Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in

34 Pages·2017·1.3 MB·English

nutrients
Review
Impact of Inflammation on Ferritin, Hepcidin and the
Management of Iron Deficiency Anemia in Chronic
Kidney Disease
NorishiUeda1,*andKazuyaTakasawa2,3
1 DepartmentofPediatrics,PublicCentralHospitalofMattoIshikawa,3-8Kuramitsu,Hakusan,
Ishikawa924-8588,Japan
2 DepartmentofInternalMedicine,PublicCentralHospitalofMattoIshikawa,3-8Kuramitsu,Hakusan,
Ishikawa924-8588,Japan;[email protected]
3 DepartmentofInternalMedicine,PublicTsurugiHospital,Ishikawa920-2134,Japan
* Correspondence:[email protected];Tel.:[phone];Fax:[phone]
(cid:1)(cid:2)(cid:3)(cid:1)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:1)
(cid:1)(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)
Received:26June2018;Accepted:17August2018;Published:27August2018
Abstract: Iron deficiency anemia (IDA) is a major problem in chronic kidney disease (CKD),
causing increased mortality. Ferritin stores iron, representing iron status. Hepcidin binds to
ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin
and hepcidin independent of iron status, which reduce iron availability. While intravenous iron
therapy(IIT)issuperiortooralirontherapy(OIT)inCKDpatientswithinflammation, OITisas
effectiveasIITinthosewithout. Inflammationreducespredictivevaluesofferritinandhepcidin
forironstatusandresponsivenesstoirontherapy. Upperlimitofferritintopredictironoverload
ishigherinCKDpatientswithinflammationthaninthosewithout. However,magneticresonance
imaging studies show lower cutoff levels of serum ferritin to predict iron overload in dialysis
patientswithapparentinflammationthanupperlimitofferritinproposedbyinternationalguidelines.
ComparedtoCKDpatientswithinflammation, optimalferritinlevelsforIDAarelowerinthose
without,requiringreducedirondoseandleadingtodecreasedmortality. ThemanagementofIDA
should differ between CKD patients with and without inflammation and include minimization
ofinflammation. Furtherstudiesareneededtodeterminetheimpactofinflammationonferritin,
hepcidinandtherapeuticstrategyforIDAinCKD.
Keywords: chronic kidney disease; ferritin; C-reactive protein; hepcidin; inflammation; iron
deficiencyanemia
1. Introduction
Irondeficiency(ID)occursintwomajorforms;absoluteIDasdefinedbyadecreaseinthebody
iron stores and functional ID (FID), a disorder in which the total body iron stores are normal or
increasedbuttheironsupplytothebonemarrowisinadequate[1]. IDanemia(IDA)isfrequently
associatedwithchronicinflammatoryconditions,inwhichinflammationispathogenicallyinvolved,
includinginflammatoryboweldisease(IBD,e.g.,ulcerativecolitis,Crohn’sdisease),chronicheart
failure,chronicliverdisease,obesity,rheumatoidarthritis(RA)andchronickidneydisease(CKD)[1].
IDAisaglobalpublichealthproblemaffecting7.2–13.96per1000person-yearsandaccountingfor
800,000deathsperyearworldwide[2]. IDAalsohasanimpactonmortalityinchildrenandadults
withCKD[3,4]. Thus,appropriatemanagementofIDAiscrucialforimprovingqualityoflife(QOL)
andmortalityinCKDpatients.
Ironisacomponentofhemeproteins(hemoglobin;Hbandmyoglobin),whichcarryorstoreoxygen
andessentialforthefunctioningofallorgans. Ironisalsopresentinhemeenzymes,non-hemeiron
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Nutrients2018,10,1173 2of34
enzymesandiron-sulfurproteinsthatregulatevariouscellfunctionsincludingelectrontransportin
mitochondrialrespiration,redoxreactionsandDNAsynthesis[5]. However,excessiveironleavesa
fractionoffreeiron(knownas“labile”iron)andmakesredoxactive,formingreactiveoxygenspecies
thatcauseoxidantstress. Becauseofnoexcretionsystemforironfromthebody,ironhomeostasisis
tightlyregulatedviaanetworkofproteinsinvolvedintheimport,storage,exportandtransportof
ironwithinthebody.
There are two major molecules that regulate iron metabolism and iron availability for
erythropoiesis. Ferritinbindsironasaferriccomplexwithinaproteinshell,inwhichironfluxesin
and out and functions as iron storage site and ferroxidase [5,6]. Thus, alteration of serum ferritin
maybeadeterminantofmortalityinadultsonmaintenancehemodialysis(HD)[7–9]. Whileiron
supplementation reduced mortality in HD adults [9], excess iron therapy increased ferritin levels,
leadingtohighmortality[7]. Todate,optimallevelsofserumferritinduringirontherapyforIDA
remaintobedeterminedinCKDpatients. Ontheotherhand,hepcidin-25(referredtoashepcidin),
a 25 amino acid peptide, is a major iron-regulatory hormone that binds to ferroportin (FPN) and
inhibitsironexportfromenterocytes,hepatocytesandmacrophagesthroughtheinternalizationand
degradationofFPN,therebyregulatingironmetabolisminvariousdiseases,includingCKD[10–12].
Inflammation as defined by the innate immune response to stimuli such as pathogens,
cellular injury and metabolic stress [13] is part of the complex biologic response to tissue injury,
infection, ischemia and autoimmune diseases. It is characterized by the acute-phase response
including elevated inflammation markers such as C-reactive protein (CRP, >0.3 mg/dL) [14] and
pro-inflammatorycytokineswhichpromoteCRPsynthesis[15]. Inflammationischaracteristicfeature
of CKD and caused by multiple factors of the toxic uremic milieu and the dialysis procedure
itself. The interpretation of iron biomarkers is hindered by inflammation, which can directly
affect the concentrations of most iron biomarkers [14], including ferritin and hepcidin [16–18].
