nA1u8L 8LvlLWS | n L P 8C L C C ?

vCLuML 7 | nCvLM8L8 2011 | 633

ulvlslon of edlaLrlc
nephrology !ohns
Popklns unlverslLy
School of Medlclne ,
200 n Wolfe SLreeL ,
8oom 3064 8alLlmore ,
Mu 21287 uSA
) M A ALklnson .(
Chlldren's PosplLal of
hlladelphla ,
34
Lh
SLreeL and Clvlc
CenLer 8oulevard ,
hlladelphla ,
A 19104 uSA
) S L lurLh .(
Correspondence Lo :
M A ALklnson
maLklns3[[hmledu
Anemla ln chlldren wlLh chronlc kldney dlsease
MeredlLh A ALklnson and Susan L lurLh
AbsLracL | Anemla ls a common comorbldlLy ln chlldren wlLh chronlc kldney dlsease (Cku)
1hls condlLlon ls
assoclaLed wlLh mulLlple adverse cllnlcal consequences and lLs managemenL ls a core
componenL of nephrology
care lncreased morbldlLy and morLallLy lncreased rlsk of cardlovascular dlsease and
decreased quallLy of
llfe have been assoclaLed wlLh anemla of Cku ln chlldren AlLhough numerous complex
facLors lnLeracL ln Lhe
developmenL of Lhls anemla eryLhropoleLln deflclency and lron dysregulaLlon (lncludlng lron
deflclency and lronresLrlcLed eryLhropolesls) are Lhe prlmary causes ln addlLlon Lo lron
supplemenLaLlon eryLhropoleLlnsLlmulaLlng
agenLs (LSAs) can effecLlvely LreaL Lhls anemla buL Lhere are lmporLanL dlfferences ln LSA
dose requlremenLs
beLween chlldren and adulLs Also hyporesponslveness Lo LSA Lherapy ls a common
problem ln chlldren wlLh
Cku AlLhough escalaLlng LSA doses Lo LargeL lncreased hemoglobln values ln adulLs has
been assoclaLed wlLh
adverse ouLcomes no sLudles have demonsLraLed Lhls assoclaLlon ln chlldren 1he quesLlon
of approprlaLe
LargeL hemoglobln levels ln chlldren and Lhe approach by whlch Lo achleve Lhese levels
remalns under debaLe .
8andomlzed conLrolled sLudles are needed Lo evaluaLe wheLher normallzaLlon of
hemoglobln concenLraLlons ls
beneflclal Lo chlldren and wheLher Lhls pracLlce ls assoclaLed wlLh lncreased rlsks .
ALklnson M A lurLh S L naL 8ev nephrol 7 633641 (2011) publlshed onllne 6
SepLember 2011 dol101038/nrneph2011113
lnLroducLlon
A low hemoglobln level ls a common comorbldlLy ln
chlldren wlLh chronlc kldney dlsease (Cku) and ls
assoclaLed wlLh mulLlple adverse cllnlcal consequences ,
lncludlng morLallLy and Lhe developmenL and progres -
slon of cardlovascular rlsk facLors such as lefL venLrlcular
hyperLrophy (LvP .(
1 3
uaLa from Lhe llLeraLure lndlcaLe
LhaL unconLrolled anemla mlghL be relaLed Lo Lhe progres -
slon of Cku as well as Lo an lncreased rlsk of hosplLallza -
Llon .
4 7
8y conLrasL lncreased hemoglobln values ln
chlldren wlLh Cku have been assoclaLed wlLh lmproved
healLhrelaLed quallLy of llfe .
8
1hus anemla manage -
menL ls a core componenL of cllnlcal pedlaLrlc nephro -
logy pracLlce AlLhough many facLors such as shorLened
llfespan of red blood cells and lron deflclency conLrlbuLe
Lo CkuassoclaLed anemla eryLhropoleLln deflclency ls
Lhe prlmary eLlologlcal facLor .
ueflnlng anemla ln chlldren wlLh Cku ls noL sLralghL -
forward and requlres nuanced evaluaLlon AlLhough
normal hemoglobln values ln boLh adulLs and chlldren
are known Lo vary based on age race and sex anemla
managemenL guld el lnes f rom L he naL lona l kldne y
loundaLlon kldney ulsease CuLcomes CuallLy lnlLlaLlve
) nklkuCCl) have noL conslsLenLly recognlzed Lhese
demographlc dlfferences wlLh regard Lo Lhe evaluaLlon
and managemenL of Lhe anemla of Cku .
9 11
ln adulL
paLlenLs wlLh Cku a flxed cuLoff hemoglobln value of
> 110 g/l has been used Lo deflne anemla based on evl -
dence LhaL ouLcomes are worse below Lhls Lhreshold .
12
revlous verslons of Lhe kuCCl anemla guldellnes
slmply applled Lhe adulL hemoglobln cuLoff Lo chlldren ,
buL Lhls deflnlLlon has been shown Lo subsLanLlally under -
esLlmaLe Lhe prevalence of anemla ln paLlenLs wlLh Cku
aged 18 years .
6
Clven LhaL chlldren are llkely Lo suffer
dlfferenLly from Lhe effecLs of varlous Cku compllca -
Llons lncludlng anemla compared wlLh adulLs Lhe
uLlllLy of applylng an adulL hemoglobln LreaLmenL LargeL
Lo anemla managemenL ln chlldren has been called lnLo
quesLlon 1he mosL recenL nklkuCCl cllnlcal pracLlce
guldellnes use reference daLa from Lhe naLlonal PealLh
and nuLrlLlon LxamlnaLlon Survey (nPAnLS) lll Lo
clLe normaLlve values ln chlldren and recommend lnlLl -
aLlng an evaluaLlon for anemla when hemoglobln levels
fall below Lhe agespeclflc and sexspeclflc 3
Lh
percenLlle
value alLhough hemoglobln dlfferences by race are sLlll
noL Laken lnLo accounL (1able 1 .(
12
1he nPAnLS lll
survey daLa provlde means sLandard errors and percenLlle
dlsLrlbuLlons for hemaLologlc laboraLory values collecLed
from Lhe uS populaLlon beLween 1988 and 1994 .
9
ln Lhls 8evlew we wlll explore Lhe adverse assocl -
aLlons of anemla of Cku ln chlldren wlLh aLLenLlon Lo
rlsk facLors for lLs developmenL 1he eLlologlcal facLors
for Lhls anemla wlll be dlscussed along wlLh LherapeuLlc
sLraLegles and ongolng challenges ln lLs managemenL .
