1srier SLE

8/11/2019 1srier SLE

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The kidney is afected in a clinically important way in about 38% o

patients with systemic lupus erythematosus (SLE) althou!h renal

in"ol"ement "aries considerably by race and ethnicity# $aucasians

(European European mericans) ha"e an incidence o renal lupus o

&'% to 33% whereas black (rican merican ro$aribbean)

ispanic or sian patients ha"e a *+% or !reater incidence# &,- .

the patients who e"entually ha"e clinical renal in"ol"ement -+% to

/+% ha"e o"ert 0ndin!s o kidney disease at the time o initial

dia!nosis o SLE# &'- 1idney dama!e in SLE is most oten due to

lupus nephritis (L2) in which !lomerular immune comple

accumulation leads to an in4ammatory response that dama!es

!lomeruli and e"entually the renal interstitium# L2 is associated

with a worse outcome in SLE in part due to the de"elopment o

chronic kidney disease ($15) or endsta!e renal disease (ES65)#

*/The incidence o ES65 attributed to L2 in adults rom &77/ to'++- was -#- to -#7 cases per million in the !eneral population

accordin! to the nited States 6enal 5ata Ser"ice# 9 owe"er in

blacks and ispanics the incidence o ES65 was / to '+ per million

compared to $aucasians ('#* per million)# Similarly in the nited

1in!dom &7% o $aucasians "ersus /'% o blacks with L2

pro!ressed to ES65# 3 The pre"alence o $15 in patients with SLE is

di:cult to estimate but because current therapies induce complete

remission in *+% or ewer L2 patients $15 is likely to be hi!h in the

lupus population# L2 is !enerally treatable# ;resently this re


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acti"ation# >n addition to their role in breakin! tolerance many o

these pathways also directly contribute to the clinical

maniestations o SLE# The patho!enesis o L2 mirrors in many

respects the patho!enesis o systemic lupus particularly immune

comple (>$)dri"en in4ammation# >n4ammatory kidney inBury occurs

ollowin! intrarenal >$ accumulation# owe"er there appears to be


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be trapped in the !lomeruli perhaps acilitated by interactions

between the positi"ely char!ed histones and the ne!ati"ely

char!ed !lomerular basement membrane# &'ntids52 can

reco!nie the 52 in nucleosomes and the bindin! o antids52 in

lupus renal tissue occurs at the site o !lomerular nucleosome

deposition#&3 nother mechanism is based on crossreacti"ity

between anti52 and one or more renal tissue anti!ens# Cany

poten tial tissue anti!ens ha"e been implicated and two o the

more rele"ant candidates are alphaactinin epressed in both

!lomerular podocytes and mesan!ial cells &- and annein >> on

mesan!ial cells# &* 6e!ardless o which mechanism predominates

the result is localied antids52 containin! >$ with the potential to

dri"e local tissue in4ammation# ntids52 autoantibodies appear

to be predominantly immuno!lobulin =& (>!=&) &/ which is an

in4ammatory >!= subtype due to its ability to acti"ate complementand en!a!e ?c receptors or >!=# ntibodies to $&!=' '' which is a poor acti"ator o

complement and binds ?c receptors with low a:nity# .ther >!=

subtypes (mainly >!=&) can be present in these >$ so the role o

anti$&< in L2 patho!enesis may depend on the relati"e amounts oeach anti$&< >!= subtype#

The $omplement and ?cG(!amma) 6eceptor Systems The ormation

o >$ leads to the acti"ation o both the complement cascade and

cells bearin! ?c receptors or >!= (known as ?cG receptors or ?cG6)#

The acti"ation o complement and ?cG6 by >$ can pro"ide protecti"e


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efects a!ainst SLE mainly by promotin! proper clearance o

circulatin! >$# owe"er once >$ are deposited in tissue both o

these pathways can dri"e tissue in4ammation and dama!e either

throu!h direct efects on tissue (complement membrane attack

comple) or by acti"atin! cells to produce proin4ammatory

cytokines and toic mediators# $omplement is thou!ht to pro"ide

protection rom SLE in a ew diferent ways# ?irst classical

complement acti"ation by >$ results in a more soluble less

phlo!istic orm o >$ that is less likely to be trapped in tissue# '3

Second complement contributes to clearance o apoptotic debris

throu!h opsoniation by $&$ clearance throu!h $-bF$3bF$3bi

receptors#'* The type one complement receptor ($6& $53*) whichbinds $-b $3b and $3bi and acts as a re!ulator o complement

acti"ation is epressed in the circulation predominantly on

erythrocytes (E$6&) and mediates the bindin! o complement

opsonied >$ to erythrocytes (a process known as immune

adherence)# '/ This bindin! allows erythrocytes to shuttle >$

throu!h the circulation minimiin! !lomerular trappin! o >$ and

promotin! >$ deli"ery to the li"er and spleen or sae remo"al# '/

The e"idence that all o these complement unctions protect a!ainst

SLE include studies showin! that indi"iduals with homoy!ous

de0ciencies o classical pathway components ha"e an increased risk

or de"elopin! SLE and SLElike diseases '9 and that E$6& le"els

are decreased in SLE and 4uctuate in chronically acti"e disease#

'8'7 >n contrast se"eral obser"ations su!!est complement

mediated in4ammation and direct tissue dama!e contribute to the

patho!enesis o L2@

$irculatin! le"els o $3 and $- are lower in acti"e L2 compared

to inacti"e L2 or nonrenal SLE indicatin! on!oin! complement

acti"ation#3+3&

$omplement components includin! the membrane attack

comple are deposited in L2 kidneys# 3+3'33

Lon!itudinal assessment o circulatin! $3 and $- le"els durin!

SLE 4are showed that le"els decrease si!ni0cantly at the time o a


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renal 4are but not at nonrenal 4are e"en i the nonrenal 4are

occurred in patients with a history o L2# '7

6enal tubular production o $3 and complement actor A occurs

in L2 patients but not healthy controls# 3-3*

The in4ammatory receptor or $3a ($3a6) absent rom healthy

kidneys becomes epressed in !lomerular endothelium in

association with >$ deposits in L2 and the epression le"el

correlates with L2 se"erity# 3/

The in4ammatory receptor or $*a ($*a6) althou!h present in

normal kidneys is !reatly upre!ulated in the mesan!ium and

podocytes o L2 kidneys# 39

The epression o $6& is decreased in L2 !lomeruli compared

to its normal epression on podocytes# 38

The epression o another complement re!ulator decay

acceleratin! actor (5? $5**) is also reduced in L2 patients rom

its normal epression in the Buta!lomerular apparatus and

appears de no"o in the renal "asculature interstitium and

mesan!ium# 37lthou!h there ha"e been no human studies o

complement inhibition in L2 to "eriy its patho!enic role such

eperiments ha"e been done in eperimental animals# ?or instance

in the 2HAF2HD murine lupus model anti$* antibody blocks the

de"elopment o !lomerulonephritis su!!estin! $*a andFor the

membrane attack comple are critical nephritic actors# -+ >n the

C6LFlpr mouse model o SLE the administration o a rodent

inhibitor o complement acti"ation ($rry) was efecti"e at protectin!

a!ainst !lomerulonephritis#-& >nterestin!ly nephritis in the

C6LFlpr model appears to be dependent on the alternati"e pathway

o complement acti"ation as deletin! either the actor A or actor 5

!enes si!ni0cantly reduced the de!ree o renal inBury# -'-3 The

alternati"e complement pathway is an ampli0cation pathway that is

ti!htly re!ulated su!!estin! that renal dama!e in L2 is due toampli0ed complement acti"ation occurrin! in the ace o inade


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responses by acti"atin! the cells epressin! ?cG6#-- Studies o

polymorphic orms o ?cG6 ha"e clari0ed which role has the most

in4uence in SLE patho!enesis# There are three classes o ?cG6

(?cG6>?cG6>> and ?cG6>>>) with diferent !enes that produce ull

len!th products or ?cG6>> (?cG6>> ?cG6>>A ?cG6>>$)and ?cG6>>>

(?cG6>>> and ?cG6>>>A)# Sin!le nucleotide polymorphisms (S2;s)

that afect the peptide se$ clearance rather thandri"e tissue in4ammation and that relati"e de0ciencies in this

unction contribute to L2# >t should be noted that there is an

etensi"e body o work in mouse models o SLE that su!!ests >$

in4ammation is mainly ?cG6mediated with little contribution rom

the complement system# -7 This includes nephritis in the 2HAF2HD

model where deletin! the si!nalin! unit o ?cG6> and ?cG6>>>

which also pre"ents epression o these ?cG6 si!ni0cantly reduces

proteinuria and increases sur"i"al time# *+ lthou!h these studies

support the potential o ?cG6 to dri"e in4ammation they do not

ne!ate the contributions o complement to this process# $aution

must also be taken n their interpretation as the relati"e

contribution o complement and ?cG6 to mouse models o >$

in4ammation includin! L2 depends on the mouse strain that is

bein! tested#*&*' ?inally i the role o ?cG6 particularly

?cG6>>>ain lupus and L2 is mainly to dri"e in4ammation hi!her

a:nity orms o the receptor should be associated with worse >$

in4ammation and L2# owe"er the studies in human lupus

discussed pre"iously demonstrate the oppositeK hi!her a:nity

orms o ?cG6>>>a and ?cG6>>a are associated with protection a!ainstSLE and L2# Thus the etent to which these models recapitulate the

comple nature o human SLE and L2 must be considered# 6enal

$hemokines $ytokines and $ellular >n0ltrates The presence o >$

and the acti"ation o the complement system are key initiators o

in4ammation that de0ne L2# .ne conse


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directly induces cell membrane dama!e throu!h the ormation o