Inflammation-mediated increase in hepcidin leads to iron trapping within the macrophages
and hepatocytes, resulting in FID [19]. This leads to high association of inflammation with
FID anemia (FIDA) in CKD patients [16–18], requiring higher dose of IV iron to maintain
Hb targets [20]. Inflammation also induces hyporesponsiveness to iron therapy [20–22] and
erythropoiesis-stimulatingagents(ESA)inHDpatients[21,23]byincreasingferritinandhepcidin.
Conversely, aggressiveintravenousirontherapy(IIT)mayenhanceinflammationinpatientswith
end-stage renal disease (ESRD) [16], leading to further disturbance of iron metabolism. Thus,
inflammationhasanimpactontheexpressionofferritinandhepcidinaswellastherapeuticstrategy
forthemanagementofIDAinCKDpatients.
Theaimofthisreviewistoprovideanoverviewofclinicalandexperimentalstudiesregarding
aroleofferritin,hepcidinandinflammationintheregulationofIDA,efficacyoforalirontherapy
(OIT)andIIT,predictivevaluesofferritinandhepcidinfortheresponsetoirontherapy,upperlimit
offerritinlevelstopredictironoverload,optimalferritinlevelsduringirontherapy,complications
andoutcomeinCKDpatients. Thisreviewespeciallyfocusesontheimpactofinflammationonthese
issuesinCKDpatients.
2. FerritinRegulationbyIronStatusandInflammation
Ferritinhastwoisoforms;theheavychain(FtH)andthelightchainofferritin(FtL).Incontrastto
FtH,FtLlacksdetectableferroxidaseactivitybutcanstoremoreiron[6]. Ferritinsequestersironina
nontoxicform,whereasthelevelsoffreeironregulatecellularferritinlevels[6]. Cytoplasmicferritin
synthesisisstimulatedbyanincreaseofiron,whileitisdecreasedbyirondepletion. Thisprocess
is mediated by the interaction between the two RNA-binding proteins (iron regulatory proteins 1
and 2; IRP1/2) and a region in the 5_untranslated region of FtH and FtL mRNA, termed the iron
responsiveelement(IRE)thathasa“stem-loop”structure.BindingofIRP1/2totheIREinhibitsmRNA
ferritintranslation. IRP1andIRP2aredifferentiallyregulated,dependingonironstatus. Wheniron
isabundant,IRP1existsasacytosolicaconitase,whereasunderirondepletion,itassumesanopen
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configurationassociatedwiththelossofironatomsintheiron-sulfurclusterandcanbindtotheIRE
stemloop,therebysuppressingferritintranslation. IRP2proteinisabundantinirondepletionstatus
butisrapidlydegradedinironexcess. IRP1andIRP2havedistincttissue-specificroles[6].
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SynthesisofFtHandFtLisactivatedbypro-inflammatorycytokinessuchasinterleukin(IL)-1β
andtumsotartunse. cWrohseins ifraocnt oisr a(bTuNndFa)n-αt, I[R6P,214 e]xvisitas nasu ac lceyatorsfoalicct oacro(nNitFas)e-,κ wBhpearetahsw uanyde[r2 i5r]o.nI ndeteprlefteiroonn, it( INF)-γ
andlipoapssoulmyseas cacnh oapreidn eco(nLfPigSu)raitniodnu acsesodceiagterda dwaitthio tnheo lfosIsR oPf2 irionn natiotrmics oinx tihdee ir(oNnO-su)-lfduer pcleunsdteer natndm anner,
can bind to the IRE stem loop, thereby suppressing ferritin translation. IRP2 protein is abundant in
leading to ferritin synthesis in macrophages [26]. IL-6 also enhances synthesis of FtH and
iron depletion status but is rapidly degraded in iron excess. IRP1 and IRP2 have distinct
FtL in hepatocytes [24]. FtH transcription is predominantly active in inflammatory conditions,
tissue-specific roles [6].
whereastranscriptionofFtLcanbeinducedonlyafterexposuretoveryhighconcentrationofiron[27].
Synthesis of FtH and FtL is activated by pro-inflammatory cytokines such as interleukin
Pro-infla(ImL)m-1βa taonrdy tcuymtoork ninecersosmiso fdacutolar t(eTNthFe)-αre [l6a,t2i4v] eviraa ntiuocloefarf efarcrtiotirn (NtoF)b-κoBd pyaitrhownays t[o2r5a].g Ientberyfeirnocnr easing
ferritins(yINnFth)-eγs aisnd[2 l7ip].opolysaccharide (LPS) induce degradation of IRP2 in nitric oxide (NO)-dependent
manner, leading to ferritin synthesis in macrophages [26]. IL-6 also enhances synthesis of FtH and
3. HepciFdtLin ina nhdepIartooncyMtese t[a2b4]o. lFistHm transcription is predominantly active in inflammatory conditions,
whereas transcription of FtL can be induced only after exposure to very high concentration of iron
3.1. Hepc[2id7i]n. -PFreor-irnofplaomrinmaAtoxriys Rcyetgouklianteess mIroonduHlaotem ethoes taresliastive ratio of ferritin to body iron storage by
increasing ferritin synthesis [27].