MorbldlLy and morLallLy
ln chlldren as ln adulLs anemla ls a common compllca -
Llon of Cku whlch lncreases ln prevalence wlLh advanc -
lng sLage of Cku uaLa from Lhe norLh Amerlcan edlaLrlc
8enal 1rlals and CollaboraLlve SLudles (nA81CS) have
demonsLraLed LhaL Lhe prevalence of anemla ln chlldren ls
73 % aL sLage 3 Cku 87 aL sLage 4 and 93 aL sLage 3 .
13
1he anemla of Cku ln chlldren ls assoclaLed wlLh subsLan -
Llal morbldlLy an lncreased rlsk of cardlovascular dlsease ,
CompeLlng lnLeresLs
1he auLhors declare no compeLlng lnLeresLs .
l C C u S C n C k u l n C P l L u 8 L n
2011 Macmlllan ubllshers LlmlLed All rlghLs reserved636 | nCvLM8L8 2011 | vCLuML
7 wwwnaLurecom/nrneph
decreased quallLy of llfe and reduced exerclse capaclLy .
unllke ln adulLs however Lhe requlremenLs for llnear
growLh and Lhe lncreased prevalence of neurocognlLlve
problems ln chlldren wlLh Cku mlghL place Lhem aL dls -
proporLlonaLely lncreased rlsk for adverse effecLs relaLed Lo
perslsLenL anemla .
1413
1he anemla of Cku has been asso -
claLed wlLh numerous adverse effecLs ln chlldren Among
adolescenLs malnLalned on hemodlalysls decreased
hemoglobln levels are a sLrong and lndependenL predlc -
Lor of morLallLy .
316
Anemla has also been assoclaLed wlLh
lncreased frequency of hosplLallzaLlon and lncreased rlsk
of morLallLy ln chlldren lnlLlaLlng dlalysls .
17
An lncreased
rlsk of hosplLallzaLlon ln chlldren wlLh anemla has been
found noL only ln Lhose on dlalysls buL also among chll -
dren wlLh predlalysls Cku SLaples eL al demonsLraLed
LhaL anemla was assoclaLed wlLh a nearly 40 lncreased
rlsk of allcause hosplLallzaLlon over 1 year of followup
ln chlldren wlLh Cku sLage 2 and hlgher .
7
Anemla ls known Lo lncrease Lhe rlsk of develop -
lng LvP whlch ls prevalenL ln chlldren wlLh Cku and
confers an lncreased rlsk for cardlovascular dlsease .
218
1hls assoclaLlon has been noLed noL only ln chlldren on
dlalysls buL also among Lhose wlLh Cku sLages 24 ln
a cross secLlonal analysls of Lhe Chronlc kldney ulsease
ln Chlldren (Cklu) CohorL SLudy decreased hemoglobln
values were assoclaLed wlLh LvP lndependenLly of an
elevaLlon ln blood pressure .
18
A Luropean cohorL sLudy
slmllarly noLed an lnverse correlaLlon beLween hemoglobln
concenLraLlon and lefL venLrlcular mass lndex ln paLlenLs
wlLh early sLages of Cku .
19
uecreased hemoglobln values
were also assoclaLed wlLh an lncreased rlsk of lncldenL
LvP ln a longlLudlnal sLudy of chlldren wlLh Cku .
1
lncreaslng evldence shows LhaL anemla may be an
lndependenL rlsk facLor for Lhe progresslon of Cku A
randomlzed conLrolled Lrlal conducLed ln adulL paLlenLs
wlLh Cku found LhaL early lnlLlaLlon of eryLhropoleLln
Lherapy ln Lhose wlLh mlld anemla seemed Lo delay Lhe
lnlLlaLlon of renal replacemenL Lherapy .
20
lurLh eL al found
LhaL among adolescenLs (aged 1118 years) wlLh predlalysls
key polnLs
u Anemla ln parLlcular anemla LhaL ls poorly responslve Lo LreaLmenL ls very
common ln chlldren wlLh chronlc kldney dlsease (Cku) and endsLage renal
dlsease
u Adverse effecLs of anemla ln Lhls populaLlon lnclude Lhe developmenL of
lefL venLrlcular hyperLrophy lncreased rlsk of hosplLallzaLlon and morLallLy ,
progresslon of kldney dlsease and decreased quallLy of llfe
u lronresLrlcLed eryLhropolesls has a key role ln Lhe developmenL of CkuassoclaLed anemla
and ls medlaLed ln parL by lnflammaLlon and Lhe
lronregulaLory proLeln hepcldln
u LryLhropoleLlnsLlmulaLlng agenLs (LSAs) and lron supplemenLaLlon remaln
Lhe malnsLays of Lherapy for Lhe anemla of Cku ln chlldren wlLh chlldren
demonsLraLlng hlgher LSA doslng requlremenLs Lhan adulLs
u 1he quesLlon of Lhe approprlaLe LargeL hemoglobln level ln chlldren remalns
under debaLe and randomlzed conLrolled sLudles are needed ln chlldren
wlLh Cku Lo evaluaLe Lhe rlsks and beneflLs of LargeLlng normallzaLlon of
hemoglobln levels
u 8egardlng Lhe safeLy and efflcacy of escalaLlng LSA doses Lhe ldenLlflcaLlon
of paLhways beyond eryLhropoleLln deflclency ls needed Lo develop oLher safe ,
nonLoxlc cllnlcal lnLervenLlons Lo LreaL Lhe anemla of Cku
Cku anemla was assoclaLed wlLh an acceleraLed decllne
ln glomerular fllLraLlon raLe (Cl8) compared wlLh Lhe
decllne raLe ln paLlenLs wlLhouL anemla .
4
uaLa from
Lhe nA81CS Cku daLabase have shown LhaL anemla ,
lndependenL of oLher facLors lncludlng underlylng dlag -
nosls hyperLenslon sLage of Cku and race ls assoclaLed
wlLh an lncreased rlsk of Cku progresslon (deflned by
reachlng Cku sLage 3 .(
21
roposed mechanlsms lnclude
renal Llssue hypoxla whlch sLlmulaLes producLlon of pro -
flbroLlc cyLoklnes 8esulLs of some eryLhropoleLln Lrlals
ln adulLs have suggesLed LhaL correcLlon of anemla may
decrease Lhe rlsk of Cku progresslon .