transmembrane pores# 33 nother conse$ and

complement acti"ation is more indirect and is mediated by the

induction o chemokines and cytokines that induce in0ltration and

acti"ation o proin4ammatory cells# These chemokines and

cytokines can be initially produced by renal parenchymal tissue

includin! !lomerular endothelial cells mesan!ial cells podocytes

and tubular epithelium# *3 .nce leukocytes containin! chemokine

receptors are drawn into the kidney in4ammation is accelerated

throu!h leukocyte secretion o additional chemokines and

in4ammatory cytokines# Some notable eamples o upre!ulated

chemokines and cytokines in kidneys o L2 patients include

monocyte chemoattractant protein& (C$;&) and macropha!e

in4ammatory protein&alpha (C>;& alpha)K interleukin (>)L/ >L&+

>L&' >L&9 >L&8K intereron (>?2)!amma (>?2G)K tumor necrosisactor (T2?)alphaK and Eta&Fosteopontin# *3,*9 >n support o a

role or chemokines and cytokines in the patho!enesis o L2

deletion or inhibition o their epression substantially reduces

kidney inBury in mouse models o lupus# ?or eample deletion o the

!enes or C$;& or its receptor ($$6') in the C6LFlpr mouse *8*7

or predisease treatment o the mouse with a C$;& anta!onist/+

reduced in0ltration o macropha!es and T cells and attenuated

clinical and histolo!ic measures o inBury despite accumulation o

renal >$ comparable to wildtype animals# >n both C6LFlpr and

2HAF2HD mice anti>L/ antibody treatment reduced antids52

antibodies and !lomerulonephritis as re4ected by near normal

renal unction and !lomerular histolo!y# /&/' nti>L&8 antibodies

induced in C6LFlpr mice throu!h >L&8 c52 "accination attenuated

L2# /3 ntiT2?L; treatment o 2HAF2HD mice reduced

proteinuria renal in4ammatory in0ltrates and !lomerulosclerosis

despite increasin! circulatin! antids52 le"els# /- These data

su!!est that the renal epression o proin4ammatory chemokines

and cytokines is an inte!ral step in the patho!enesis o L2# Some o

these may speci0cally mediate kidney dama!e (e#!# C$;& and T2?alpha) whereas others may predispose to kidney inBury throu!h

!eneral efects on auto immunity# >n0ltratin! neutrophils and

monocytesFmacropha!es can cause direct renal tissue dama!e by

secretin! mediators like reacti"e oy!en species and proteolytic

enymes# The efect o in0ltratin! T cells is less direct and is

re4ected by the cytokine pro0le o these T cells# 5urin! prolierati"e


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L2 the intrarenal production o Th& cytokines appears to

predominate o"er Th' cytokines and correlates with histolo!ic

acti"ity# Th& responses are associated with acti"ated macropha!es

and with the production o >!= capable o acti"atin! complement

and ?cG6 pathways# Speci0cally relati"ely hi!h le"els o >L&' >?2

G and >L&8 are present althou!h >L&+ a Th' cytokine has also

been shown to increase# This leads to an o"erall hi!her Th&FTh'

cytokine ratio# ***//*// Th&dominant epression can also be

obser"ed in serum urine and circulatin! T cells o L2 patients# //

The Th& dominance displayed in L2 patients both locally in the

kidney and systemically in the circulation su!!ests that this may be

an important prereL&9 is ound in the kidney in L2 and two maBor cell

sources o >L&9 Th&9 cells and $5-$58 T cells ha"e beenobser"ed in renal biopsies o L2 patients# *9 Local production o >L

&9 may dri"e in4ammatory cytokine and chemokine epression by

resident !lomerular and tubular cells ha"in! the >L&9 receptor /9

leadin! to acti"ation o neutrophils and monocytes#/8 The presence

o >L&9 producin! cells in the L2 kidney may also represent a shit

away rom natural re!ulatory T cells capable o suppressin! immune

responses# /7 The role o re!ulatory T cells is discussed later#

lthou!h not usually pre"alent in4tratin! A cells ha"e also been

described in L2 kidneys# Their presence may directly tar!et

autoantibodies to the kidney as has been shown in 2HAF2HD mice#

9+ A cells in renal tissue may also present kidney anti!ens to

intrarenal T cells# 6ecent work has shown that intrarenal A and T

cells associate with "arious de!rees o or!aniation includin!

structures resemblin! !erminal centers with central ollicular

dendritic cells# 9& >nterestin!ly these structures appear to occur

mainly outside o the !lomeruli and are associated with tubular

basement membrane >$# 9& These may contribute speci0cally to

tubulointerstitial in4ammation in L2# >ntrinsic 6e!ulatory T $ells

uman re!ulatory T cells (Tre!) characteried as$5-$5'*hi?o;3 inhibit immune responses throu!h efects on T

and A cells and particularly autoantibody production# 9'93Studies

in the 2HAF2HD mouse su!!est a role or Tre!s in lupus

patho!enesis with an in"erse correlation between circulatin! Tre!

numbers and circulatin! anti ds52 le"els 9- and suppression o

lupuslike disease acti"ity includin! !lomerulonephritis by


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adopti"e transer o Tre!s# 9* Core han '* studies ha"e been done

on human SLE and the maBority o these indicate lower circulatin!

le"els o Tre!s in SLE althou!h there is no clear consensus# 9/ Dith

re!ard to the role o Tre!s in human L2 one study demonstrated an

increase in Tre! markers ollowin! rituimabinduced A cell

depletion in L2 patients (n M9) that correlated with clinical

remission 99 whereas a second study showed no relationship

between circulatin! Tre! numbers or unction and acti"e L2#98

lthou!h Tre!s are likely in"ol"ed in SLE patho!enesis the speci0c

nature o that in"ol"ement especially with respect to L2 remains

to be determined#

>ntereronlpha and ;lasmacytoid 5endritic $ells >?2alpha has

recently taken a central role in the proposed paradi!ms o SLE

patho!enesis# 97 This pathway is initiated when >?2alpha is

produced in response to a "ariety o stimuli most in"ol"in! nucleic

acids# ;lasmacytoid dendritic cells (p5$s) are the maBor sources o

>?2apha ollowin! en!a!ement o their endosomal tolllike

receptors 9 and 7 (TL69 TL67) by ss62 and unmethylated $p= in

52 respecti"ely# 8+8&Aoth TL6s are intracellular# .ther cell types

can produce >?2alpha ollowin! en!a!ement o diferent receptors

such as TL63 in myeloid dendritic cells or nonTL6 pattern

reco!nition receptors such as the helicases 6>=> and C5* in a

"ariety o cells# 8' ll these receptors sense "arious "iral and

bacterial nucleic acids and acti"ate si!nalin! cascades that end inthe production o >?2alpha# The efects o >?2alpha on the immune

response includes dri"in! maturation o con"entional dendritic cells

into potent anti!en presentin! cells 83inducin! A cell

diferentiation to plasma cells 8- and contributin! to the

de"elopment o $5- helper T cells 8* and $58 central memory T

cells# 8/The >?2alpha response receptors theoretically are

important in discriminatin! between sel and nonsel# ?or eample

TL69 shows speci0city or !uanosineFuridine rich ss62 such as

"iral ss62 whereas TL67 shows speci0city or unmethylated $p=

that occurs mainly in nonmammalian 52# Aoth receptors also can

reco!nie mammalian nucleic acid in the orm o >$ containin!

62Fprotein (e#!# anti62; >$) or antids52 containin! >$# 89 The

presence o autoantibody may be crucial or this reco!nition as

62 and 52 in the orm o >$ allow pha!ocytosis o the nucleic

acids "ia ?c 6>>a epressed on p5$s# 88Ay !eneratin! increased


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>?2 throu!h this mechanism an enhanced immune response can

occur that may break tolerance to 62 and 52 containin!

anti!ens resultin! in the types o autoantibody that are pre"alent

in SLE# >nitiation o SLE strictly by this mechanism would re?2 Fp5$ pathway initiates SLE or not e"idence su!!ests

that the pathway is important to the patho!enesis o SLE# This

e"idence includes the obser"ation that patients treated with >?2

can de"elop a lupuslike disease7+7& the identi cation o a

number o >?2 related !enes as susceptibility !enes or SLE

onset 97 an increase in >?2 induced !ene epression (the >?2

si!nature) associated with acti"e SLE 7' and the number o known

SLE autoanti!ens that can dri"e >?2 secretion# There is also

e"idence that >?2 may be particularly in"ol"ed in thepatho!enesis o L2# Serum le"els o >?2 correlate directly with

antids52 and in"ersely with $3 le"els737- markers that are

associated with L2# ;eripheral blood cell le"els o the >?2

si!nature are associated with L2 patients# 7'7* >?2 inducible

chemokines includin! C$;& correlate ne!ati"ely with $3 le"els

and are associated with acti"e L2 7- and with risk or renal are#

7/5urin! se"ere L2 p5$ disappear rom the circulation and

accumulate in !lomeruli due in part to !lomerular epression o >L

&8 and p5$ epression o the >L&8 receptor# 79 >t is plausible that

the presence o renal >$ containin! ds52 (e#!# nucleosomes)

could dri"e !lomerular p5$s to produce >?2 thus ampliyin! the

autoimmune response to local !lomerular anti!ens and contributin!

to the ormation o local !erminal centers# Studies in mouse models

also !enerally support a role or >?2 in L2 patho!enesis#

Eperimental L2 is reduced by deletion o the >?2 receptor or by

administration o TL69 or TL67 anta!onists whereas L2 is worsened

by administration o an >?2 producin! "ector or an a!onist o

TL69 or 7# 78.ne eception is seen in the C6LFlpr model in which

L2 is si!ni cantly worsened ollowin! deletion o the >?2receptor 77 su!!estin! that >?2 protects a!ainst L2 in this

mouse strain# The realiation o the importance o the >?2

pathway in SLE patho!enesis has rein"i!orated the concept o

microbial patho!en in"ol"ement in SLE patho!enesis# The acti"a

tion o TL6s and other sensors that stimulate >?2 by "iral and

bacterial nucleic acids may be important in initiatin! the break in


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tolerance or in acceleratin! the autoimmune response# The

=enetics o Lupus 2ephritis Cuch efort has !one into identiyin!