Dietaryironcontaininghemeandnon-hemeironisabsorbedbythedivalentmetaltransporter
(DMT1)3l.o Hcaetpecdidaint athned aIrpoinc aMlemtaebmolbisrman eofduodenalenterocytes[10–12](Figure1),whichtransports
onlyFe2+ butmostdietaryironisFe3+. Thus,Fe3+ shouldbereducedtoFe2+ beforeirontransport
3.1. Hepcidin-Ferroporin Axis Regulates Iron Homeostasis
byDMT1. Thisreductionstepismediatedbytheferrireductaseduodenalcytochromeb(DCYTB)at
theapicalmDemietbarrayn ireono fcodnutoaidneinnga hleemnete arnodc yntoens-.hHemeep icriodni nis babinsodrsbetod FbyP Nthea dnidvatlreingt gmeertsali ttsrainnstpeornrtaerl ization,
(DMT1) located at the apical membrane of duodenal enterocytes [10–12] (Figure 1), which
ubiquitinationandsubsequentlysosomaldegradation,leadingtoinhibitionofironexportbyFPN
transports only Fe2+ but most dietary iron is Fe3+. Thus, Fe3+ should be reduced to Fe2+ before iron
fromenterocytes,hepatocytesandmacrophagesintothecirculation.Hemeabsorbedbytheenterocytes
transport by DMT1. This reduction step is mediated by the ferrireductase duodenal cytochrome b
isdegra(dDeCdYbTyB)h aet mthee oapxiycagle mnaemseb-r1an(He oOf -d1u)oadnednatlh eentleibroecryatetes.d Hierpocnidiisnp briondces stsoe FdPiNn aansdi mtriiglgaerrms itasn neras
theabsoirnbteerdnainlizoartgioann,i ucbiriqouni.tinTahtieonex apnodr stuobfseeqnuteenrot clyystoicsoimroanl dbeygrFaPdNatiorenq, uleiardeisngh etop hinaheisbtiitino,na omf iurolnti copper
oxidaseehxopmorot bloyg FoPuNs ftroomce ernuteloropclyatsems, hinep(aCtoPc)y,twes haincdh moaxcirdoipzheasgFese i2n+toto thFee c3i+rcufolartiloona. dHinemgeo anbtsoortbreadn sferrin
(Tf)[10]b.yO tnhec eenetxerpoocyrtteesd isb dyeFgrPaNdedin btyo htehmeec oirxcyugleantaisoen-1, F(HeO2+-1i)s aonxdi dthiez leidbeirnatteod Fireo3n+ isb ypraocfeesrsreido ixni da aseCP
similar manner as the absorbed inorganic iron. The export of enterocytic iron by FPN requires
inhepatocytesandmacrophages. Iron-loaded(diferric)transferrin(Tf-Fe ,holo-Tf)istransportedto
hephaestin, a multicopper oxidase homologous to ceruloplasmin (CP), whi2ch oxidizes Fe2+ to Fe3+
othercellsortissuesforironmetabolismorstorage[10–12].
for loading onto transferrin (Tf) [10]. Once exported by FPN into the circulation, Fe2+ is oxidized
Hepinatoto Fcey3+t ebsy sae fnesrreioixriodnases tCoPr eins haenpdatorceygteusl aatned hmeapcrcoidphinagepsr. oIrmono-tlooardeadc t(idviifteyr,rict)h terraenbsfyerrrienl easing
hepcidin(Tfa-cFceo2, rhdoilno-gTlfy) .isI tnraInDspo(rFtiegdu tore ot1hAer) c,ehllse porc itdissinuesis folro iwrona mndetatbhoulissmir oorn stoisrargeel [e1a0s–e1d2]. by FPN into
the circulatiHonepafrtoocmytees nsteenrsoec yirtoens ,sthoerepsa taoncdy treegsualanted hmepaccidroinp hparogmeso,tofra caciltiitvaittyin, gtheirreobny arvelaeialsainbgil ity for
hepcidin accordingly. In ID (Figure 1A), hepcidin is low and thus iron is released by FPN into the
erythropoiesis [10–12]. Under iron overload (Figure 1B), increased hepcidin in hepatocytes is
circulation from enterocytes, hepatocytes and macrophages, facilitating iron availability for
released [10–12]. Increased hepcidin binds to FPN and inhibits FPN-mediated iron export into
erythropoiesis [10–12]. Under iron overload (Figure 1B), increased hepcidin in hepatocytes is
the circulation to reduce Tf saturation (TSAT), leading to subsequent inhibition of duodenal
released [10–12]. Increased hepcidin binds to FPN and inhibits FPN-mediated iron export into the
ironabscoirrcputliaotino.n to reduce Tf saturation (TSAT), leading to subsequent inhibition of duodenal iron absorption.

(A)
Figure1.Cont.
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(B)
Figure 1. Regulation of systemic iron homeostasis. Divalent metal transporter 1 (DMT1) at the apical
Figure1.Regulationofsystemicironhomeostasis.Divalentmetaltransporter1(DMT1)attheapical
membrane of enterocytes takes up Fe2+ from the lumen after duodenal cytochrome b (DCYTB)
membrarnedeuocfese ndtieertaorcyy tFees3+ tatok eFse2u+. pFeFrer2o+pofrrtoinm (FthPeNl)u amt tehne abfatesorladtueroadl emneamlbcyratnoec herxopmorets bFe(D2+ CinYtoT Bth)er educes
dietaryFcierc3u+latotioFne. 2+F.PNFe rcroooppoerratitens (FwPitNh )haetpthhaeesbtains otlhaatte roaxlimdizeems bFrea2n+ etoe xFpeo3+r. tsInF eh2e+piantotocytthese cainrdc ulation.
