classification of lupus glomerulonephritis: five years...

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


Class I Minimal mesangial lupus glomerulomicroscopy, but mesangial immune deposits b

Mesangial stfor IgG

Normal histology

onephritis. Normal glomeruli by light


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


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


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


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


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


Class VI Advanced sclerosis lupus glomerglobally sclerosed without residual activity. (IS


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.


veve


Percent of glomeruli per of renal biPercent of glomeruli per of renal bi



ersusersus


iopsy with the histologic finding:iopsy with the histologic finding:



veve


Peripheral IgG Staining by IFM



ersusersus


Subendothelial Deposits by EM


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

classification of lupus glomerulonephritis: five years...

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