the basis or !enetic susceptibility to SLE usin! !enomewide and

candidate !ene studies# &++ ."er 3+ !enes ha"e been identi ed

that appear to be related to speci c patho!enic pathways in SLE#

These include >$ clearanceFin ammatory pathway !enes immune

response !enes and >?2 si!nalin! and response !enes#

number o these impart particular susceptibility to L2# &+&

Eamples include !enetic "ariation in the ?c 6>> and ?c 6>>>

!enes described pre"iously in which the hi!her a nity "ariants

are associated with protection a!ainst L2# -9-8 Two cytokines

pre"iously discussed as important or cell in ltration into the

kidney the chemokine C$;& or monocytesFT cells and >L&8 or

p5$s ha"e promoter polymorphisms that in uence epression

le"els# The C$;& "ariant that results in hi!her epression le"els isassociated with L2# &+' Similarly the >L&8 "ariant that causes

hi!her epression is associated with difuse prolierati"e L2# &+3

lso o interest the L 563 allele 56A&N+3+&) correlates with

renal disease &+- and with antids52 antibodies &+- supportin! a

!enetic contribution to a type o autoantibody that may tar!et

renal tissue# ?or the >?2 pathway STT- which is important or

transmittin! the >?2 si!nal has a !enetic "ariant that is

associated with increased STT- 62 le"els and with SLE

particularly L2# &+*=enome studies ha"e identi ed si $ con

tainin! nuclear anti!ens rom microbes or apoptotic debris# 5e


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ciencies in the clearance o apoptotic debris may also lead to

!lomerular accumulation o selanti!en such as nucleosomes that

can tar!et autoantibody directly to renal tissue# >nitial

accumulation o !lomerular >$ sets the sta!e or an escalatin!

cascade o e"ents that includes local complement acti"ation and

chemokineFcytokine production leadin! to in ltration and

acti"ation o in ammatory (monocytes neutrophils) and immune

cells (p5$s T cells) and a hei!htened intrarenal Th&dominant

immune response with si!ni cant Th&9 contributions# This then

leads to an escalation o autoantibody production tar!eted to the

kidney and in ammation dri"en primarily by complement and ?c

6 acti"ation# Cany o the mediators deri"ed rom this acti"ation

contribute to kidney inBury includin! direct tissue dama!e by

complement proteins and toic actors produced by in ammatory

sells such as reacti"e oy!en species and proteolytic enymes#$ontinued in ammation can lead to matri epansion brosis

scarrin! and e"entually ES65# Dhy L2 occurs only in some SLE

patients remains an unknown althou!h the data discussed

pre"iously point to the eistence o speci c L2 !enes includin!

those that a"or ine cient >$ clearance euberant

chemokineFcytokine production and loss o tolerance and

acti"ation o T and A cells# En"ironmental contributions such as

eposure to certain microbial inections may also be in"ol"ed in the

de"elopment o L2# s the speci cs o how !enetic and

en"ironmental actors interact and contribute to L2 become clearer

so too will our understandin! o the patho!enesis o L2#

5>=2.S>S .? L;S 2E;6>T>S ;reser"ation o kidney unction in

patients with L2 is best achie"ed with early dia!nosis and

treatment# &+8,&&+ This re


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creatinine secretion lowerin! serum creatinine and leadin! to an

impression o better renal unction than in actuality# &&& ?inally in

addition to L2 SLE patients may de"elop acute renal insu ciency

because o inection medications nephrotoins hemolysis throm

bosis and cardiac ailure# rinalysis is a useul screenin! test or

patients with SLE# urine dipstick positi"e or blood andFor protein

su!!ests possible L2K howe"er a systematic study o the accuracy

o the urine dipstick as a screenin! tool ound a alsene!ati"e rate

in up to 3+% o SLE patients and a alsepositi"e rate in about -+%

o patients# &&' Thereore the urine sediment should be e"aluated

or e"idence o !lomerulonephritis# =lomerular bleedin! is

su!!ested by acanthocytes andFor red blood cell (6A$) casts# Dhite

blood cells (DA$s) and white blood cell casts in the absence o

inection are indicati"e o renal in ammation and support a

dia!nosis o !lomerulonephritis# ;roteinuria is a key indicator okidney inBury in SLE# >t has pro!nostic importance because

proteinuria may inBure the kidney and it is used as a clinical

biomarker o relapse remission and successul treatment#

Thereore accurate measurement o protein ecretion is crucial to

the on!oin! mana!ement o L2# 6andom spot urine proteinto

creatinine (;F$) ratios can be used in addition to urine dipsticks to

screen patients but are not accurate enou!h to be used to make

therapeutic decisions or to ollow chan!es in proteinuria ma!nitude

in response to therapy# The most reliable method to


14/93

mycophenolate moetil (see later) and biopsy inormation would

not chan!e the approach to therapy# &&8 There are howe"er

se"eral important reasons to obtain a biopsy@ 2ot all kidney

disease in SLE patients is classic >$ mediated !lomerulonephritis

(L2) so one therapy does not t all patients# ?or eample nonL2

!lomerular diseases ha"e been reported in SLE patients# &&7,&'&

This literature is mostly case reports but in a series o '*' patients

*% were ound to ha"e chan!es consistent with ocal se!mental

!lomerulosclerosis minimal chan!e disease thin !lomerular

basement membrane disease hypertensi"e nephrosclerosis and

amyloidosis# &&7 The incidence o podocytopathies in lupus patients

appears to be !reater than in the !eneral population su!!estin! a

causal link to the immune dysre!ulation o SLE# &''&'3myloid

() amyloidosis has also been reported re$ L;S E6GTECT.SS lthou!h the !old standard or

the eact dia!nosis and classi cation o L2 is the renal biopsy it

should be emphasied that L2 is not a renal biopsy dia!nosis# 6enal

biopsy chan!es althou!h characteristic are not speci c and the

dia!nosis o L2 cannot be made unless the patient ul lls the


15/93

merican $olle!e o 6heumatolo!y criteria or SLE# >n the absence

o a concurrent clinical dia!nosis o SLE only a dia!nosis o immune

comple !lomerulonephritis can be made with the su!!estion that

the !lomerulonephritis in the appropriate clinical settin! could be

associated with SLE# The clinical utility o the kidney biopsy

depends on obtainin! an aden as

much as e"ery biopsy is a clinicopatholo!ic correlation the

nephropatholo!ist must be !i"en all rele"ant clinical inormation in

order to properly interpret the tissue and inte!rate the microscopic

ndin!s with the clinical data# ?urthermore it is essential that the

clinician and patholo!ist re"iew the ndin!s to!ether beore

initiation o therapy to ensure that speci c clinical concerns ha"e

been addressed and that the lesions ha"e been contetualied

appropriately# The rst renal biopsy o a patient with L2 althou!himportant dia!nostically and therapeutically has somewhat limited

pro!nostic "alue because most o the acti"e lesions are re"ersible

with treatment# owe"er a ollowup biopsy perormed ater se"eral

months or years may pro"ide important pro!nostic inormation#

&3&,&33 > the de!ree o chronic inBury in the ollowup biopsy does

not chan!e substantially and the patient had a !ood response to

treatment outcome is likely to be a"orable# >n contrast i the

de!ree o chronic inBury is substantially more prominent in a ollow

up biopsy a pro!ressi"e decline in the disease course can be

anticipated# $lassi cation Schemes or Lupus 2ephritis 6enal

biopsy ndin!s in L2 in"ol"e the entire spectrum o renal

patholo!y# Thereore it became necessary to de"elop a patholo!ic

classi cation o L2# rst attempt was made in &79- by a !roup

o patholo!ists under the auspices o the Dorld ealth .r!aniation

(D.) and was later desi!nated as the D. classi cation# This

was urther modi ed in &78' and &77*# &3- The ori!inal D.

classi cation was relati"ely simple with "e classes o L2 (Table

*3#&)# SubseS2F6;S classi

cation is based primarily on characteristic li!ht microscopic

patterns o !lomerular inBury@ Cesan!ial hypercellularity#


16/93

Cesan!ial hypercellularity is almost always present in L2 ecept in

$lass > (?i!# *3#3) and is the basic and probably the earliest L2

lesion which is later combined with other patholo!ic patterns o

inBury# Endocapillary hypercellularity# Endocapillary hyper

cellularity is the hallmark lesion in orms o prolierati"e L2 (?i!s#

*3#- and *3#*)# >ntracapillary cells usually are in ltratin! in

ammatory cells (includin! monocytesFmacropha!es

polymorphonuclear leukocytes lymphocytes and rarely eosinophils

or basophils)# There may also be a component o endothelial cell

prolieration# Etracapillary hypercellularity# Etracapillary

prolieration results in crescent ormation (?i!# *3#/) and is

common in prolierati"e orms o L2# >t is re

these subendothelial deposits are lar!e enou!h they may occlude

the entire !lomerular capillary lumen and appear as Phyalin

thrombiQ (?i!s# *3#9 and *3#&+)# Dire loop lesions are positi"e or

periodic acidSchif (;S) ne!ati"e with methenamine sil"er stain

and red with CassonRs trichrome stain# Dire loop lesions are much

more common in L2 with !lobal !lomerular hypercellularity than

with biopsies showin! mainly se!mental hypercellularity andFor

necrosis# Spikes# 5iuse uniorm !lomerular capillary loop

thickenin! with PspikeQ ormation on methenamine sil"er stain

(?i!s# *3#&& and *3#&') is the main li!ht microscopic pattern o

inBury i the immune comple deposits are subepithelial inmembranous lupus nephritis# The >S2F6;S classi cation (Table