FPNcoompaecrraoptehsagwesit, hFeh2+e pish oaxeidstizinedt hbay tao fxeirdroixziedsasFee, 2c+ertuoloFpela3+sm.Iinn (hCePp).a Dtoifceyrrtiecs iraonnd (Fme3a+2c)-rtorapnhsafegrerisn, Fe2+is
oxidized(hboylo-aTff)e rsruopxpidlieass ei,rocne rutol oaplll acsemllsi na(nCdP t)i.sDsuiefse rtrhircoiurgohn (bFined3+ing) -ttroa nTsf ferrercienpt(ohr o1lo -(TTffR)1s)u panpdl iesiron
2
endocytosis. Erythrocytes are phagocytized by macrophages. Hemoglobin-derived heme in
to all cells and tissues through binding to Tf receptor 1 (TfR1) and endocytosis. Erythrocytes are
enterocytes and macrophages is catabolized by heme oxygenase-1 (HO-1). After sensing iron,
phagocytized by macrophages. Hemoglobin-derived heme in enterocytes and macrophages is
hepatocytes produce and release hepcidin. In iron deficiency (A), low hepcidin facilitates iron
catabolizedbyhemeoxygenase-1(HO-1).Aftersensingiron,hepatocytesproduceandreleasehepcidin.
export by FPN into the circulation. In iron overload (B), high hepcidin binds to FPN and inhibits
Inirondireofinc ieexnpcoyrt( Afr)o,mlo wentheeropccyitdeisn, fhaecpialittoactyetessi raonnde xmpaocrrotpbhyagFePsN byin ttroigtgheericnigr ciunltaetrinoanli.zaIntioinro annodv erload
(B),highdhegerpacdiadtiionnb oinf dFPsNto, lFePadNinagn tdo irnedhuibctiitosni roofn ireoxnp sotortrafgroe.m Deanshteedro lcinyet eins,dhiceapteast olecsys tierosna nsudpmplayc. rxo: phages
bytriggeinrhinibgitiionnte. Frnigaulrizesa taidoanptaendd frdomeg [r1a2d].a tionofFPN,leadingtoreductionofironstorage.Dashedline
indicateslessironsupply.x:inhibition.Figuresadaptedfrom[12].
3.2. Hepcidin Regulation by Iron Status
After sensing iron, bone morphogenetic protein (BMP)-6 is produced in the liver [28] and
3.2. HepcidinRegulationbyIronStatus
increases hepcidin via BMP/small mothers against decapentaplegic (SMAD) proteins-mediated
Aftseirgnsaelninsgin pgatihrowna,yb [o2n8]e (mFigourpreh 2o)g. Henoelot-iTcfp driostpelaince(sB tMheP in)-t6eriascptiorond ouf cheedreidnittahrye hlievmeorc[h2r8o]maantdosiins creases
hepcidinprovtieain BM(HPFE/)s-TmfRa1ll manodt hsetarsbilaizgeas intshte daescsaopcieatniotanp loefg iHcF(ES-MTfRA2D )wpithro tmeienmsb-mraneed-iaantcehdoresdig naling
hemojuvelin (mHJV), forming a complex of HFE/TfR2/HJV which is dispensable for hepcidin
pathway [28] (Figure 2). Holo-Tf displaces the interaction of hereditary hemochromatosis protein
transcription [10,11,28]. mHJV exclusively expressed in hepatocytes acts as a co-receptor for BMP-6,
(HFE)-TfR1andstabilizestheassociationofHFE-TfR2withmembrane-anchoredhemojuvelin(mHJV),
leading to activation of BMP/SMAD-mediated hepcidin transcription [28]. Neogenin acts as a
formingscaaffcooldm ptol efxacoiliftaHteF aEs/seTmfRbl2y/ oHf JHVJVw/BhMicPh/BiMsPd irsepceepntsoar b(lBeMfPoRr) hceopmcpidleixn [t2r9a] nasncdr ipmtaiionntai[n1s0 ,11,28].
mHJV epxrcolpuesri vmeHlyJVe xfupnrcetisosne d[28in]. Mheaptraipttoacsye t(eMsTa)c-2t s(aalssoa kcnoow-rne caesp TtoMrPfRoSrS6B)M fuPn-c6ti,onlesa ads ian gnetgoataivcet ivation
of BMPr/egSuMlaAtoDr o-fm heedpciiadtiend-rehlaetepdc iBdMinP/StrMaAnsDc sriigpntaiolinng [b2y8 c].leavNinego mgeHnJiVn inatcot ssolausblea HsJcVa f(fsoHlJdV)t [o11f].a cilitate
assemblyofHJV/BMP/BMPreceptor(BMPR)complex[29]andmaintainspropermHJVfunction[28].
Matriptase(MT)-2(alsoknownasTMPRSS6)functionsasanegativeregulatorofhepcidin-related
BMP/SMADsignalingbycleavingmHJVintosolubleHJV(sHJV)[11].
ID reduces BMP-6, leading to inhibition of BMP/SMAD-dependent hepcidin transcription.
Decreased holo-Tf in ID destabilizes the TfR2-HFE interaction, thereby inhibiting hepcidin
transcription [28]. Decreased holo-Tf and non-Tf-bound iron increase sHJV, leading to inhibition
ofhepcidin,whileincreasedholo-Tfandnon-Tf-boundironhavetheoppositeeffect[28]. IDstabilizes
MT-2,therebysuppressinghepcidin[28,30]. Furin,whichcleavesmHJVintosHJV,isupregulated
by ID and inhibits hepcidin [31]. In iron overload, increased holo-Tf stabilizes the TfR2-HFE
interaction[10,11,28]anddecreasesfurin[32],therebyincreasinghepcidintranslation.