43
Anemla also adversely affecLs Lhe quallLy of llfe of pedl -
aLrlc paLlenLs wlLh Cku lncludlng Lhelr neurocognlLlve
developmenL and exerclse capaclLy .
12
Anemlc adolescenLs
wlLh Cku have reporLed greaLer llmlLaLlons ln physlcal
funcLlonlng schoolwork and acLlvlLles wlLh frlends
and famlly Lhan Lhelr peers who do noL have anemla ,
lndependenL of demographlc characLerlsLlcs lnclud -
lng sex race and level of kldney funcLlon .
8
ln Lerms of
growLh a domaln ln whlch many chlldren wlLh Cku
demonsLraLe lmpalrmenL early LreaLmenL of anemla wlLh
eryLhropoleLln ls assoclaLed wlLh lmprovemenL .
22
aLhogenesls of anemla ln pedlaLrlc Cku
A lL houg h mu lL lpl e c ompl e x f a c Lors lnLe r a c L ln L he
developmenL of Lhe anemla of Cku decreased pro -
ducLlon of eryLhropoleLln by Lhe dlseased kldney ls Lhe
prlmary defecL (8ox 1) ln Lhe ma[orlLy of chlldren wlLh
lmpalred renal funcLlon eryLhropoleLln producLlon ls
lnapproprlaLely low aL any glven hemoglobln concenLra -
Llon 1he mechanlsm for Lhls decreased producLlon has
noL been fully elucldaLed alLhough lL ls Lheorlzed LhaL lL
could be a resulL of progresslve loss of Lhe eryLhropoleLln -
produclng perlLubular flbroblasLllke lnLersLlLlal cells ln
Lhe kldney .
23
MulLlple oLher cllnlcal facLors mlghL conLrlbuLe Lo
anem l a among p aL l enL s w lL h Cku wh l ch wors ens
wlLh decllnlng Cl8 lron deflclency ls clearly assocl -
aLed wlLh anemla and ln chlldren wlLh Cku mlghL be
a resulL of nuLrlLlonal deflclency poor enLeral absorp -
Llon of lron supplemenLs or chronlc blood loss from
frequenL laboraLory LesLlng or ln Lhe conLexL of chronlc
hemodlalysls lndlvldual facLors LhaL cause anemla ln
Cku may have varylng lnfluence aL dlfferenL levels of
Cl8 AL earller sLages of Cku nuLrlLlonal facLors and
lron deflclency may have a more promlnenL role ln Lhe
eLlology of anemla 8y conLrasL decreased producLlon of
1able 1 | 3
Lh
percenLlle hemoglobln values ln chlldren
12
Age (years) 3
Lh
percenLlle for hemoglobln value (g/l (
lemales Males
1 2 108 107
3 3 111 112
6 8 113 113
9 11 119 120
12 14 117 124
13 19 113 133
8 L v l L W S
2011 Macmlllan ubllshers LlmlLed All rlghLs reservednA1u8L 8LvlLWS | n L P 8C L C
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eryLhropoleLln by Lhe dlseased kldney mlghL have a more
subsLanLlal conLrlbuLlon aL laLer sLages of Cku .
lmpalred eryLhropolesls
LvaluaLlng Lhe adequacy of lron sLores for eryLhropolesls
ls complex ln chlldren wlLh Cku lronresLrlcLed eryLhro -
polesls lnLerferes wlLh Lhe producLlon of healLhy red blood
cells by several mechanlsms absoluLe lron deflclency
from lnadequaLe lnLake or excesslve loss 'funcLlonal' lron
deflclency (whlch refers Lo lnadequaLe sLorage of lron Lo
supply bone marrow sLlmulaLed wlLh eryLhropoleLln -
sLlmulaLlng agenLs LSAs) and lmpalred lron Lrafflck -
lng ln Lhe seLLlng of lnflammaLlon .
24
ln order Lo address
Lhls lssue cllnlcally Lhe presence of sufflclenL lron sLores
musL be documenLed ln pracLlce serum levels of ferrlLln
and Lransferrln saLuraLlon (1SA1) are mosL ofLen used Lo
assess lron avallablllLy for eryLhropolesls 1he kuCCl
anemla guldellnes recommend LhaL durlng LSA LreaL -
menL chlldren wlLh nondlalysls Cku should achleve
serum ferrlLln levels of 223 pmol/l and 1SA1 20 buL
Lhere are no speclflc recommendaLlons for LargeL ferrlLln
and Lransferrln levels for chlldren noL recelvlng LreaL -
menL wlLh an LSA .
12
Clear evldence from Lhe llLeraLure
shows LhaL normal values for lron parameLers lncludlng
ferrlLln Lransferrln and 1SA1 vary wlLh age ln chlldren ,
wlLh reference values for all Lhree generally lncreaslng
from lnfancy Lhrough adolescence .
2326
AlLhough Lhe
kuCCl guldellnes do recognlze agespeclflc varlaLlons
ln hemoglobln ln Lhe recommendaLlons for anemla
evaluaLlon agespeclflc dlfferences ln lron parameLers
are noL consldered CLher poLenLlally more senslLlve ,
lndlcaLors of lron sLaLus lnclude reLlculocyLe hemoglobln
conLenL whlch measures Lhe lmmedlaLe lncorporaLlon
of lron lnLo reLlculocyLes percenLage of hypochromlc
red cells deflned as red blood cells wlLh cellular hemo -
globln concenLraLlon 280 g/l and serum soluble Lrans -
ferrln recepLor whlch ls upregulaLed when lron sLores are
decreased .
232728
AlLhough Lhese LesLs may provlde beLLer
esLlmaLes of lron avallablllLy Lhan ferrlLln or 1SA1 levels
alone none have aLLalned wldespread cllnlcal use .
ln cllnlcal pracLlce serum levels of ferrlLln are con -
sldered Lo be reflecLlve of lron sLores ln Lhe body and
1SA1 lndlcaLlve of Lhe amounL of lron avallable Lo be
LransporLed Lo Lhe bone marrow 1SA1 ls calculaLed from
serum lron concenLraLlon dlvlded by LoLal lronblndlng
capaclLy whlch ls lLself an lndlrecL measure of Lransferrln
levels .
28
Powever ferrlLln and 1SA1 boLh have llmlLa -
Llons as lndlcaLors of lron sLores ln paLlenLs wlLh Cku .