*3#&) retained the main subclasses o the modi ed D. classi

cation but introduced se"eral modi cations@ The >S2F6;S classi

cation diferentiates acti"e () and chronic ($) and se!mental (S)

and !lobal (=) !lomerular lesions# cti"e !lomerular lesions include

!lomerular endocapillary hypercellularity with or without leukocyte


17/93

in ltration and with substantial luminal reduction karyorrheis

brinoid necrosis rupture o the !lomerular basement membrane

cellular or brocellular crescents wire loop lesions and lar!e

intraluminal immune complees (hyalin thrombi) (?i!s# *3#- to *3#8

and *3#&+)# $hronic lesions include !lomerular sclerosis (se!mental

or !lobal) brous adhesions and brous crescents (?i!s# *3#&3 to

*3#&*)# Se!mental lesions in"ol"e less than hal o the !lomerular

capillary tut areaK !lobal lesions in"ol"e more than *+% o the

!lomerular capillary tut area#

$lass >@ Cinimal Cesan!ial Lupus 2ephritis >n class > L2 the

!lomeruli appear entirely normal by li!ht microscopy# owe"er

immuno uorescence and electron microscopy re"eal ob"ious

mesan!ial immune comple deposits (?i!# *3#&/)# $lass >>@

Cesan!ial ;rolierati"e Lupus 2ephritis >n class >> L2 there is pure

mesan!ial hypercellularity (?i!# *3#3) without !lomerular

endocapillary hypercellularity or crescents# >mmuno uorescence

and electron microscopy re"eal mesan!ial deposits (?i!s# *3#&9 and

*3#&8) as in class > L2# Ay electron microscopy a ew isolated !lo

merular capillary deposits may be seen# > many peripheral

lomerular capillary immune comple deposits are present the

dia!nosis o class >> L2 should not be made# $lass >>>@ ?ocal Lupus

2ephritis >n class >>> L2 ob"ious endocapillary or etracapillary

(crescents) prolierati"e lesions are seen (?i!s# *3#9 *3#8 and

*3#&7) but in less than *+% o all !lomeruli includin! sclerotic!lomeruli which are also taken into account# =lomerular lesions in

ocal L2 are almost always se!mental (?i!# *3#8)# Ay immuno

uorescence and electron microscopy abundant mesan!ial immune

comple deposits are een usually associated with se!mental

!lomerular capillary deposits (?i!# *3#'+)# There are three possible

subclasses o ocal L2# >n class >>> () there are only acti"e

lesions (ocal prolierati"e L2)# >n class >>> (F$) both acti"e

and chronic lesions are present (ocal prolierati"e and sclerosin!

L2)# >n such cases ocal or se!mental sclerosin! !lomeruli coeist

with !lomeruli with acti"e prolierati"eFnecrotiin! lesions# >n

class >>> ($) only ocal sclerosin! !lomerular lesionsare noted with

!lomerular scars and se!mental or !lobal sclerosis (ocal sclerosin!

L2)# cti"e lesions are not seen#


18/93

$lass >J@ 5ifuse Lupus 2ephritis >n this class o L2 se!mental or

!lobal endo or etracapillary !lomerular prolierati"e lesions are

seen in more than *+% o all !lomeruli (?i!s# *3#- to *3#8)# Lar!e

subendothelial deposits "isible under the li!ht microscope (wire

loop lesions) (?i!s# *3#9 and *3#&+) are common# >n class >J L2 the

!lomerular lesions can be !lobal or se!mental# lso acti"e and

chronic !lomerular lesions are e"aluated separately# >mmuno

uorescence and electron microscopy re"eal abundant !lomerular

mesan!ial and capillary loop deposits# The !lomerular capillary loop

deposits are mainly subendothelial and re


19/93

houseQ pattern (see later tet) and the >!= deposits contain mainly

>!=& and >=!3 as opposed to >!=' and >!=- (see later)# owe"er we

encountered se"eral cases o class J L2 with >!=- predominant

!lomerular capillary deposits# Cesan!ial immune comple deposits

are almost in"ariably present# ew small subendothelial deposits

are possible# Electron microscopy usually re"eals endothelial

tubuloreticular inclusions (T6>s) (?i!# *3#'*)# $lass J>@ d"anced

Sclerosin! Lupus 2ephritis >n class J> L2 o"er 7+% o the !lomeruli

are !lobally sclerosed without residual acti"ity (?i!# *3#&-)# There

has to be clinical or morpholo!ic e"idence that the ad"anced

!lomerular sclerosis is secondary to L2# >mmuno uorescence and

electron microscopy still reS2F6;S $lassi cation lthou!h se"eral

ollowup studies emphasie the bene ts o the >S2F6;S classi cation o L2 &3/&39 not all in"esti!ators share this enthusiasm#

&38&37 The classi cation is based purely on morpholo!ic ndin!s

and arbitrary de nitions# ?or eample the classi cation o

prolierati"e L2 into ocal and difuse orms is based on an

arbitrary cut of "alue o *+% !lomerular in"ol"ement# >t is hard to

ima!ine that a patient with L2 and -+% !lomerular in"ol"ement

would e treated and respond diferently than a patient with /+%

!lomerular in"ol"ement# The de nitions o se!mental and !lobal

lesions are e"en more contro"ersial# se!mental lesion is de ned

by in"ol"ement o less than *+% o the !lomerular surace area in

the tissue section# >n contrast a !lobal lesion is de ned as

in"ol"ement o more than *+% o the !lomerular surace area# The

de!ree o in"ol"ement in a !i"en tissue section depends on the

plane o the section throu!h the !lomerular tut# Thus dependin!

on the le"el o the cut a se!mental lesion could appear to in"ol"e

more or less than *+% o the !lomerular capillary surace area#

?urthermore some in"esti!ators ar!ue that the patho!enesis o L2

with true !lobal lesions is diferent rom L2 with se!mental

!lomerular lesions and that this afects outcomes and may re


20/93

not nd any dierence in outcome between patients with class >JS

and class >J= L2 &-3,&-/ but this may be because cases o class

>J= with se!mental lesions in"ol"in! more than *+% o the

!lomerular tut were !enerally not separated out rom class >J=

with &++% tut in"ol"ement# &37&-'&-9t the present time these

concerns remain unresol"ed# >mmuno uorescence ?indin!s in

Lupus 2ephritis Cost renal patholo!y laboratories perorm

immuno uorescence with a panel o antibodies to >!= >! >!C

kappa and lambda li!ht chains complement components $&nterestin!ly !lomerular immune comple deposits in

L2 oten show a Pull houseQ pattern meanin! that all or almost all

immunoreactants (>!= >! >!C kappa and lambda li!ht chains

$&!= subclass distributions# &-8 >n !eneral most cases o L2 immunecomplees contain >!=& and >!=3 less >!=' and minimal >!=-# The

diferences in >!= subclass distribution in diferent renal

compartments raise the possibility that !lomerular and

etra!lomerular immune comple deposits ha"e a diferent

patho!enesis#


21/93

lectron Cicroscopy in Lupus 2ephritis ltrastructural eamination

practically always re"eals mesan!ial immune comple deposits in

any orm o L2 (?i!# *3#&8)# Sometimes the electron dense deposits

may ha"e a P n!erprintQ substructure (?i!# *3#'8)# T6>s seenmainly in endothelial cells are a "ery common ultrastructural

ndin! in L2 (?i!# *3#'*)# lthou!h not dia!nostic o L2 T6>s re ect

hi!h intereron le"els in patients with acti"e SLEK thereore they

are also called intereron ootprints# T6>s are present all o"er the

body not only in renal endothelial cells# Tubulointerstitial Lesions

in Lupus 2ephritis Li!ht microscopic lesions in the

tubulointerstitium are nonspeci c# >nterstitial in ammatory cell

in ltrates may or may not be present in biopsies with L2 (?i!#

*3#'7)# They are more common in patients with prolierati"e L2

(class >>> or >J) and indicate an acti"e disease process# >nterestin!ly

the de!ree o interstitial in ammatory cell in ltrate does not

correlate with the de!ree o tubulointerstitial immune comple

deposition# &-8&-7 >n later sta!es o L2 interstitial brosis and

tubular atrophy appear and indicate pro!ressi"e chronic inBury (?i!#

*3#3+)# >nterstitial brosis and tubular atrophy may or may not be

associated with acti"e in ammatory cell in ltrate in the same

biopsy specimen# rterialFrteriolar Lesions in Lupus 2ephritis

lthou!h any type o "ascular patholo!y may occur in a patient

with SLE there are our basic "ascular patterns o inBury that areattributed to SLE# &*+ ncomplicated arterialFarteriolar immune

comple deposits (?i!# *3#'9)# This is the most common pattern o

"ascular patholo!y related to SLE and is ren more chronic sta!es concentric thickenin!


22/93

(onion skinnin!) o the arterialFarteriolar walls may de"elop#

rterialFarteriolar immune comple deposits may or may not be

present# The !lomerular chan!es include brin thrombi andFor

prominent thickenin! o the !lomerular capillaries secondary to

subendothelial electron lucent widenin! between the !lomerular

capillary basement membrane and the swollen endothelium (seen

on electron microscopy)# Aecause o the capillary wall thickenin!

the !lomerular capillary lumen is narrowed and many o these

!lomeruli appear Pbloodless#Q ?ra!mented 6A$s are not unusual in

the !lomerular capillaries# >n some !lomeruli the dominant eature

is ischemic wrinklin! o the capillaries particularly i there is se"ere

obliteration o arterialFarteriolar lumen# 2onin ammatory

necrotiin! lupus "asculopathy (?i!# *3#3')# This is a somewhat

contro"ersial "ascular pattern o inBury in patients with SLE# >n such

cases there is necrosis o the wall o the small arteriesF arterioleswithout ob"ious thrombus ormation and in ammatory cell

reaction# The lesion is thou!ht to be related to abundant "ascular

immune comple deposits and is "ery di cult to dierentiate rom

TC# True lupus "asculitis# >t is "ery rare to see true lupus

"asculitis in a renal biopsy specimen probably because o samplin!