NNuuttrriieennttss 22001188,, 1100,, x1 1F7O3R PEER REVIEW 5 5oof f3334

Figure 2. Regulation of hepcidin by iron status and inflammation. Under high iron conditions,
Figure 2. Regulation of hepcidin by iron status and inflammation. Under high iron conditions,
increased holo-Tf induces bone morphogenetic protein (BMP)-6 in non-parenchymal cells in the
increased holo-Tf induces bone morphogenetic protein (BMP)-6 in non-parenchymal cells in the
liver,disruptshereditaryhemochromatosisprotein(HFE)-transferrinreceptor(TfR)1interactionto
lpivroerm, odtiesrHupFtEs- ThefRre2diintatreyra hcteimonocahnrdomitsataosssiso cpiarotitoeninw (HithFEm)-etrmanbsrfaenrer-inan rcehcoepretdorh (eTmfRo)j1u vinetleinra(cmtioHnJ Vto),
pforormmiontge aHcFoEm-TpflRex2 oinftHerFaEc/tiTonfR a2n/dB MitsP -a6s/sBocMiaPtiRo/nH wJVit/h nmeoegmebnriann,ew-ahnicchhoisreddis hpeemnsoajbulveefloinr h(mepHciJdVi)n,
ftorarmnsicnrgip ati ocnomvipaleBxM oPf /HsmFEa/lTlmfRo2t/hBeMrsPa-6g/aBiMnsPtRd/eHcaJVpe/nnetaopgleengiinc, (wSMhiAchD )iss idgnisapleinngsa.bInlei rfoonr ohveeprcliodaidn,
tfruarninsc,rwiphtiiocnh vclieaa BvMesPm/sHmJaVll, misodtohwerns raeggauilnastte dd,ecthapereenbtyapilnecgrieca (sSinMgAhDe)p sciigdnina.linLgo. wIni rioronnc oovnedriltoioands,
fiunrcirne,a swehmicaht ricpletaavsees( MmTH)-J2Va, nids fduorwinn,rwehguiclhatceldea, vthesermebHyJ Vin,rcerdeausciensgB hMepPc-6idpinro. dLuocwti oinroann dcofancdiliittiaotness
itnhcereHasFeE -mTfaRt1ripintatesrea c(tMioTn),-2le aadnidng ftuoriinn,h iwbihtiiochn ocfleBaMvePs /SmMHAJVD, -dreepdeuncedse nBtMhePp-6ci dpinrotdruanctsicornip tainodn .
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((ECRR)E B)sHtretshsa tbaisnsdosciaantedda ctiwviatthe shienpflcaimdimnaptrioomn oteinrcarcetaisveitsy . Ihneflpacmidmina tiovniai ncrSeMasAesDh1e/5p/c8i dinanbdy
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pheerpoaxtioscoymteen ucpleroarliffaecratotorr4-αac.tIinvflaatemdm artieocne-pintodru ceγd ILc-1oβacetnivhaatnocre sh(PepGcCid)-in1αtr anwschriipchti onabnytaingdouncizinesg
lCip/oEpBoPlyδs.aHccehpacriiddien-itnradnuscleadti ohnepiscimdiend tiraatnedscirnipdtiiroenc tvlyiat hthreo uingtherearcyttihonro wpoitihe thinep(EatPoOcy)/teE nPuOcRle-ainr dfauccteodr
4eαry. thInroflpaomiemsiastaionnd-ipnodsusicbeldy gIrLo-w1βth ednihffaenrecnetsi ahtieopncifdacinto rtr(aGnDscFr)i1p5t.ioDna sbhye dinlidnue:cicnlega vCa/gEeB,P→δ.: aHcteipvcaitdioinn,
t(cid:96)ra:ninshlaibtiiotino nis. mediated indirectly through erythropoietin (EPO)/EPOR-induced erythropoiesis and
possibly growth differentiation factor (GDF)15. Dashed line: cleavage, →: activation, ├: inhibition.
3.3. InflammationIncreasesHepcidinExpression
ID reduces BMP-6, leading to inhibition of BMP/SMAD-dependent hepcidin transcription.
Pro-inflammatorycytokinesareincreasedinCKD[17,18]. Pro-inflammatorycytokinessuchas
Decreased holo-Tf in ID destabilizes the TfR2-HFE interaction, thereby inhibiting hepcidin
IL-1βandIL-6stimulatehepcidinexpressionviatheJanuskinase(JAK)/signaltransducerandactivator
transcription [28]. Decreased holo-Tf and non-Tf-bound iron increase sHJV, leading to inhibition of
oftranscription3(STAT3)pathways[10–12,28](Figure2). Inflammationinducesothercytokineactivin
hepcidin, while increased holo-Tf and non-Tf-bound iron have the opposite effect [28]. ID stabilizes
BwhichstimulatesBMP-6/SMADpathwaysynergicallywithIL-6andSTAT3,leadingtohepcidin
MT-2, thereby suppressing hepcidin [28,30]. Furin, which cleaves mHJV into sHJV, is upregulated
expression[11]. Endoplasmicreticulum(ER)stressassociatedwithinflammationincreaseshepcidin
by ID and inhibits hepcidin [31]. In iron overload, increased holo-Tf stabilizes the TfR2-HFE
byactivatingSMAD1/5/8[33],IL-6-dependentphosphorylatedSTAT3[34]andERstress-activated
interaction [10,11,28] and decreases furin [32], thereby increasing hepcidin translation.
transcription factor, cyclic AMP response element–binding protein H (CREBH), which bind and
activatehepcidinpromoteractivity[35]. InflammationinhibitsMT-2bysuppressingSTAT5[36]and
3.3. Inflammation Increases Hepcidin Expression
peroxisomeproliferator-activatedreceptorγcoactivator-1α(PGC-1α)whichantagonizesLPS-induced
hepcPidrion-itnrfalnasmcrmipattioornyv ciyattohkeininetse ararec tiinocnrweaistehdh ienp aCtKocDy t[e1n7,u1c8l]e. aPrrfoa-citnofrla4mαm[3a7t]o,rlyea cdyitnogkitnoeasc tsiuvcahti oans
IL-1β and IL-6 stimulate hepcidin expression via the Janus kinase (JAK)/signal transducer and
activator of transcription 3 (STAT3) pathways [10–12,28] (Figure 2). Inflammation induces other
Nutrients2018,10,1173 6of34
ofhepcidintranslation. Inflammation-inducedIL-1βalsoactivateshepcidinexpressionbyinducing
CCAATenhancer-bindingprotein(C/EBP)δinhepatocytes[38].