Serum ferrlLln concenLraLlon ls dlfflculL Lo lnLerpreL
as an lndependenL marker of lron sLaLus as lL ls also an
acuLephase reacLanL whose producLlon ls upregulaLed
by lnflammaLlon AlLhough serum ferrlLln concenLraLlon
ls presumed Lo reflecL a sLeadysLaLe leakage of ferrlLln
sLored lnLracellularly serum levels may noL accuraLely
reflecL LoLal lron sLores ln Lhe body Lhe process by whlch
lnLracellular ferrlLln enLers Lhe clrculaLlon from whlch lL ls
dlrecLly measured ls noL well undersLood .
28
roducLlon of
Lransferrln ls also affecLed by lnflammaLlon alLhough ln
conLrasL Lo Lhe effecL on ferrlLln lnflammaLlon decreases
Lransferrln producLlon resulLlng ln mlsleadlngly elevaLed
1SA1 values even ln Lhe seLLlng of lronresLrlcLed eryLhro -
polesls .
2328
ln chlldren speclflcally serum lron levels have
been shown Lo be lnversely correlaLed wlLh 8Ml zscore ,
alLhough a clear relaLlonshlp beLween 8Ml and ferrlLln has
noL been esLabllshed CbeslLyassoclaLed varlaLlons ln lron
parameLers mlghL also be medlaLed by lnflammaLlon .
29
lnflammaLlon
Chronlc lnflammaLlon ls common ln paLlenLs wlLh Cku
and ls clearly assoclaLed wlLh an lncreased rlsk of anemla .
rolnflammaLory cyLoklnes such as lL6 and Lumor
necrosls facLor are assoclaLed wlLh anemla and conLrlbuLe
Lo decreased hemaLopolesls by reduclng lron avallablllLy
and lnhlblLlng Lhe maLuraLlon of eryLhrold precursor cells
ln Lhe bone marrow .
30
lncreased levels of lnflammaLory
markers have been deLecLed ln boLh adulLs and chlldren
wlLh predlalysls Cku well before Lhe lnlLlaLlon of renal
replacemenL Lherapy .
31 33
ln a sLudy of 64 chlldren wlLh
Cku nearly half had CreacLlve proLeln levels of 1mg/l ,
lndlcaLlng lnflammaLlon .
33
1he anemla of lnflammaLlon has long been assocl -
aLed wlLh elevaLed cyLoklne levels buL for many years Lhe
underlylng mechanlsm of Lhls anemla was noL known 1he
anLlmlcroblal and lronregulaLory pepLlde hepcldln has
emerged as Lhe llnk beLween Lhe lnflammaLory response
and Lhe handllng of lron for eryLhropolesls Pepcldln ls an
acuLephase proLeln produced ln Lhe llver and ls a nega -
Llve regulaLor of lron uLlllzaLlon whlch conLrols blood lron
levels boLh by downregulaLlng Lhe absorpLlon of lron ln Lhe
lnLesLlne and by lnhlblLlng Lhe release of lron from lron -
sLorlng reLlculoendoLhellal cells 1he mechanlsm for Lhls
process ls Lhrough hepcldln lnduced downregulaLlon
of ferroporLln whlch ls Lhe ma[or Lransmembrane lron
LransporLer presenL on Lhe surface of lronsLorlng cells .
34 36
Pepcldln blnds dlrecLly Lo ferroporLln channels lnduc -
lng Lhelr lnLernallzaLlon and degradaLlon effecLlvely
Lrapplng lron wlLhln macrophages hepaLocyLes and
enLerocyLes (and reduclng lnLesLlnal absorpLlon .(
3437
lron
ls Lhus noL made avallable for eryLhropolesls Pepcldln ls
freely fllLered aL Lhe glomerulus and excreLed by Lhe
kldney and decreased hepcldln excreLlon ln Lhe conLexL
of decreased Cl8 ls llkely Lo conLrlbuLe Lo anemla .
34
ln
addlLlon hepcldln has been shown Lo be dlrecLly lnduced
8ox 1 | aLhogenlc facLors ln Lhe developmenL of anemla ln chlldren wlLh Cku
u LryLhropoleLln deflclency
u lronresLrlcLed eryLhropolesls (eg absoluLe lron deflclency lmpalred lron
Lrafflcklng funcLlonal lron deflclency (
u nuLrlLlonal deflclency (eg vlLamln 8
12
, follc acld carnlLlne (
u uremla
u 8one mlneral meLabollsm dlsorder
u lnflammaLlon (chronlc or acuLe (
u Chronlc blood loss
u lnadequaLe dlalysls
u MedlcaLlon
u ure red cell aplasla
AbbrevlaLlon Cku chronlc kldney dlsease .
l C C u S C n C k u l n C P l L u 8 L n
2011 Macmlllan ubllshers LlmlLed All rlghLs reserved638 | nCvLM8L8 2011 | vCLuML
7 wwwnaLurecom/nrneph
by prolnflammaLory cyLoklnes lncludlng lL6 and ls
poslLlvely correlaLed wlLh levels of CreacLlve proLeln ln
adulL paLlenLs wlLh Cku .
38 40
ln a sLudy of 48 chlldren wlLh
Cku sLages 24 26 chlldren on dlalysls and 32 adulLs
wlLh Cku sLages 24 serum hepcldln levels were com -
pared wlLh Lhose of healLhy pedlaLrlc and adulL conLrols .
Pepcldln levels among chlldren wlLh boLh endsLage renal
dlsease and earller sLage Cku were slgnlflcanLly hlgher
Lhan levels ln Lhe healLhy conLrols (0001 .(
40
nuLrlLlonal deflclencles
Aslde from lron deflclency Lhere are mulLlple oLher
nuLrlLlonal deflclencles lncludlng vlLamln 8
12
, folaLe and
perhaps vlLamln C whlch could lnLerfere wlLh Lhe produc -
Llon of healLhy maLure red blood cells lolaLe deflclency
ls common ln chlldren wlLh Cku and ln a small cohorL
of chlldren on hemodlalysls oral follc acld supplemen -
LaLlon resulLed ln an 114 mean lncrease ln hemoglobln
levels and decreased LSA dose requlremenL .
41
CarnlLlne
deflclency mlghL also decrease Lhe survlval of red blood
cells ln paLlenLs wlLh Cku as lL leads Lo an lncrease ln Lhe
membrane fraglllLy of red blood cells .
42
uremla and hyperparaLhyroldlsm
lndependenL of nuLrlLlonal facLors chronlc uremla may
also conLrlbuLe Lo anemla uremlc serum has been shown
Lo shorLen Lhe survlval of eryLhrocyLes and mlghL also
sLlmulaLe hemolysls .