issues# The morpholo!y o lupus "asculitis is similar to other orms

o "asculitis and includes brinoid necrosis o the wall o arteries

with an associated acti"e mied in ammatory cell in ltrate (?i!#

*3#33)# This "ascular wall necrosisFin ammation may or may not be

associated with secondary thrombus ormation#

$ombination o 5iferent $lasses o Lupus 2ephritis Cild L2 with

only mesan!ial deposits (classes > and >>) is the basic lesion o L2K

thereore we do not dia!nose combinations o classes >>> >J or J

class > or >># Ay >S2F6;S de nition classes >>> and >J cannot

combine# $lass J L2 is common in combination with class >>> or class

>J L2# >n these combined patterns o inBury the prolierati"e

component is listed rst (such as classes >>> J or classes >J J)#

lass Transormation in Lupus 2ephritis ?ollowup biopsies o L2

oten show a class diferent rom the initial biopsy# &33&3- > the

initial biopsy re"eals class > or >> L2 the ollowup biopsy commonly


23/93

shows ocal difuse prolierati"e or membranous L2# nother

common transormation is or ocal prolierati"e L2 (class >>>) to

e"ol"e into difuse prolierati"e L2 (class >J)# $lasses > >> >>> or >J

may transorm into membranous (class J) L2# >n cases o

prolierati"e L2 this transition usually re ects a combination o

prolierati"e and membranous L2# ny class can turn into class J>

(ad"anced sclerosin!) L2 e"entually# >t is less common or a hi!her

class L2 to turn into a lower class L2 in a renal biopsy because this

kind o transormation usually re ects a !ood response to treat

ment and most centers would not perorm a repeat biopsy in this

situation# Cembranous (class J) L2 on initial biopsy may turn into

combined prolierati"e and membranous L2# Less $ommon ;atterns

o =lomerular >nBury ssociated with Systemic Lupus Erythematosus

Cinimal chan!e disease# .ccasional patients with SLE de"elop

acute onset nephrotic syndrome and kidney biopsy re"eals onlyminimal chan!e disease without immune comple deposits or with

only mild mesan!ial immune comple deposits# $onsiderin! the

autoimmune nature o lupus it is likely that immunolo!ic podocyte

dama!e can occur and induce minimal chan!elike disease

responsi"e to corticosteroids# &'' $ollapsin! !lomerulopathy#

>t has been reported that occasionally !lomerular chan!es o

collapsin! !lomerulopathy may de"elop in patients with SLE# &*'

The patho!enesis is unclear# ;auciimmune prolierati"e

!lomerulonephritis# This may rarely occur in patients with SLE#

&*3&*- Aiopsies show acti"e prolierati"e lesions includin!

occasional crescents in the absence o rele"ant !lomerular immune

comple deposits# ntineutrophil cytoplasmic antibody (2$) is

ne!ati"e in such patients# > 2$ is positi"e and necrotiin!

prolierati"e lesions are present it is likely that the patient with SLE

also de"eloped 2$associated crescentic and necrotiin!

!lomerulonephritis# &-+ Lupus patients rarely can de"elop

renal diseases not related to SLE such as diabetic nephropathy

hypertensi"e nephrosclerosis or inectionrelated

!lomerulonephritis# cti"ity and $hronicity >ndices in Lupus2ephritisAecause renal biopsy ndin!s pro"ide important !uidance

to treatment o patients with L2 but the renal biopsy interpre

tation can be


24/93

pro"ide !uidelines as to what to look or while e"aluatin! renal

biopsies (Table *3#')#

$linicopatholo!ic $orrelations There is a reasonable correlationbetween clinical presentation and the class o L2 in many patients

(Table *3#3)# sually patients with acti"e prolierati"e orms o L2

ha"e se"ere proteinuria hematuria and low complement le"els#

owe"er these clinicopatholo!ic correlations are ar rom perect

and the de!ree o acti"ity and chronicity cannot be determined

based on clinical presentation alone# s mentioned earlier the

pro!nostic "alue o acti"e lesions in the biopsy is poorK howe"er a

ollowup biopsy may re"eal important pro!nostic normation# ?or

eample ad"anced chronic inBury in a biopsy specimen Bust as in

any other renal disease condition indicates poor renal outcome#?ollowup biopsies in L2 are not yet uni"ersally done but many

clinicians are be!innin! to think o these as part o the standard o

care or L2 patients# C2=ECE2T .? L;S 2E;6>T>S The

treatment o L2 should be based on biopsy ndin!s and

historically has been tied to the patholo!ic class o the kidney

lesion# owe"er within each >S2F6;S lupus class there is

considerable clinical "ariation (se"erity o proteinuria and renal

dysunction) and se"erity o kidney inBury (prolieration necrosis

crescents brosisFsclerosis)# These "ariations should be taken intoaccount to indi"idualie the application o the a!!ressi"e

immunosuppressi"e re!imens outlined later# >n addition to the

protocols described subse


25/93

prolierati"e or membranous L2 (classes >>> >J J)# n o"er"iew o

!enerally accepted approaches to mana!ement o L2 is shown in

?i!ure *3#3-# $lass > is rarely dia!nosed because there are no or ew

clinical renal maniestations that would warrant a biopsy# ;atients

with class >> L2 may ha"e !lomerular hematuria and proteinuria

(usually nonnephrotic) but kidney unction is normal# &*7 The

immunomodulatory re!imens used to treat etrarenal SLE are !en

erally su cient or class >> (and >) alon! with renoprotecti"e

measures or hypertension and proteinuria as clinically indicated#

t the other end o the spectrum o kidney unction inacti"e

sclerosin! L2 such as class J> and ad"anced sta!e sclerosin! class

>>> ($) or class >J ($) are clinically associated with se"ere chronic

kidney disease ($15)# Dhen L2 has reached this sta!e the

therapeutic strate!y should shit rom an immunosuppression ocus

ecept as needed or etrarenal SLE to a renal protection ocus#The !oal o renoprotection in inacti"e sclerosin! L2 is to prolon!

kidney unction and a"oid ES65 re>> or >J) can be an a!!ressi"e disease that

remportantly the

bene cial eect o cytotoic a!ents to preser"e kidney unction

was only apparent ater * years o ollowup# &/+,&/' This ndin!

has implications or assessin! the bene ts o new therapies# s a

result o the 2> trials hi!hdose corticosteroids and

cyclophosphamide !i"en intra"enously e"ery month ollowed by


26/93

aathioprine (H) or mycophenolate moetil (CC?) to si monthly

pulses o cyclophosphamide ollowed by ntra"enous

cyclophosphamide has dominated prolierati"e L2 protocols

althou!h oral cyclophosphamide shows comparable e cacy alon!

with ease o administration and !enerally less cost# &/+&/-,&/8.ral cyclophosphamide was ori!inally associated with increased

toicity especially cystitis &/+ but many o the early studies were

done usin! "ery hi!h doses (up to '#* m!Fk!Fday) or / or more

months# owe"er lower dose shorter duration oral cyclophospha

mide (?i!# *3#3*) is efecti"e welltolerated and results in a

cumulati"e cyclophosphamide eposure similar to / months o pulse

therapy# &/7 >mportant ca"eats with any cyclophosphamide re!i

men include dose reduction by '+% to 3+% in patients with

moderatese"ere renal insu ciency &9+ and doseadBustment to

keep the neutrophil count '+++ cells per l# To protect ertility

women should be ofered prophylais with leuprolide and men

testosterone while cyclophosphamide is bein! !i"en# &9&&9'

Sperm bankin! and o"arian tissue cryopreser"ation are additional

options# To a"oid increasin! risk o uture mali!nancy lietime

cumulati"e eposure to cyclophosphamide should be limited to 3/

!rams or less# &93&9-

>n an efort to reduce cyclophosphamide eposure in L2 a lowdose

cyclophosphamide induction re!imen (?i!# *3#3*) was desi!ned and

compared to si monthly pulses ollowed by two


27/93

patient population was mostly $aucasian and the prolierati"e L2

was o mildmoderate se"erity# To completely eliminate the

undesirable side efects o cyclophosphamide non

cyclophosphamide containin! protocols ha"e been e"aluated# The

re!imen that has achie"ed widespread utiliation used CC? or both

initial treatment and maintenance o L2 (?i!# *3#3*)# The spre"a

Lupus Cana!ement Study (LCS) prospecti"ely compared CC?

corticosteroids to intra"enous pulse cyclophosphamide corti

costeroids lookin! or superiority in response at the end o a /

month induction period# &99 This endpoint was not achie"ed# The

LCS induction trial showed the response to CC? and pulse

cyclophosphamide was entra"enous

cyclophosphamide was compared prospecti"ely to H plus

corticosteroids# 6epeat biopsy showed more chronic dama!e in the

H !roup and those treated with H had a hi!her incidence o

renal relapse and doublin! o the serum creatinine# &97 owe"er in

some areas o the world H may be the only option because o cost

or a"ailability and at least some lar!e retrospecti"e studies ha"e

shown lon!term responses similar to initial treatment with

cyclophosphamide# &8+ $alcineurin inhibitors ha"e recently been

tested as an alternati"e to cyclophosphamide or initial therapy inprolierati"e and mied prolierati"e plus membranous L2# >n a

prospecti"e randomied nonineriority trial 8& patients were

treated either with pulse intra"enous cyclophosphamide and

corticosteroids or tacrolimus (T$) and corticosteroids# &8& t /

months there was no diference between !roups in terms o

complete or complete plus partial remissions but lon!term ollow


28/93

up was not a"ailable# 2ine patients with class >J L2 reractory to

treatment with prolon!ed cyclophosphamide recei"ed T$ and

corticosteroids and 98% showed impro"ement with two complete

remissions# &8' nother small (n -+) randomied controlled study

compared 7 months o cyclosporin ($S) ollowed by a 7month

taper to an unusual 7month courseFdosin! re!imen o intra"enous

cyclophosphamide ollowed by 7 months o maintenance with oral

cyclophosphamide# &83 t the end o &8 months there were no

diferences between the two treatments# Lon!term ollowup (-+

months) continued to show no diference between treatmentsK

howe"er this was determined retrospecti"ely and maintenance

therapy ater &8 months was not protocol prescribed# dditionally

patients had only mild renal insu ciency because o concern o"er

reductions in !lomerular ltration rate (=?6) by $S but had

rather hi!h renal biopsy chronicity scores# >n summary calcineurininhibitors may ha"e a role in treatin! prolierati"e L2 but that role

remains to be determined based on lon!term prospecti"e

randomied trials# Le unomide is a dru! that blocks lymphocyte

prolieration T cell acti"ation and suppresses production o cy

tokines such as interleukin'# >t is currently used to treat

rheumatoid arthritis# There ha"e been two small trials rom $hina

usin! le unomide to treat L2# &8-&8* 6esponse rates were similar

to those o cyclophosphamide# >nterestin!ly in one study repeat

biopsies at / months showed a lar!e increase in the chronicity

inde &8- but this was not seen in repeat biopsies rom the second

study# &8* Thus lon!term trials will be re>> and

>J L2 with any o the initial therapies discussed is only about /+% at

/ to &' months (see later) an addon strate!y was employed in a

randomied controlled trial to determine i rituimabplus CC? and

corticosteroids could impro"e this outcome#&8/ This was based on

se"eral small openlabel uncontrolled trials that su!!ested

rituimab may be efecti"e in prolierati"e L2 either or reractorydisease or as initial therapy# &89,&7+ t &' months howe"er there

were no diferences between the rituimab and placebo !roups in

terms o complete or partial remissions# Thus rituimab cannot be

recommended as adBuncti"e initial therapy# The choice o initial

therapy or prolierati"e L2 is currently between a

cyclophosphamidecontainin! re!imen and an CC?only re!imen#


29/93

The patients in the two lar!est studies o CC? "ersus

cyclophosphamide !enerally had less se"ere L2 accordin! to the

le"el o proteinuria and kidney unction&7&&7' than the patients in

some o the randomied clinical trials o cyclophosphamide# &/'