4. BiomarkersofIronStatusandInflammationinCKD
A number of biomarkers of iron status have been used in a clinical setting. However,
traditionalbiochemicalironparameterssuchasserumiron,Tfandserumferritinareinfluencedby
inflammation[14],makingthemlesssuitableindicators. Duetoconfoundingeffectsoftheacute-phase
responseontheinterpretationofmostironindicators,theassessmentofironstatusischallengingwhen
concomitantinflammationispresent. Infact,serumlevelsofferritinwerepositivelycorrelatedwith
CRP,ameasureofinflammation,inchildrenandadultsonHD[16,39,40]. Underminorinflammation,
serumferritinappearstobeamostreliablebiomarkeroftotalbodyironstoresandIDisdiagnosed
belowthecutoffserumferritinlevelsof<15ng/mLinindividualsolderthan5years[1]. However,
serumferritinlevelsof50ng/mLorhighercouldstillbeIDwhenapparentinflammationispresent[1].
Thus, the interpretation of serum ferritin, an acute phase reactant, is complicated by concomitant
inflammation[1,14,41].
Asnegativeacutephasereactants,concentrationsofserumironandTf,anirontransportprotein,
aredecreasedinresponsetoinflammation[14,41–43]. LowTSAT(<20%)withlowserumferritinis
diagnosticofIDA[1,44]. LowTSATcombinedwithnormalorelevatedserumferritinisdiagnostic
ofFIDA[44]. Asdiscussedlater,manyinternationalguidelinesforthemanagementofIDAinCKDuse
thecombinationoflowserumferritinandTSATfordiagnosisofIDA.TSATrepresentsthepercentage
ofbindingsitesonallTfmoleculesoccupiedwithironmoleculesandiscalculatedastheratioofserum
irontoTforserumirontototaliron-bindingcapacity(TIBC)whichindicatesthemaximumamount
of iron necessary to saturate all available transferrin iron-binding sites [1,44]. TIBC is a negative
acute-phase reactant and reduction in TIBC induced by inflammationleads to higher TSAT levels
independent of iron status [41]. Thus, reliability of TSAT as a measure of iron status is reduced
byinflammationassociatedwithCKD.SolubleTfR(sTfR),whichisproducedbyproteolysisofthe
membraneTfR,isincreasedinHDpatientswithIDandinverselycorrelatedwiththeamountofiron
available for erythropoiesis [44]. As a marker of iron status, sTfR is not an acute-phase reactant
andlessinfluencedbyinflammationthanserumferritinis,whileitisincreasedinindividualswith
generalinflammation[14]. Inaddition,sTfRappearstorepresenterythropoieticactivitymorethan
iron-restrictederythropoiesisinCKDpatientsreceivingESA[44]. Thus,theinterpretationofsTfRis
alsoconfoundedbytheuseofESA[1,41]. Thus,itisaninferiormarkertocellularmeasuressuchasthe
contentofHbinreticulocytes(CHr)orthepercentageofhypochromicredbloodcells(%Hypo)[41,44].
OtherlimitationsofsTfRmeasurementincludecostforthemeasurementandlackofstandardcutoff
andwidespreadavailability[1,41]. Theinterpretationoftotalbodyiron(TBI),thelogratioofsTfR
toserumferritin,isalsocomplicatedbythesameconfoundingfactorsasforserumferritinandsTfR
concentrations[14].
Other laboratory markers of iron status include CHr and %Hypo. Both iron biomarkers are
influencedbyinflammation[45,46]. CHrisinverselyrelatedtologCRP[45]andthereisapositive
correlationbetween%HypoandCRP[46].CHrisaveryearlyindexofironavailableforerythropoiesis
within 3–4 days [1,41,44]. The CHr of <27.2 pg is diagnostic of ID, while false normal values are
frequentlyencountered[1]. Themeasurementof%Hypoasaproportionofhypochromiccellsdefined
aserythrocyteswithmeancellularHbconcentrationlessthan28g/dLintotalredbloodcellsisthe
most sensitive marker of ID in CKD (cutoff, <6%) [1] and FID [41]. However, it is not suitable for
the assessment of short-term changes in iron status [1,41,44]. Furthermore, a fresh blood sample
isneededandautomatedanalyzersarenotwidelyavailableinclinicalsetting. Currently, noneof
themeasurementsareadequateandaccurateindicatorsofironstatus,especiallywhenconcomitant
inflammationispresent.
ItiscontroversialaboutwhetherhepcidinisareliablebiomarkerofironstatusinCKDpatients.
Serumhepcidinhasbeenshowntobepositivelycorrelatedwithserumferritin,percentironsaturation,
Nutrients2018,10,1173 7of34
CRP and sTfR and negatively with glomerular filtration rate (GFR) in CKD patients [47]. As GFR
decreased,serumhepcidinlevelswereincreasedinnon-dialysis(ND)-CKDpatients[48]. Dialysis
canremovehepcidin[49]andinflammationincreaseshepcidinlikeferritin[18,48,50]. Asignificant
intra-individualvariabilityofhepcidinwasdependentonshort-termfluctuationsintheinflammatory
condition[50]. Thus,short-termmeasurementofserumhepcidinshouldnotbeusedasabiomarkerof
ironstatusinHDpatients[50]. Interpretationofthedataforserumhepcidinshouldbewithcaution
duetotheconfoundingfactorsasdescribed. However,hepcidincouldbeagoodbiomarkerofiron
statusinCKDpatientsintheabsenceofapparentinflammation.
5. IDAinCKD
5.1. ImpactofInflammationonDiagnosisofIDA
The cutoff levels of Hb for diagnosis of anemia depend on age, sex and pregnancy [1]
(Table 1). In general, low serum ferritin (<15 ng/mL) and TSAT (<16%) are used for diagnosis
of IDA in individuals without inflammatory conditions [1]. However, IDA could be diagnosed
based on higher cutoff levels of serum ferritin and TSAT in the presence of chronic inflammatory
condition such as CKD [1]. Table 2 summarizes diagnostic criteria for IDA in ND-CKD and HD
patients used by international guidelines for the management of IDA in CKD patients [51–60].