2343
PyperparaLhyroldlsm has been
assoclaLed wlLh a poor response Lo eryLhropoleLln and
mlghL be assoclaLed wlLh decreased bone marrow pro -
ducLlon of red blood cells as a resulL of myeloflbrosls .
4443
Powever alLhough secondary hyperparaLhyroldlsm has
been assoclaLed wlLh anemla ln adulLs a sLudy of chll -
dren on hemodlalysls could noL esLabllsh an assoclaLlon
beLween paraLhyrold hormone levels and Lhe achlevemenL
of adulL hemoglobln LargeL levels of 110g/l .
46
8lsk facLors
MulLlple rlsk facLors for Lhe developmenL of anemla ln
chlldren wlLh Cku have been ldenLlfled wlLh Lhe level of
kldney funcLlon belng one of Lhe maln rlsk facLors uaLa
from Lhe nA81CS cohorL have conslsLenLly demonsLraLed
LhaL Lhe rlsk of anemla lncreases as Cku sLage advances .
713
A sLudy performed wlLhln Lhe Cklu cohorL has shown LhaL
anemla ls common ln pedlaLrlc paLlenLs wlLh Cku across
all sLages of Cku buL LhaL hemoglobln levels decllne more
rapldly as Lhe Cl8 (deLermlned by plasma dlsappearance
of lohexol) falls below 43 ml/mln/173 m2
.
47
1reaLmenL
wlLh anLlhyperLenslve medlcaLlons has also emerged as a
rlsk facLor for anemla ln chlldren wlLh Cku whlch may
be aLLrlbuLable Lo Lhe lncreased rlsk of anemla conferred by
angloLensln converLlngenzyme lnhlblLors .
132148
8ace ls also recognlzed as a rlsk facLor for anemla .
8aclal dlsparlLles ln Lhe prevalence of anemla among
adulLs wlLh Cku are well descrlbed ,
49
and dlfferences ln
hemoglobln by race have also been noLed ln Lhe pedlaLrlc
Cku populaLlon Among chlldren enrolled ln Lhe Cklu
sLudy Lhose of Afrlcan Amerlcan descenL were noLed Lo
have average hemoglobln levels of 6g/l lower Lhan Lhose of
whlLe chlldren (93 Cl 9 Lo 2g/l) even afLer ad[usLlng
for oLher relevanL characLerlsLlcs lncludlng Cl8 use of
lron supplemenLaLlon and exogenous eryLhropoleLln and
socloeconomlc sLaLus .
11
1herapeuLlc sLraLegles
1herapy for anemla ls a key facLor for Lhe reducLlon of
morbldlLy and morLallLy ln chlldren wlLh Cku 1he Lwo
prlmary componenLs of effecLlve anemla managemenL are
LreaLmenL wlLh an exogenous LSA and supplemenLal lron
Lherapy Ad[uncLlve Lheraples can lnclude LreaLlng oLher
nuLrlLlonal deflclencles and conLrolllng bone mlneral
meLabollsm dlsorders As recommended by Lhe kuCCl
guldellnes prlmary anemla prevenLlon ln chlldren wlLh
Cku lncludes monlLorlng hemoglobln levels aL leasL
annually for deLecLlon of anemla and lnlLlaLlng Lherapy
for absoluLe lron deflclency as lndlcaLed .
12
1reaLmenL wlLh LSAs
8ecomblnanL human eryLhropoleLln
MosL chlldren wlLh Cku and anemla wlll ulLlmaLely
requlre LreaLmenL wlLh an LSA 8ecomblnanL human
eryLhropoleLln (rPuLC) whlch may be admlnlsLered
lnLravenously or subcuLaneously effecLlvely LreaLs anemla
boLh ln chlldren wlLh predlalysls Cku and Lhose on maln -
Lenance dlalysls .
12
LpoeLln alfa ls one of Lhe mosL com -
monly used forms of rPuLC ln Lhe uSA wlLh epoeLln
beLa more commonly used ln Lurope MulLlple oLher
eryLhropoleLln analogues are emerglng and Lhe pedlaL -
rlc nephrologlsL musL be consLanLly aLLuned Lo lssues of
safeLy and efflcacy and how Lhese agenLs acL ln chlldren
compared wlLh adulLs .
30
ln addlLlon lL ls lmporLanL Lo
noLe LhaL Lhe doslng requlremenLs may dlffer subsLan -
Llally beLween chlldren and adulLs ln cllnlcal pracLlce Lhe
rPuLC 'sLarLlng dose' of 130u/kg per week ls based on
daLa from an adulL cllnlcal Lrlal .
31
uaLa from nA81CS
have demonsLraLed LhaL young chlldren requlre hlgher
rPuLC doses Lhan adulLs ranglng from 273 u/kg Lo
330 u/kg per week for lnfanLs Lo 200230u/kg per week
for older chlldren .
43
An analysls performed by 8amgbola
eL al among paLlenLs on chronlc hemodlalysls found
LhaL chlldren and adolescenLs requlred hlgher absoluLe
doses of rPuLC Lhan adulLs Lo malnLaln LargeL hemo -
globln levels ln splLe of Lhe facL LhaL mean body welghL
was lower ln Lhe chlldren .
32
unllke Lhe doslng of many
drugs ln chlldren whlch ls Lyplcally based on body slze
Lo accounL for a decreased volume of dlsLrlbuLlon ln chll -
dren compared wlLh adulLs Lhe rPuLC doses requlred
for successful achlevemenL of LargeL hemoglobln levels ln
pedlaLrlc paLlenLs seems Lo be lndependenL of welghL .
3233
8aLher Lhan deLermlnlng rPuLC doses ln chlldren
based on body welghL lL has been suggesLed LhaL doslng
should be based on hemoglobln deflclL ln facL Lhere ls
evldence LhaL an absoluLe rPuLC dose of 1000u glven
lnLravenously can lncrease hemoglobln by 04 g/l boLh
ln chlldren and adulLs .
31
1he underlylng mechanlsms
relaLed Lo Lhe lncreased requlremenL of rPuLC seen ln
chlldren have noL been fully elucldaLed buL may be due
Lo an lncreased presence of nonhemaLopoleLlc eryLhro -
poleLln blndlng slLes (for example endoLhellal kldney ,
skeleLal muscle braln hearL and reLlnal cells) ln chlldren ,
8 L v l L W S
2011 Macmlllan ubllshers LlmlLed All rlghLs reservednA1u8L 8LvlLWS | n L P 8C L C
C ? vCLuML 7 | nCvLM8L8 2011 | 639
whlch may resulL ln lncreased clearance of Lhe drug .