Thus in se"ere class >>>F>J L2 a cyclophosphamidecontainin!

protocol or initial therapy may be preerred# Lowdose

cyclophosphamide could be considered in $aucasians with moderate

L2# The !oal o lon!term preser"ation o kidney unction should

also be considered when choosin! an initial therapy# s mentioned

earlier the superiority o cyclophosphamide plus corticosteroids

"ersus corticosteroids alone on preser"ation o kidney unction was

only apparent ater 3 to * years o ollowup# &/+,&/' >n a lon!term

study o initial therapy with CC? compared to initial therapy with

cyclophosphamide there were no si!ni cant dierences in renal

unction between the !roups ater a median o /- months#&/8owe"er more patients in the CC? !roup had relapses

prolon!ed proteinuria & ! per day and persistent serum

creatinine ' m! per dL# These combined clinical ndin!s ha"e

been associated in other studies with deterioration o kidney

unction o"er time# Similarly ater the initial / month treatment

period the LCS trial was etended (see later) or 3 years to

e"aluate maintenance therapy with either CC? or H# &73

lthou!h not desi!ned to compare the lon!term e cacy o initial

therapy on kidney unction there was a (nonsi!ni cant) trend

toward ewer treatment ailures in those who recei"ed

cyclophosphamide as initial therapy as opposed to CC?# This result

was independent o whether maintenance therapy was H or CC?#

Thus it cannot yet be stated with certainty that initial therapy with

CC? is e


30/93

CC? and H as maintenance therapies ater the /month initial

treatment period with either CC? or cyclophosphamide# ;atients

entered this etension phase only i they achie"ed a complete or

partial remission with initial therapy# ."er 3 years the composite

treatment ailure endpoint (death ES65 renal are sustained

doublin! o serum creatinine or re


31/93

only -+% o patients with class >>>F>J re"erted to class >> consistent

with the need or a prolon!ed maintenance phase# &97 >t is

reasonable to consider slowly taperin! immunosuppressi"e therapy

ater patients ha"e been in complete remission or a year# > a

patient has a history o renal relapses it may be prudent to etend

maintenance therapy# lthou!h there is no standard de nition o

complete remission or L2 in the literature or preser"ation o

kidney unction the most important clinical "ariable currently

a"ailable is proteinuria# ;roteinuria less than +#* ! per day should

be the tar!et or complete remission# '+- Serum creatinine should

impro"e to a patientRs preL2 baseline i known# ca"eat is that

serum creatinine may be increased (acceptably) by renoprotecti"e

therapies# Thus a stable serum creatinine should be the minimum

remmunosuppression should be continued inde nitely

or patients who achie"e only a partial remission and reno

protecti"e therapies intensi ed# This is supported by the ndin!

o continued acti"ity in biopsies taken ' or more years ater initial

therapy when si!ni cant proteinuria or an abnormal serum

creatinine is still present# '+/ lthou!h the strate!y o tryin! to

con"ert a partial remission to a complete remission by increasin!

corticosteroids or usin! alternati"e immunosuppressi"e a!ents is

not supported by e"idence it is oten tried# repeat kidney biopsy

may be useul to determine the le"el o patholo!ic acti"ity which i

se"ere could pro"ide a rationale or reinduction therapy#

Cembranous Lupus 2ephritis Cembranous L2 (class J) is a

nonprolierati"e !lomerulopathy that can be seen alone or with

superimposed prolierati"e L2# ;atients with mied membranous

and prolierati"e L2 are treated as or the prolierati"e component

but may ha"e a less a"orable pro!nosis# '+9 lternati"ely in asmall randomied controlled trial rom $hina in patients with mied

class >J and J L2 the combination o T$ (- m! per day) CC? (& !

per day) and oral corticosteroids was compared to pulse monthly

intra"enous $G$ (+#9* ! per m ' or / months) plus oral

corticosteroids# t / months 7+% o patients treated with this

lower dose Pmultitar!etQ therapy and -*% o patients treated with


32/93

$G$ achie"ed either completeor partial remission ( ; #++')#

'+8;ure membranous L2 occurs in 8% to '+% o patients with L2#

'+9'+7'&+ >t is !enerally re!arded as a less a!!ressi"e orm o

L2 but lon!term ollowup su!!ests a '+% incidence o chronic

kidney disease and ES65 de"elops in about 8% to &'% o patients#

'+9'+7,'&& >n addition to renal insu ciency the hea"y

proteinuria characteristic o membranous L2 i chronically present

predisposes to hyperlipidemia and atherosclerosis contributin! to

cardio"ascular morbidity and mortality# '&''&3 ea"y proteinuria

can also lead to a hypercoa!ulable state and arterial and "enous

thromboses# '&3'&- Thrombotic e"ents occur in &3% to '3% o

lupus patients and ha"e been linked to the presence o

antiphospholipid antibodies andFor the nephrotic syndrome#

'+9'+7'&* Spontaneous remission o hea"y proteinuria occurs in

only a minority o membranous L2 patients# '&/'&9Thusmembranous L2 althou!h indolent compared to prolierati"e L2

can be associated with important morbidities and thereore

warrants therapy# 6enoprotecti"e and antiproteinuric therapies

should be used or pure membranous L2 with low le"el proteinuria#

>n addition to renoprotecti"e and antiproteinuric measures class J

L2 patients with nephroticran!e proteinuria andFor renal insu

ciency should be considered or immunosuppression# sin!le

prospecti"e randomied clinical trial showed that the addition o

cyclophosphamide (si intra"enous pulses o +#* to & ! per m '

e"ery other month) or cyclosporin (* m!Fk!Fday or && months) to

corticosteroids was superior to corticosteroids (prednisone & m! per

k! e"ery other day or 8 weeks then taper) alone but within a year

o nishin! treatment -+% o the cyclosporin !roup had relapsed#

'&8 6elapses were not seen in the cyclophosphamide !roup or -8

months posttreatment# '&8 CC? (' to 3 ! per day) was ound to be

as e cacious as cyclophosphamide when sub!roup analysis o

class J L2 was perormed on data collected prospecti"ely in two

trials o CC? "ersus cyclophosphamide or classes >>> >J and J L2#

'&7 This is consistent with a number o smaller nonrandomiedretrospecti"e or openlabel studies o CC? and H (& to '

m!Fk!Fday) with or without corticosteroids in class J L2# '&*''+,

'''Thereore CC? plus corticosteroids may be tried initially to

induce remission and i that ails a switch in immunosuppression

to cyclophosphamide or cyclosporin plus corticosteroids in

patients with membranous L2 and hea"y proteinuria appears Busti


33/93

ed (?i!# *3#3-)# T6ETCE2T .T$.CES >2 L;S 2E;6>T>S

Treatment obBecti"es or L2 include remission in the short term and

pre"ention o relapse $15 ES65 or death in the lon! term# The

rst / months o L2 treatment is !enerally considered induction#

&99''3 lthou!h the term induction carries an epectation o

remission the number o complete responses at / and &' months is

low# >t is di cult to make direct comparisons o shortterm

outcomes amon! studies because treatment re!imens difer and

the de nitions o response and complete remission are not

uniorm# To !eneralie a complete response re>> and >J L2 &/3&/7&9*&99&7'''- showed a median

(ran!e) /month complete response rate o 8#/% (9#-% to '*%) and

an o"erall (complete plus partial) response rate o *3#*% (&8% to

8*%)# The median (ran!e) response &' months ater initiation o

therapy was /+#*% (3'% to 8*%)# These studies were done in

black ispanic and $aucasian patients and used corticosteroids

plus low or usualdose intra"enous cyclophosphamide oral

cyclophosphamide or CC?# >nterestin!ly in our studies o

$hinese SLE patients &/-,&/9 the median complete response at &'

to '- months was 9&% (*9% to 8&%) and the median o"erall

response was 7+% (93% to 7*%)# >t is not known why $hinese

patients respond so much better than most !roups to initial

therapy# These patients were howe"er more oten treated with oral

cyclophosphamide than intra"enous cyclophosphamide and their

!enetic and en"ironmental diferences may ha"e contributed to

response rates# ?or membranous L2 treatment trials su!!est that

the addition o an immunosuppressi"e to back!round corticosteroidwill yield a complete response in the nei!hborhood o -+% to /+%

o the patients within / to &' months#'&*'&8''&'''''*

6esponse may be more rapid with calcineurin inhibitors but the risk

o relapse is hi!h# The lon!term outcomes or prolierati"e L2 in

most studies were death doublin! o serum creatinine ES65 and

renal relapse# $onsiderin! "e studies &/3&/-&//''-''/ that


34/93

included black ispanic $aucasian and $hinese patients ob er"ed

or a median (ran!e) o / years (3 to &+ years) the rate o mortality

and ES65 were *% (+% to '+%) and -% (+% to &+%) respecti"ely#

5oublin! o serum creatinine occurred in 9#'% (+#+-% to &8#'%) o

patients and renal relapse in '3% (+#+-% to -'%)# Similarly '*% o

patients reached a composite endpoint o death doublin! serum

creatinine or ES65 in &+ years o ollowup ater treatment with the

lowdose (Eurolupus) cyclophosphamide protocol# &9/>n uni"ariate

analyses a lar!e number o risk actors or treatment outcomes o

prolierati"e L2 ha"e been reported# owe"er multi"ariate analyses

demonstrated that many were not independent risk actors#

>ndependent risk actors or L2 outcomes rom se"eral multi"ariate

analyses#&/-,&//&98&97'+''+3''/,''8 are shown in Table

*3#-# mon! these studies only serum creatinine at the be!innin!