Some guidelines in Canada, US [51,52,55] and Taiwan [57] recommend higher cutoff levels of
serumferritin≤200–500ng/mLandTSAT≤30%[54,57]fordiagnosisofIDAandinitiationofiron
supplementation in ND-CKD and HD patients than those (serum ferritin <100 ng/mL and TSAT
<20%)recommendedbytheJapaneseSocietyforDialysisTherapy(JSDT)guidelines[53]andother
guidelines from Europe [55,56,58–60]. The Japanese nationwide study showed low cutoff levels
ofserumferritin(<50–100ng/mL)andTSAT(<20%)todiagnoseIDAinHDpatientswithlowCRP
(median; 1.0 mg/mL) [61]. The reason for the difference in the criteria for diagnosis of IDA and
theinitiationofirontherapyinCKDpatientsbetweenJapanandsomeWesterncountriesisunclear.
However, itmaybeinpartduetolowerprevalenceofinflammationassociatedwithHDpatients
in Japan than those in Western countries [15,61,62]. While the specific biologic basis underlying
differences by race and ethnicity is unclear [62], one of the reasons may be higher prevalence of
arteriovenous (AV) fistula and lower prevalence of. catheter use and AV graft in Japan [15,63,64]
thatareassociatedwithhigherlevelsofCRP[65]ascomparedtoWesterncountries. Nonetheless,
theimpactofinflammationcouldincreasethecutofflevelsofserumferritinandTSATfordiagnosisof
IDAtoinitiateirontherapyinCKDpatients.
Table1.Cutoffofhemoglobin(Hb)fordiagnosisofanemia.
Age/GenderGroups HbBelow(g/dL)
Children
6monthsto4years <11.0
5to11years <11.5
12to14years <12.0
Adults
Non-pregnantwomen≥15years <12.0
Pregnantwomen≥15years <11.0
Men≥15years <13.0
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Table2.InternationalclinicalguidelinesfordiagnosisofIDAandupperlimitofserumferritinandTSATinCKDpatients.
RecommendedIDCutoff
Organization Origin ID/IDA SerumFerritin(ng/mL) TSAT(%) UpperLimitofSerum TSAT(%) Reference
(Year) Ferritin(ng/mL)
ND HD ND HD
KDOQI(2007) USA ID/IDA ≤100 ≤200 ≤20 ≤20 ≤500 NA [51]
CSN(2008) Canada ID/IDA ≤100 ≤200 ≤20 ≤20 ≤800 NA [52]
JSDT(2008) Japan ID/IDA ≤100 ≤100 ≤20 ≤20 ≤800 ≤50 [53]
Children ≤100 ≤100 ≤20 ≤20 NA NA
KDIGO(2012) International ID/IDA ≤500 ≤500 ≤30 ≤30 ≤500–800 NA [54]
Children ≤100 ≤100 ≤20 ≤20 ≤500–800 NA
ERBP(2016) Europe ID/IDA <100 <100 <20 <20 ≤500 ≤30 [55]
KHA-CARI(2013) Australia ID <100 <100 <20 <20 ≤500 NA [56]
TPG(1996) Taiwan ID/IDA ≤300 ≤300 ≤30 ≤30 ≤800 ≤50 [57]
NICE(2015) UK ID/IDA ≤100 ≤100 ≤20 ≤20 <800 NA [58,59]
UKRA(2017) UK ID/IDA ≤100 ≤100 ≤20 ≤20 ≤500–800 NA [60]
Children ≤100 ≤100 ≤20 ≤20 ≤500–800 NA
CKD:chronickidneydisease;CSN:CanadianSocietyofNephrology;ERBP:EuropeanRenalBestPractice;HD:hemodialysis;ID:irondeficiency;IDA:IDanemia;JSDT:TheJapaneseSociety
forDialysisTherapy;KDIGO:TheKidneyDisease,ImprovingGlobalOutcomes;KDOQI:TheKidneyDiseaseOutcomesQualityInitiative;KHA-CARI:KidneyHealthAustralia-Caring
forAustralianswithRenalImpairment;ND:non-dialysis,NICE:TheNationalInstituteforHealthandCareExcellence;TPG:TaiwanPracticeGuidelines;TSAT:transferrinsaturation;
UKRA:UnitedKingdomRenalAssociation.IDisdefinedasadecreaseinthebodyironstores.NA:notavailable.
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5.2. IDA,InflammationandClinicalOutcomeinCKD
IDAandFIDAarefrequentlyassociatedwithchronicinflammation,includingCKD.IDAoccurs
in42.0%inchildrenwithCKD[66]and1.2–13.9%inthosewithout[67,68]aswellasin24.0–85.0%of
adultswithCKD[69,70]and1.0–4.5%ofthosewithout[67,71],suggestingthatIDAismorefrequently
associatedwithCKDpatientsthangeneralpopulation. IDAismoreprevalentinbothgirlsandwomen
thanboysandmenandinpatientswithadvancedCKDthaninthosewithlowgradeCKD[66,69].
FIDAoccursin12.0–21.4%ofND-CKDadults[18,48]and23.0–42.9%ofHDadults[17,72]although
prevalenceofFIDAremainsunknowninCKDchildrenandgeneralpopulation. Thus,bothIDAand
FIDAmorefrequentlyoccurasCKDadvances.
IDAincreasesariskofhospitalization[73]andmortality,includingall-causeandcardiovascular-
relatedmortalityinND-CKD[4,73,74]andHDadults[75,76]. Severalshort-termstudiesshowedthat
Hb<10g/dLwasariskfactorofmortalityinND-CKD[77]andHDadults[78,79]. Thelong-term
studiesshowedthatHblevelsof<10–12g/dL[80–82]wereariskfactorofmortalityinHDadults.