4334
1he ma[or funcLlon of eryLhropoleLln ln Lhese varlous cell
Lypes seems Lo be lnhlblLlon of apopLosls .
34
ln addlLlon ,
eryLhropoleLln demand ln chlldren may be lncreased
durlng perlods of acceleraLed body growLh whlch clearly
ls more of a facLor ln younger chlldren .
31
uarbepoeLln alfa
uarbepoeLln alfa an eryLhropoleLln analogue wlLh a
longer halfllfe Lhan rPuLC ls now wldely used ln chll -
dren wlLh Cku 1he beneflL of longer doslng lnLervals
compared wlLh Lhose requlred for rPuLC has made sub -
cuLaneous darbepoeLln alfa an aLLracLlve alLernaLlve for
LreaLlng anemla ln young chlldren and ls llkely Lo lmprove
adherence uarbepoeLln alfa may be admlnlsLered lnLra -
venously or subcuLaneously and whlle drug clearance ,
halfllfe and bloavallablllLy are slmllar for adulLs and chll -
dren regardless of rouLe of admlnlsLraLlon Lhe absorp -
Llon of Lhe drug when glven subcuLaneously may be more
rapld ln chlldren Lhan ln adulLs .
12
A randomlzed cllnlcal
Lrlal conducLed by Warady eL al ln pedlaLrlc paLlenLs aged
> 18 years wlLh Cku sLages 4 or 3 (boLh dlalysls and non -
dlalysls Cku) demonsLraLed LhaL darbepoeLln alfa ls as
safe and effecLlve for Lhe correcLlon of anemla as rPuLC ,
wlLh Lhe added advanLage of less frequenL doslng .
33
A poLenLlal llmlLlng facLor ln Lhe use of darbepoeLln alfa
ln pedlaLrlc paLlenLs ls Lhe reporLed dlscomforL assoclaLed
wlLh lLs admlnlsLraLlon SchmlLL eL al conducLed a small
randomlzed conLrolled Lrlal ln chlldren wlLh endsLage
renal dlsease and demonsLraLed LhaL subcuLaneous ln[ec -
Llons of darbepoeLln alfa were assoclaLed wlLh slgnlfl -
canLly hlgher paln percepLlon ln chlldren Lhan ln[ecLlons
of subcuLaneous epoeLln beLa (003 .(
36
oLenLlal expla -
naLlons for Lhls dlfference lnclude dlfferences ln Lhe Lypes
of buffer uLlllzed ln each preparaLlon wlLh Lhe epoeLln
beLa preparaLlon havlng a more physlologlcal pP Lhan
darbepoeLln alfa .
36
LSA hyporesponslveness
Anemla LhaL ls hyporesponslve Lo LSA Lherapy ls prev -
alenL ln chlldren wlLh Cku alLhough clarlfylng Lhe
lssue of apparenL LSA reslsLance versus lnadequaLe
LSA doslng can be challenglng WlLhln Lhe nA81CS
cohorL sLudy 20 of chlldren wlLh Cku sLage 4 have
been shown Lo have perslsLenLly low hemoglobln levels
whlle on LSA LreaLmenL .
13
ln mosL cenLers Lhe manage -
menL of LSA hyporesponslveness lnvolves escalaLlon ln
LSA dose .
32
Powever desplLe Lhe absence of dlrecL evl -
dence ln Lhe pedlaLrlc populaLlon daLa from cohorLs of
adulLs wlLh nondlalysls Cku enrolled on Lhe CorrecLlon
of Pemoglobln and CuLcomes ln 8enal lnsufflclency
) CPCl8) Lrlal and Lhe Cardlovascular 8lsk 8educLlon by
Larly Anemla 1reaLmenL wlLh LpoeLln 8eLa (C8LA1L (
Lrlal have caused concern among pedlaLrlc nephro -
loglsLs regardlng Lhe approprlaLeness of Lhls sLraLegy ln
Lhe CPCl8 Lrlal Lhe ongolng escalaLlon of LSA dose Lo
LargeL a hemoglobln level of 133g/l was assoclaLed wlLh an
lncreased rlsk of cardlovascular evenLs and deaLh wlLh
no concurrenL lmprovemenL ln quallLy of llfe .
37
uaLa from
C8LA1L demonsLraLed LhaL ln adulLs wlLh Cku sLages 3
or 4 early correcLlon of anemla wlLh subcuLaneous
epoeLln beLa dld noL reduce rlsk of cardlovascular evenLs ,
alLhough lncreased hemoglobln LargeLs were assoclaLed
wlLh lmproved physlcal funcLlonlng and quallLy of llfe .
38
1hus Lhe quesLlon of Lhe approprlaLe LargeL hemoglobln
levels ln chlldren remalns under debaLe 1here are many
reasons Lo advocaLe Lhe normallzaLlon of hemoglobln
levels ln chlldren wlLh Cku lncludlng opLlmlzaLlon
of growLh cognlLlve and cardlovascular funcLlon and
quallLy of llfe 8andomlzed conLrolled sLudles ln chll -
dren wlLh Cku are clearly needed Lo evaluaLe wheLher
LargeLlng hlgher (and perhaps normallzlng) hemoglobln
concenLraLlons ls assoclaLed wlLh beneflLs Lo chlldren and
more speclflcally wheLher Lhe pracLlce ls assoclaLed wlLh
lncreased rlsks as has been demonsLraLed ln adulLs ln Lhe
absence of such daLa currenL recommendaLlons are Lo
LargeL hemoglobln levels of 100120 g/l ln concordance
wlLh Lhe luA guldellnes LhaL apply Lo adulLs .
39
Aslde from LSA doslng lssues ln chlldren Lhere are
paLlenLs ln whom escalaLlng LSA Lherapy does noL
correcL hemoglobln levels Lo even a mlnlmal goal and
Lhese are paLlenLs ofLen Lermed LSA hyporesponslve or
' reslsLanL' ln adulLs wlLh Cku facLors assoclaLed wlLh
LSA hyporesponslveness lnclude lron deflclency chronlc
blood loss chronlc lnflammaLlon oxldaLlve sLress and
posslbly hyperparaLhyroldlsm .