o treatment appears to reach consensus as a biomarkero utureremission renal relapse $15 or ES65# >t is interestin! that ailure

to achie"e a complete remission was identi ed by only a ew

in"esti!ations to be a si!ni cant risk actor or relapse $15 ES65

or mortality &//''7'3+ especially considerin! that or most

proteinuric kidney diseases resolution o proteinuria is the

stron!est predictor o renal sur"i"al# '&3'3&'3' >t is possible that

i a more ri!orous de nition o complete remission had been

applied more studies would ha"e ound achie"in! a complete

remission to be an important actor in lon!term renal preser"ation#

?inally ew studies included socioeconomic status in their analyses

which may ha"e afected the stren!th o race and ethnicity as

independent risk actors# There is ar less inormation on risk

actors or the outcome o membranous L2 ater treatment# Ay

multi"ariate analysis the only independent predictor o ailure to

achie"e remission was initial proteinuria o"er * ! per day and

ailure to achie"e sustained remission was a risk actor or decline

in kidney unction# '&8 6ace or ethnicity did not appear to afect

response# ?.LL.D>2= ;T>E2TS D>T L2 ter successul initial

treatment o L2 patients must be careully ollowed because L2relapses# 6enal ares in L2 patients who had participated in

randomied clinical trials occurred in -+% o complete responders

within a median o -& months o remission and /3% o partial

responders within a median o &* months o response# '33

;utati"e risk actors or renal relapse are listed in Table *3#- but

there is no consensus on what predisposes patients to are# >t is


35/93

important to reco!nie and treat ares because with each episode

o acti"e L2 the kidney sustains chronic dama!e as demonstrated

by repeat biopsy studies that showed an increase in the renal

chronicity inde at the second biopsy# &97&79&77'++'+8'3- L2

relapses may thus culminate in $15 or e"entually ES65# 6enal

are is dia!nosed by increases in acti"ity o the urine sediment

amount o proteinuria and serum creatinine# $onsensus de

nitions or SLE and L2 ares ha"e cently been published '3*'3/

and one way o operationaliin! these as criteria is shown in Table

*3#*# '39 .ther ndin!s that support a dia!nosis o renal are

but are not necessarily always present (see later) include a all in

serum complement le"els and a rise in anti,doublestranded 52

antibody titers# ?lares are less likely to occur in patients who ha"e

been hi!hly immunosuppressed# 5epressed serum immuno!lobulin

le"els may indicate o"ert immunosuppressionK howe"er in se"erenephrotic syndrome due to L2 are serum immuno!lobulins can

also be low# 2onL2 causes o an increase in creatinine or an

increase in proteinuria must be ecluded (see also pa!e &*'8)#

>ncreases in proteinuria can occur with pre!nancy uncontrolled

hypertension and increased sodium intake# n approach to are

therapy based on are se"erity is !i"en in ?i!ure *3#3/#

$omplement components 3 and - ($3 $-) and anti,doublestranded

52 antibodies ha"e been used to support the dia!nosis o renal

are and also to anticipate impendin! are# owe"er these

serolo!ies ha"e low sensiti"ity (-7% to 97%) and speci city (*&%

to 9-%) or concurrent renal are and do not reliably predict

impendin! are e"en when measured serially with sensiti"ities

and speci cities around *+% and 9+% respecti"ely# '38,'-+ >n

one cohort the positi"e predicti"e "alues or $3 and $- to orecast

impendin! are were 9#-% and *#*% respecti"ely# '38

ein! able to anticipate imminent renal are and potentially start

therapy preempti"ely could attenuate the de"elopment o chronic

kidney inBury and minimie eposure to cytotoic a!ents# Similarly

modi cation o dru! dose and duration o therapy based on

biomarkers that predict outcome o a are would be epected to

impro"e treatment e cacy and reduce toicity# ?inally because

kidney biopsies are not repeated at e"ery are a nonin"asi"e

surro!ate o renal patholo!y would be "ery useul in choosin!

therapy# This approach to L2 treatment represents a undamental


36/93

chan!e rom a reacti"e to a proacti"e paradi!m and will re$ >26G T. TE 1>52EG >2 SGSTEC>$ L;S

E6GTECT.SS The most common clottin! e"ents that afect the

kidney in SLE occur as a maniestation o the antiphospholipid syn

drome (;S)# The incidence o renal ;S is about 3+% in SLE

usually in conBunction with L2 but also alone# &'*'*+Serolo!ic

studies show that lupus anticoa!ulant is present in 3+% to *'% ocases o renal ;S anticardiolipin antibodies in 9'% to 7*% o

patients but up to &*% had neither# &'-&'*Thrombi or e"idence o

past clottin! may be ound in any o the kidney blood "essels# The

term ;S nephropathy describes renal inBury due to thrombi or

their conse


37/93

the clinical acti"ity o L2 hypocomplementemia appears to be a risk

actor or etal loss whereas the use o lowdose aspirin may be

protecti"e# '**

here is also risk to the kidneys in patients with L2 who become

pre!nant# .ne study noted that renal ares and pro!ressi"e renaldysunction were not diferent between pre!nant and nonpre!nant

patients with L2# '*3 >n other studies renal ares were ound to

be hi!her in patients who became pre!nant and had only achie"ed

partial remission o the L2 or who had more than & ! per day

proteinuria or renal insu ciency# '**'*9 6enal are rates o

&+% to /7% ha"e been reported durin! or directly ollowin!

pre!nancy# '*3'**,'*9ydroychloroES >2 SGSTEC>$ L;S E6GTECT.SS

ES65 occurrin! as a result o SLE re


38/93

more years o dialysis SLE acti"ity remained pre"alent (-+% to

*+%) or worsened in peritoneal dialysis recipients#

'*8'*7'/''/31idney allo!rat sur"i"al in transplant recipients

with SLE appears to be close to that o nonSLE ES65 patients

accordin! to multi"ariate analyses o the nited States 6enal 5ata

Ser"ice (S65S) and the nited 2etwork or .r!an Sharin! (2.S)

databases# '/-'/* These lar!e studies looked at inormation rom

-3+++ to 73+++ transplant recipients '+++ to 3+++ ha"in! been

transplanted or ES65 due to L2# nalysis o the S65S lupus

patients who recei"ed deceased donor kidneys showed lower

allo!rat and patient sur"i"al rates than a diabetic ES65 reerence

!roup but the haard ratios were small at &- and

respecti"ely# '/-The analysis o 2.S showed that compared to

nonSLE recipients in !eneral recipients with SLE had the same rate

o patient and allo!rat sur"i"al# '/* dditionally in smaller studiesSLE recipients did not seem to ha"e a hi!her re> and only &'%

were class >>> >J or J# '9& lthou!h some studies did not nd

recurrent L2 to afect allo!rat loss '/8,'9+ in the lar!est

in"esti!ation '/9which eamined /8*+ SLE recipients recurrent

L2 was independently associated with allo!rat loss (haard ratio

-#+7K 7*% $> 3#-&,-#7')# The attributable risk or allo!rat loss was

low howe"er because the recurrence rate o L2 was so low ('#-%)#

6ecurrent L2 did not afect patient sur"i"al# '//'/9>n summary

lupus patients who come to ES65 should be ofered the option o akidney transplant# Aeore transplantation SLE should be


39/93

warranted# > dialysis is needed beore transplantation

hemodialysis may be the preerred modality# Dhile on dialysis e"en

thou!h lupus can become 6E$T>.2 .?

L;S 2E;6>T>S T6ETCE2T The need or new approaches to the

treatment o L2 is hi!hli!hted by the low complete remission rate

the modest o"erall remission rate and the hi!h occurrence o side

efects rom current therapies# The therapeutics now under

de"elopment and in "arious phases o clinical trial assessment

attempt to tar!et cytokines or cells speci cally in"ol"ed in the

patho!enesis o SLE# This will presumably result in less o"erall

immunosuppression but increased e cacy# ?i!ure *3#39

summaries the relationship o these no"el biolo!ic a!ents to

patho!enic mediators in SLE and L2# Tar!eted A cell therapies ha"erecei"ed the most attention because the A cell has such a wide

array o rele"ant unctions includin! autoantibody production

anti!en presentation and re!ulation o T and dendritic cells# The

most widely studied antiA cell a!ent is rituimab a monoclonal

antibody to the A cell anti!en $5'+# 6ituimab auses proound

depletion o circulatin! A cells that lasts or se"eral months#

number o small openlabel uncontrolled trials ha"e su!!ested

that rituimab is efecti"e in prolierati"e L2 either or reractory

disease or as induction therapy# &88,&7+'9' n eL= scores# A cells reL or sur"i"al and prolieration# 5ru!s that inhibit

these actors includin! belimumab an antiALyS monoclonal

antibody and atacicept a soluble receptor that binds to ALyS and


40/93

;6>L are bein! e"aluated in SLE# lthou!h belimumab has not

been used speci cally or L2 two phase >>> trials in SLE were

recently completed and at &' months successully met the

composite endpoint o impro"ement in the Systemic Lupus

Erythematosus 5isease cti"ity >nde no worsenin! o physicianRs

!lobal assessment o disease acti"ity and no new A>L= or!an

occurrences# '9-'9* utoreacti"e A cells communicate with and

acti"ate T cells throu!h interaction o A9#&FA9#' receptors with

$5'8 on T cells# 6ecombinant $TL- used to >!= hea"y chain

components (abatacept) blocks the interaction between $5'8 and

A9#&FA9#' and has been shown to reduce proteinuria in a rodent

model o L2# '9/ batacept is currently appro"ed or rheumatoid

arthritis and is bein! tested in human L2# utoreacti"e T cells rom

SLE patients bind and prolierate to a peptide containin! residues

&3& to &*& o the 9+1 spliceosomal protein within the & smallnuclear 62;# phosphorylated analo! called ;&-+ (lupuor)

