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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$) ratios can be used in addition to urine dipsticks to
screen patients but are not accurate enou!h to be used to make
therapeutic decisions or to ollow chan!es in proteinuria ma!nitude
in response to therapy# The most reliable method to
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mycophenolate moetil (see later) and biopsy inormation would
not chan!e the approach to therapy# &&8 There are howe"er
se"eral important reasons to obtain a biopsy@ 2ot all kidney
disease in SLE patients is classic >$ 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
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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#
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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
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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 >>> ($) only ocal sclerosin! !lomerular lesionsare noted with
!lomerular scars and se!mental or !lobal sclerosis (ocal sclerosin!
L2)# cti"e lesions are not seen#
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$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
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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
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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#
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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!
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(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
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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
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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
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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
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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
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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
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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#
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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
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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
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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
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$G$ 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
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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
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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
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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 $- to orecast
impendin! are were 9#-% and *#*% respecti"ely# '38
ein! able to anticipate imminent renal are and potentially start
therapy preempti"ely could attenuate the de"elopment o chronic
kidney inBury and minimie eposure to cytotoic a!ents# Similarly
modi cation o dru! dose and duration o therapy based on
biomarkers that predict outcome o a are would be epected to
impro"e treatment e cacy and reduce toicity# ?inally because
kidney biopsies are not repeated at e"ery are a nonin"asi"e
surro!ate o renal patholo!y would be "ery useul in choosin!
therapy# This approach to L2 treatment represents a undamental
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chan!e rom a reacti"e to a proacti"e paradi!m and will re$ >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
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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
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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*% $> 3#-&,-#7')# The attributable risk or allo!rat loss was
low howe"er because the recurrence rate o L2 was so low ('#-%)#
6ecurrent L2 did not afect patient sur"i"al# '//'/9>n summary
lupus patients who come to ES65 should be ofered the option o akidney transplant# Aeore transplantation SLE should be
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warranted# > dialysis is needed beore transplantation
hemodialysis may be the preerred modality# Dhile on dialysis e"en
thou!h lupus can become 6E$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
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;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# $linical and immunolo!ical maniestations in /'-
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'++7K&&93@-9,* &8# Trendelenbur! C LopeTrascasa C
;otluko"a E et al# i!h pre"alence o anti$&< 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
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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
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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
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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
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6a"etch J# ncouplin! o immune comple ormation and
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&778K'97@&+*',&+*-# * eller T =essner E Schmidt 6E et
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*// *'# Catsumoto 1 Datanabe 2 kikusa A et al# ?c
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6heum# '++3K-8(')@-8/,-7-# *3# 6o"in A# The chemokine
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'++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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rabia# Lupus# '++7K&8@-/*,
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6heumatol# '++7K3/@/3,
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&7/9K-/(-)@*/7,*97#http@FFwww#ncbi#nlm#nih#!o"FpubmedF-&/-'/+ &'#
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