60
8amgbola eL al have
demonsLraLed LhaL cllnlcal facLors found Lo be assoclaLed
wlLh a poor response Lo rPuLC among chlldren maln -
Lalned on hemodlalysls lnclude chronlc lnflammaLlon (as
measured by Lhe ob[ecLlve malnuLrlLlonlnflammaLlon
score) nuLrlLlonal deflclLs (as measured by normallzed
proLeln caLabollc raLe) lnadequaLe dlalysls (as measured
by urea reducLlon raLlo and kL/v) chronlc blood loss and
hyperparaLhyroldlsm .
32
lnLeresLlngly age and sex were
noL found Lo be predlcLlve of a poor response Lo Lherapy .
1hls observaLlon ls ln conLrasL Lo daLa ln adulLs wlLh
Cku whlch suggesL LhaL older age use of angloLensln -
converLlngenzyme lnhlblLors and angloLenslnrecepLor
blockers hlgh 8Ml and dlabeLes melllLus are predlcLors
of a poor response .
61
llnally pure red cell aplasla second -
ary Lo neuLrallzlng anLlbodles agalnsL eryLhropoleLln has
been observed ln paLlenLs wlLh Cku LreaLed wlLh exo -
genous eryLhropoleLln and should be suspecLed ln cases
where hemoglobln levels are noL responslve Lo lncreaslng
LSA dose or lron Lherapy ulagnosls requlres Lhe deLec -
Llon of anLleryLhropoleLln anLlbodles whlch are gen -
erally crossreacLlve wlLh all forms of endogenous and
exogenous eryLhropoleLln and LreaLmenL ofLen lnvolves
lmmunosuppresslve Lherapy .
4362
lron Lherapy
SupplemenLal lron Lherapy ls anoLher key componenL of
Lhe LreaLmenL of anemla of Cku ln chlldren ln chlldren
wlLh Cku lron deflclency defecLs ln lron handllng and
lmpalred producLlon of eryLhropoleLln are llkely Lo have
a subsLanLlal role ln Lhe developmenL of anemla Powever ,
llLLle ls known abouL lron sLaLus among chlldren wlLh
nondlalysls Cku AlLhough cllnlcal pracLlce recommen -
daLlons from kuCCl for Lhe assessmenL of lron sLaLus
and LreaLmenL LargeLs do exlsL for chlldren wlLh Cku
l C C u S C n C k u l n C P l L u 8 L n
2011 Macmlllan ubllshers LlmlLed All rlghLs reserved640 | nCvLM8L8 2011 | vCLuML
7 wwwnaLurecom/nrneph
LreaLed wlLh an LSA deflnlLlons of lron deflclency and
dlsLrlbuLlons of lndlces of lron sLores ln chlldren wlLh
mlld Lo moderaLe Cku have noL been well descrlbed 1he
kuCCl anemla guldellnes recommend LhaL durlng LSA
LreaLmenL chlldren wlLh nondlalysls Cku achleve serum
ferrlLln levels of 223 pmol/l and 1SA1 20 .
12
Powever ,
Lhere are no speclflc recommendaLlons for LargeL ferrlLln
and 1SA1 levels for chlldren noL recelvlng LreaLmenL wlLh
an LSA aLlenLs wlLh Cku ofLen have normal or above -
normal ferrlLln values low 1SA1 levels and perslsLenL
anemla whlch mlghL lndlcaLe lnflammaLlonmedlaLed
lronresLrlcLed eryLhropolesls 1he normal or elevaLed
ferrlLln value mlghL noL reflecL LoLal body lron sLores LhaL
can be uLlllzed approprlaLely for eryLhropolesls buL mlghL
lnsLead be a marker of lnflammaLlon .
Cral lron supplemenLaLlon alLhough lnexpenslve and
readlly avallable has llmlLed efflcacy for malnLalnlng
adequaLe lron sLores for eryLhropolesls owlng Lo poor
gasLrolnLesLlnal absorpLlon and lssues of compllance ln
addlLlon oral lron supplemenLaLlon ls ofLen lnadequaLe Lo
keep up wlLh chronlc blood loss for chlldren malnLalned
on hemodlalysls SLudles ln chlldren have conflrmed Lhe
efflcacy of lnLravenous lron preparaLlons ln chlldren on
hemodlalysls ln Lerms of lmprovlng measured lron sLores ,
lncreaslng serum hemoglobln levels and decreaslng Lhe
dose of LSA requlred Lo malnLaln hemoglobln .
4263
ln addl -
Llon admlnlsLraLlon of lnLravenous lron has been shown
Lo resulL ln lncreased hemoglobln levels ln chlldren wlLh
nondlalysls Cku noL malnLalned on an LSA .
64
uesplLe
Lhe beneflLs of lnLravenous lron lron overload remalns a
conslderable concern wlLh nephrologlsLs ofLen heslLaLlng
Lo admlnlsLer addlLlonal lron Lo paLlenLs wlLh serum ferrl -
Lln levels 11241798 pmol/l lndeed lron overload sLaLes
mlghL be assoclaLed wlLh mulLlple adverse cllnlcal effecLs
ln addlLlon Lo causlng lncreased oxldaLlve sLress .
6366
1hus ,
escalaLlon of lron Lherapy ln an aLLempL Lo overcome LSA
hyporesponslveness has pracLlcal llmlLaLlons .
Concluslons
Anemla ls prevalenL among chlldren wlLh Cku and ls
assoclaLed wlLh mulLlple adverse ouLcomes LryLhropoleLln
deflclency and lron deflclency are Lhe ma[or underlylng
eLlologlcal facLors and are Lhe mechanlsms mosL llkely
Lo be LargeLed by currenL Lheraples Powever assess -
lng Lhe lron sLaLus of paLlenLs can be challenglng espe -
clally ln Lhe seLLlng of lnflammaLlon and lronresLrlcLed
eryLhropolesls WlLh regard Lo quesLlons concernlng Lhe
safeLy and efflcacy of escalaLlng LSA doses ln response Lo
refracLory anemla Lhere ls a need for Lhe ldenLlflcaLlon of
paLhways beyond eryLhropoleLln deflclency for Lhe devel -
opmenL of oLher safe nonLoxlc cllnlcal lnLervenLlons LhaL
could serve Lo ad[uncLlvely LreaL Lhe anemla ln chlldren
wlLh Cku .