pre"ents T cell prolieration and induces secretion o the antiin

ammatory cytokine interleukin&+# This peptide may tolerie T cells

and in a human SLE phase >> trial had minimal side efects and a

reduction in anti,doublestranded 52 antibody le"els by o"er

'+% su!!estin! possible utility in treatment# '99 s pre"iously

discussed a number o cytokines ha"e been implicated in the

patho!enesis andFor tissue dama!e o SLE and L2# . these

anta!onists o >?2 >L/ complement component $* and TL69

and 7 or their receptors ha"e been de"eloped and are at "arious

sta!es o preclinical or clinical testin!# '9-

re

li!man J Lum 6? .lson L et al# 5emo!raphic diferences in

the de"elopment o lupus nephritis@ retrospecti"e analysis#

m Ced# '++'K&&'@ 9'/,

9'7#http@FFwww#ncbi#nlm#nih#!o"FpubmedF&'+979&- '# Aastian

C 6oseman C Cc=win = r et al# Systemic lupus erythema

tosus in three ethnic !roups# U>># 6isk actors or lupusnephritis ater dia!nosis# Lupus# '++'K&&(3)@&*',

&/+#http@FFwww#ncbi#nlm#nih#!o"FpubmedF&'++-988'# dler C $hambers S Edwards $ et al# n assessment o renal

ailure in an SLE cohort with special reerence to ethnicity

o"er a '*,year period# 6heumatol#'++/K-*@&&--,&&-9# -# raB

S 1halil 2# $linical and immunolo!ical maniestations in /'-


41/93


42/93

'++7K&&93@-9,* &8# Trendelenbur! C LopeTrascasa C

;otluko"a E et al# i!h pre"alence o anti$&< antibodies in

biopsypro"en acti"e lupus nephritis# 2ephrol 5ial Transplant#

'++/K'&(&&)@3&&*,3&' &7# Carto 2 Aertolaccini CL

$alabui! E et al# nti$&< antibodies in nephritis@ correlation

between titres and renal disease acti"ity and positi"e

predicti"e "alue in systemic lupus erythematosus# nn 6heum

5is# '++*K/-(3)@---,--8# '+# Trouw L =roene"eld TD Seelen

C et al# nti$&< autoantibodies deposit in !lomeruli but are

only patho!enic in combination with !lomerular $&n"est# '++-K&&-(*)@/97,

/88# ' ?lierman 6 5aha C6# ;atho!enic role o anti$&mmunol >mmunopathol#

&77'K/3(&)@8-,88# '3# Schiferli ;eters 51# $omplement

the immunecomple lattice and the pathophysiolo!y o

complementde ciency syndromes# Lancet#

&783K'(83*/)@7*9,7*7# '-# ;ickerin! C$ Aotto C Taylor ;6

et al# Systemic lupus erythematosus complement de ciency

and apoptosis# d" >mmunol# '+++K9/@''9,3'-# '*# ebert

L# The clearance o immune complees rom the circulation o

man and other primates#m 1idney 5is# &77&K&9@3*',3/

'/# Airmin!ham 5 ebert L# $6& and $6&,like@ The primate

immune adherence receptors# >mmunol 6e"# '++&K&8+@&++,

&& '9# 2a"ratil S 1orb L$ hearn C# Systemic lupus

erythematosus and complement de ciency@ clues to a no"el

role or the classical complement pathway in the maintenance

o immune tolerance#>mmunopharmacolo!y# &777K-'(&,3)@-9,

*'# '8# Dalport C 6oss =5 Cackworth G$ et al# ?amily

studies o erythrocyte complement receptor type & le"els@

reduced le"els in patients with SLE are acmmunol# &78*K*7(3)@*-9,**-# '7# Airmin!ham 5

=a"it 1? Cc$arty SC et al# $onsumption o erythrocyte $6&

($53*) is associated with protection a!ainst systemic lupus

erythematosus renal are# $lin Ep >mmunol#

'++/K&-3(')@'9-,'8+# 3+# 1o er 5 !nello J $arr 6> et al#

Jariable patterns o immuno!lobulinand complement


43/93

deposition in the kidneys o patients with systemic lupus

erythematosus# m ;athol# &7/7K*/@3+*,3&/# 3 6icker 5C

ebert L 6ohde 6 et al# Serum $3 le"els are dia!nostically

more sensiti"e and speci c or systemic lupus erythematosus

acti"ity than are serum $- le"els# The Lupus 2ephritis

$ollaborati"e Study =roup# m 1idney 5is# &77&K&8(/)@/98,

/8*# 3'# Jerroust ; Dilson $A $ooper 26 et al# =lomerular

complement components in human !lomerulonephritis# $lin

>n"est# &79-K*3(&)@99,8-# 33# Aiesecker = 1at S 1o er 5#

6enal localiation o the membrane attack comple in systemic

lupus erythematosus nephritis# Ep Ced# &78&K&*-(/)@&997,

&97-# 3-# Delch T6 Aeischel LS Ditte 5;# 5iferential

epression o complement $3 and $- in the human kidney#

$lin >n"est# &773K7'(3)@&-*&,&-*8# 3*# Delch T6 Aeischel LS

?renke C et al# 6e!ulated epression o complement actor Ain the human kidney# 1idney >nt# &77/K*+(')@*'&,*'*# 3/#

Ciuno C Alanchin S =asnt#

&787K3/(&)@&++,&+9# -+# Dan! G u O Cadri et al#

melioration o lupuslike autoimmune disease in 2HAFD?&

mice ater treatment with a blockin! monoclonal antibody

speci c or complement component $*# ;roc 2atl cad Sci

S # &77/K73(&/)@8*/3,8*/8# - Aao L aas C 1raus 5C et

al# dministration o a soluble recombinant complement $3inhibitor protects a!ainst renal disease in C6LFlpr mice# m

Soc 2ephrol# '++3K&-(3)@/9+,/97# -'# Datanabe =arnier =

$ircolo et al# Codulation o renal disease in C6LFlpr mice

!enetically de cient in the alternati"e complement pathway

actor A# >mmunol# '+++K&/-(')@98/,97-# -3# Elliott C1 armi

T 6ui ; et al# Eects o complement actor 5 de ciency on


44/93

the renal disease o C6LFlpr mice# 1idney >nt# '++-K/*(&)@&'7,

&38# --# Li U ;tacek TS Arown EE et al# ?c !amma receptors@

structure unction and role as !enetic risk actors in SLE#

=enes >mmun# '++7K&+(*)@38+,387# -*# Darmerdam ;C "an

de Dinkle = Jlu! et al# sin!le amino acid in the second

>!like domain o the human ?c receptor >> plays a critical

role in human >!=' bindin!## >mmunol# &77&K&--@&338,&3-3#

-/# 1oene 6 1leiBer C l!ra et al# ?c !amma6>>>a&*8JF?

polymorphism in uences the bindin! o >!= by natural killer

cell ?c !amma6>>>a independently o the ?c !amma6>>>a

-8LF6F phenotype#Alood# &779K7+(3)@&&+7,&&&-# -9# 1arassa

?A Trikalinos T >oannidis ;# 6ole o the ?c !amma receptor

>>a polymorphism in susceptibility to systemic lupus

erythematosus and lupus nephritis@ a metaanalysis#rthritis

6heum# '++'K-/(/)@&*/3,&*9 -8# 1arassa ?A Trikalinos T>oannidis ;# The ?c !amma 6>>>?&*8 allele is a risk actor or

the de"elopment o lupus nephritis@ a metaanalysis#1idney

>nt#'++3K/3(-)@&-9*,&-8'# -7# 6a"etch J $lynes 6#

5i"er!ent roles or ?c receptors and complement in "i"o#nnu

6e" >mmunol# &778K&/@-'&,-3'# *+# $lynes 6 5umitru $

6a"etch J# ncouplin! o immune comple ormation and

kidney dama!e in autoimmune !lomerulonephritis#Science#

&778K'97@&+*',&+*-# * eller T =essner E Schmidt 6E et

al# $uttin! ed!e@ ?c receptor type > or >!= on macropha!es

and complement mediate the in ammatory response in

immune comple peritonitis# >mmunol# &777K&/'(&+)@*/*9,

*// *'# Catsumoto 1 Datanabe 2 kikusa A et al# ?c

receptorindependent de"elopment o autoimmune

!lomerulonephritis in lupusprone C6LFlpr mice# rthritis

6heum# '++3K-8(')@-8/,-7-# *3# 6o"in A# The chemokine

network in systemic lupus erythematosus nephritis#?rontiers in

Aioscience# '++9K&3@7+-,7''# *-# ;eterson 1S uan! ? Hhu

et al# $haracteriation o hetero!eneity in the molecular

patho!enesis o lupus nephritis rom transcriptional pro leso lasercaptured !lomeruli# $lin >n"est# '++-K&&3(&')@&9'',

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!ene epression in lupus nephritis#nn 6heum 5is#

'++9K//(9)@88/,87'# */# Casutani 1 kahoshi C Tsuruya 1

et al# ;redominance o Th& immune response in difuse

prolierati"e lupus nephritis# rthritis 6heum#


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'++&K--(7)@'+79,'&+/# &**& 3# dler C $hambers S Edwards

$ et al# n assessment o renal ailure in an SLE cohort with

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tol# '++/K-*@&&--,&&-9# -# r aB S 1halil 2# $linical and

immunolo!ical mani estations in /'- SLE patients in Saudi

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important predictor o mortality within the dama!e inde@

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*-*#http@FFwww#ncbi#nlm#nih#!o"FpubmedF&7'3388- 9# Dard

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Dinkler T enschel T 1alies > et al# $onstant isotype

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