial Class II B Clahypercellularity
Focal (<50%) proliferative GN
Class III Claproliferative GNSegmental (>50%) GN
Class IV Cla
Diffuse (>50%) Proliferative GN
Class IV Cla
Membranous Class V ClaMembranous plus Proliferative
Class V&III Class V&IV
ClaCla
Churg 82
ISN/RPS04
I A N l GNass I A No lupus GN
ass I B Class I
ass II A,B Class II
ass III A,B,C Class III A,A/C,C
ass IV B,C,D Class IVS A,A/C,C
ass IV A,B,C,D Class IVG A,A/C,C
ass V Class Vass VCass VD
Class III&V Class IV&V
Clinical I II III
Presenting clinical Manifestations
Feature n=5 n=54 n=10Asymptomatic hematuria
40 19 22
Asymptomatic proteinuria
40 42 25
Nephrotic 20 15 17Nephrotic syndrome
20 15 17
Nephritic syndrome
0 20 34sy d o eAcute renal failure
0 4 2
Chronic renal 0 0 0Chronic renal failure
0 0 0
100%
100%
100%% % %
Seshan S, Jennette JC. Renal disease in systemic lupof lupus glomerulonephritis: advances and implication
IV-G IV-S V VI
s of Different ISN/RPS Classes
07 n=111 n=87 n=159 n=18
2 4 6 5 0
5 7 6 13 0
7 40 38 65 117 40 38 65 11
4 27 26 7 0
18 16 2 0
4 8 8 894 8 8 89
0 100%
100%
100%
100%% % % %
pus erythematosus with emphasis on classification ns. Arch Pathol Lab Med 2009;133:233-48.
Najafi Mittal (2004) Yokoyama
Comparison of ISN/RPS Class IV Seg
Najafi (2001)
Mittal (2004) Yokoyama (2004)
# of patients 24 S 35 G 11 S 22G 6 S 17 G
S C S > G G > S G SS Cr S > G G > S G = S
Proteinuria G > S G > S G = S
HTN G > S G > S NRHTN G > S G > S NR
Wireloops G > S G > S NR
Focal necrosis S > G S > G NRFocal necrosis S > G S > G NR
Cellularity G > S G > S NR
Ac index G = S G = S G > SAc index G S G S G S
Chr index S > G G = S G > S
Worse outcome S > G G = S S > G Trend
Follow-up 10yrs 55-38mth 95-214 mth
Hill Schwartz Kim Hiramatsu
gmental (S) and Global (G) Variants
Hill (2005)
Schwartz (2007)
Kim (2008)
Hiramatsu (2008)
15 S 31G 22 S 22 Q 39 G
12 S 30G 14 S 41G
G> S G Q S G S G SG> S G=Q=S G = S G = S
G > S G=Q=S G > S G > S
G > S G=Q=S G = S G = SG > S G=Q=S G = S G = S
G > S G>Q>S NR
S > G G>Q>S NRS > G G>Q>S NR
G > S NR G > S
G > S G=Q>S G = S G = SG S G Q S G S G S
G > S Q>S>G G = S G = S
G > S Q>S>G G > S G > SQTrend
10yrs 10yrs 10yrs 10yrs
Lupus Sever Segmental Glomerulonephri
veve
Lupus Diffuse Proliferatic Glomerulonephr
Number (%) of renal biopsy specimNumber (%) of renal biopsy specim
Behara VY, Whittier WL, Korbet SM, Schwartz Mof severe segmental lupus nephritis. Nephrol Di
itis (SSGN, similar but not identical to IV-S)
ersusersus
ritis (DPGN, similar but not identical to IV-G)
mens with the histologic finding:mens with the histologic finding:
MM, Martens M, Lewis EJ. Pathogenetic features al Transplant. 2010;25:153-9.
Lupus Sever Segmental Glomerulonephri
veve
Lupus Diffuse Proliferatic Glomerulonephr
Percent of glomeruli per of renal biPercent of glomeruli per of renal bi
Behara VY, Whittier WL, Korbet SM, Schwartz Mof severe segmental lupus nephritis. Nephrol Di
itis (SSGN, similar but not identical to IV-S)
ersusersus
ritis (DPGN, similar but not identical to IV-G)
iopsy with the histologic finding:iopsy with the histologic finding:
MM, Martens M, Lewis EJ. Pathogenetic features al Transplant. 2010;25:153-9.
Lupus Sever Segmental Glomerulonephri
veve
Lupus Diffuse Proliferatic Glomerulonephr
Peripheral IgG Staining by IFM
Behara VY, Whittier WL, Korbet SM, Schwartz Mof severe segmental lupus nephritis. Nephrol Di
itis (SSGN, similar but not identical to IV-S)
ersusersus
ritis (DPGN, similar but not identical to IV-G)
Subendothelial Deposits by EM
MM, Martens M, Lewis EJ. Pathogenetic features al Transplant. 2010;25:153-9.
ISN/RPS IV
does not result in thedoes not result in the
Lewis-WHO III ≥ 50%
Schwartz MM, Korbet SM, Lewis EJ; Collaboratpathogenesis of severe lupus glomerulonephriti
V-S and IV-G
same classification as same classification as
% and Lewis-WHO IV
tive Study Group. The prognosis and s. Nephrol Dial Transplant. 2008;23:1298-306.
ISN/RPS IV
does not result in the
Lewis-WHO III ≥ 50%
Renal Survival
Schwartz MM, Korbet SM, Lewis EJ; Collaboratpathogenesis of severe lupus glomerulonephriti
V-S and IV-G
same classification as
% and Lewis-WHO IV
ISN/RPS IV-S (n=22)
ISN/RPS IV-G (n=39)
Lewis-
Lewis “IV-Q” (n=22)
( ) LewisWHO III ≥ 50% (n=44)
tive Study Group. The prognosis and s. Nephrol Dial Transplant. 2008;23:1298-306.
Crescents are a marker of an aggincluding the Lewis-
Schwartz MM, Korbet SM, Katz RS, Lewis EJ. Emechanisms determining the pathology of seve
ressive variant of lupus GN -WHO III ≥ 50%
Evidence of concurrent immunopathological re lupus nephritis. Lupus 2009;18:149-58.
Crescents are a marker of an aggincluding but not limited to th
Schwartz et al “propose that diffuse global las WHO class IV + WHO class III.”
Schwartz MM, Korbet SM, Katz RS, Lewis EJ. Emechanisms determining the pathology of seve
ressive variant of lupus GN he Lewis-WHO III ≥ 50%
upus GN with crescents is best described
Evidence of concurrent immunopathological re lupus nephritis. Lupus 2009;18:149-58.
Five Yea
•The ISN/RPS Classification widespread acceptance and
•The ISN/RPS Classification higher level of interobserver r
•Multiple studies have found tClass IV-S has similar or bettnephritis ISN/RPS Class IV-G
•Schwartz et al conclude thatSchwartz et al conclude thatIV-G does not capture the maand pathogenesis of severe lp ground of classification adjustm
ars Later:
System has garnered use.
System has resulted in a reproducibility.
that lupus nephritis ISN/RPS ter outcomes than lupus pG.
t ISN/RPS class IV-S versust ISN/RPS class IV S versus ajor differences in prognosis upus GN, and thus another pments is likely.
Anyone WHO ISNll d ’treally doesn’t un
situation.Edward R. Mu
N’t confused d t d thnderstand the
urrow