8evlew crlLerla
MaLerlal for Lhls 8evlew was obLalned by searchlng
ubMed uslng Lhe followlng Lerms (alone and ln
varlous comblnaLlons) kldney fallure chronlc" endsLage kldney dlsease" chronlc"
kldney" anemla " ,
hemoglobln" paLhogenesls" rlsk facLors " ,
mechanlsm" LreaLmenL" eryLhropoleslssLlmulaLlng
agenLs" LC" recomblnanL human eryLhropoleLln " ,
darbepoeLln" chlldren" pedlaLrlc" morbldlLy " ,
morLallLy" progresslon" hosplLallzaLlon" lefL
venLrlcular hyperLrophy" growLh" lron deflclency " ,
ferrlLln" lnflammaLlon" and hepcldln" SelecLed
maLerlals were fulllengLh Lngllshlanguage papers wlLh
a focus on sLudles of lndlvlduals aged 18 years and
on papers publlshed slnce 2000 1he reference llsLs of
ldenLlfled papers were searched for furLher maLerlal .
1 . MlLsnefes M M eL al rogresslon of lefL
venLrlcular hyperLrophy ln chlldren wlLh early
chronlc kldney dlsease 2year followup sLudy .
! edlaLr 149 671673 (2006 .(
2 . Schaefer l Cardlac dlsease ln chlldren wlLh
mlldLomoderaLe chronlc kldney dlsease Curr .
Cpln nephrol PyperLens 17 292297 (2008 .(
3 . Amaral S eL al AssoclaLlon of morLallLy and
hosplLallzaLlon wlLh achlevemenL of adulL
hemoglobln LargeLs ln adolescenLs malnLalned
on hemodlalysls ! Am Soc nephrol 17 ,
2878 2883 ) 2006 .(
4 . lurLh S L eL al 1he assoclaLlon of anemla and
hypoalbumlnemla wlLh acceleraLed decllne ln
Cl8 among adolescenLs wlLh chronlc kldney
dlsease edlaLr nephrol 22 263271 (2007 .(
3 . Wuhl L Schaefer l 1herapeuLlc sLraLegles Lo
slow chronlc kldney dlsease progresslon .
edlaLr nephrol 23 703716 (2008 .(
6 . llller C Mylrea k leber ! Wong P Pow Lo
deflne anemla ln chlldren wlLh chronlc kldney
dlsease? edlaLr nephrol 22 702707 (2007 .(
7 . SLaples A C eL al Anemla and rlsk of
hosplLallzaLlon ln pedlaLrlc chronlc kldney
dlsease Clln ! Am Soc nephrol 4 4836
) 2009 ( .
8 . Cerson A eL al Anemla and healLhrelaLed
quallLy of llfe ln adolescenLs wlLh chronlc kldney
dlsease Am ! kldney uls 44 10171023
) 2004 .(
9 . Pollowell ! C eL al PemaLologlcal and lronrelaLed analyLesreference daLa for persons
aged 1 year and over unlLed SLaLes 198894 .
vlLal PealLh SLaL 11 247 1136 (2003 .(
10 . !ackson 8 1 SeparaLe hemoglobln sLandards for
blacks and whlLes a crlLlcal revlew of Lhe case for
separaLe and unequal hemoglobln sLandards .
Med PypoLheses 32 181189 (1990 .(
11 . ALklnson M A eL al Pemoglobln dlfferences by
race ln chlldren wlLh Cku Am ! kldney uls 33 ,
1009 1017 ) 2010 .(
12 . kuCCl naLlonal kldney loundaLlon kuCCl
cllnlcal pracLlce guldellnes and cllnlcal pracLlce
recommendaLlons for anemla ln chronlc kldney
dlsease Am ! kldney uls 47 (Suppl 3 ( ,
S11S143 (2006 .(
13 . ALklnson M A MarLz k Warady 8 A . &
neu A M 8lsk for anemla ln pedlaLrlc chronlc
kldney dlsease paLlenLs a reporL of nA81CS .
edlaLr nephrol 23 16991706 (2010 .(
14 . Sllckers ! uuqueLLe Pooper S Clpson u .
Cllnlcal predlcLors of neurocognlLlve deflclLs ln
chlldren wlLh chronlc kldney dlsease edlaLr .
nephrol 22 363372 (2007 .(
13 . Selkaly M C Salhab n Clpson u ?lu v . &
SLableln u SLaLure ln chlldren wlLh chronlc
kldney dlsease analysls of nA81CS daLabase .
edlaLr nephrol 21 793799 (2006 .(
16 . Amaral S eL al Serum albumln level and rlsk for
morLallLy and hosplLallzaLlon ln adolescenLs on
hemodlalysls Clln ! Am Soc nephrol 3 ,
739 767 ) 2008 .(
17 . Warady 8 A Po M MorbldlLy and morLallLy
ln chlldren wlLh anemla aL lnlLlaLlon of
dlalysls edlaLr nephrol 18 10331062
) 2003 .(
18 . MlLsnefes M eL al Masked hyperLenslon
assoclaLes wlLh lefL venLrlcular hyperLrophy ln
chlldren wlLh Cku ! Am Soc nephrol 21 ,
137 144 ) 2010 .(
19 . MaLLeuccl M C eL al for Lhe Lscape 1rlal Croup .
LefL venLrlcular geomeLry ln chlldren wlLh mlld Lo
moderaLe chronlc renal lnsufflclency ! Am Soc .
nephrol 17 218226 (2006 .(
20 . Couva C nlkolopoulos loannldls ! . &
Slamopoulos k C 1reaLlng anemla early ln
renal fallure paLlenLs slows Lhe decllne of renal
funcLlon a randomlzed conLrolled Lrlal kldney
lnL 66 733760 (2004 .(
21 . SLaples A C eL al AssoclaLlon beLween cllnlcal
rlsk facLors and progresslon of chronlc kldney
dlsease ln chlldren Clln ! Am Soc nephrol 3 ,
2172 2179 ) 2010 .(
22 . 8oehm M Larly eryLhropoleLln Lherapy ls
assoclaLed wlLh lmproved growLh ln chlldren wlLh
chronlc kldney dlsease edlaLr nephrol 22 ,
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C ? vCLuML 7 | nCvLM8L8 2011 | 641
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AuLhor conLrlbuLlons
M A ALklnson and S L lurLh conLrlbuLed equally Lo
dlscusslon of conLenL for Lhe arLlcle researchlng daLa
Lo lnclude ln Lhe manuscrlpL and revlewlng and edlLlng
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l C C u S C n C k u l n C P l L u 8 L n
2011 Macmlllan ubllshers LlmlLed All rlghLs reserved