Ontheotherhand,inHDchildren,Hb<12g/dLwasassociatedwithincreasedriskofhospitalization
andmortality[83]. ThesedatasuggestthatthelevelsofHbof<12g/dLareariskfactorofmortality
inbothchildrenandadultswithND-CKDandHD.Additionally,longertimerequiredtoreachthe
tHblevelwasassociatedwithhigherriskofhospitalizationandmortalityinHDadults[84]. Thus,
earlyinterventionwithirontherapyforIDAcanimproveQOLandmortalityinCKDpatients.
Littleisknownwhetherinflammationaffectsthecutofflevelsofferritindeficiencyasariskfactor
ofmortalityinCKDpatients. ThestudyfromEuropereportedthatinHDadults,mortalityratewas
13.8/100patient-yearsandthatserumferritinlevelsof<100ng/mLwereariskfactorofcardiovascular-
relatedmortalityinHDpatientswithpositiveCRP[76]. However,theJapanesestudyshowedthat
lowserumferritinlevelsofeither<30ng/mLor<50ng/mLwereassociatedwithasignificantrisk
of mortality in Japanese HD patients with normal CRP receiving IIT and ESA [8,85]. These data
suggestthatlowlevelsofserumferritinareariskfactorofmortalityinCKDpatients,whereasthe
cutofflevelsofferritindeficiencytopredictmortalityislowerinHDpatientswithoutthanthosewith
apparentinflammation.
In addition to low ferritin, low serum iron (<45.3 µg/dL) [86], TSAT (≤20%) [74,87,88] and
TIBC[75]havebeenshowntoberiskfactorsofhospitalizationandmortalityinND-CKDandHD
adults. IDAinducesresistancetoESA[88]whichaggravatesrenalanemia,leadingtoworseoutcome
inHDpatients[89].ThesedatasuggestthatIDAisasignificantriskfactorofmortalityinCKDpatients.
Asdiscussedearlier,inflammationaffectstheseindicatorsofironstatus,especiallythecutofflevelsof
serumferritindeficiencytopredictmortalityinCKDpatients.
5.3. Inflammation,IncreasedSerumFerritinandMortalityinCKD
ThemanagementofIDAwithironsupplementationiscrucialforbetteroutcomeinCKDpatients.
However, aggressive iron therapy causes iatrogenic iron overload, leading to inflammation and
increasing a risk of mortality. In support of this hypothesis, inflammation and hyperferritinemia
(>500ng/mL) were associated with cardiovascular and all-cause mortality in HD adults [90].
Inaddition,indialysischildrenandadolescentswithironoverload,ferritinlevelsshowedapositive
correlationwithinflammationmarkers(CRPandIL-6)andleftventricularmass(LVM)[39].
Itiscontroversialwhetherironoverloadisassociatedwithariskofinfectionorinfection-related
mortality[91]. Highserumferritinhasbeenshowntobeanindependentriskfactorofinfection-related
mortalityinHDpatients[7,92–95]. Bolusdosingofferricgluconatecouldincreaseariskofinfection-
relatedmortalityandhospitalizationinHDpatientswithcatheter[96]. However,norelationhasbeen
reportedbetweenferritinandariskofinfection-relatedmortalityinHDpatients[97].
Toreduceariskofironoverload-mediatedtoxicity,internationalguidelinesforthemanagement
of IDA in CKD recommend that upper limit of serum ferritin and TSAT should be maintained at
<500–800 ng/mL [51–60] and <30–50% [53,55,57], respectively (Table 2). Other study groups in
Europe and US recommend that serum ferritin should be maintained at 400–600 ng/mL [98] and
Nutrients2018,10,1173 10of34
200–1200ng/mL[99]inHDpatients. ThepercentageofUSfacilitieswithanupperferritintarget
of1200ng/mLincreasedfrom20%to40%from2010to2011andmorethan90%facilitieshadan
upper ferritin target of 800 ng/mL in 2014 [100]. Upper ferritin targets of 500 ng/mL remained
commoninEuropeandnoEuropeanfacilityhadupperferritintargetsof1200ng/mLin2014.InJapan,
upperferritintargetswerelower,withmostfacilitiestargetingupperlimitsof300ng/mL[100]. Inthis
study,thedataforCRPwerenegativeinJapanesefacilitiesalthoughdataforCRPinUSfacilitiesare
notavailable. TheseguidelinesandthestudiesdescribedhereexceptforthosefromJapanarelikelyto
bebasedonthedataobtainedfrominflamedCKDpatientsassuggestedbyotherstudies[15,61,62].
Thus,inflammationsignificantlyaffectsupperserumferritintargetstoavoidironoverloadforthe
managementofIDAinCKDpatients. Insupportofthishypothesis, inthesettingofconcomitant
inflammation,serumferritinlevelsof≥500–800ng/mLarefoundtobepredictiveofhighmortalityin
HDpatientsofEurope[9,101]andTaiwan[92]andUSA[95]. HighCRPlevelsalonemaypredicthigh
mortalityinHDpatients[62,102]. Takentogether,thesedatasuggestthatironoverloadasreflectedby
highserumferritinandconcomitantinflammationindependentlyorsynergicallycanincreasearisk
ofmortalityinCKDpatients.
Bycontrast,intheabsenceofinflammation,evenslightincreaseinserumferritin(≥200ng/mL)is
associatedwithariskofmortalityinJapaneseHDpatients[85]. Thus,thecutofflevelsofserumferritin
topredictironoverloadandariskofmortalityaresignificantlylowerinHDpatientswithoutthanin
thosewithapparentinflammation. Sinceinflammationincreasesferritinindependentofironstatus,
upperserumferritintargetstopredictironoverloadandmortalitymaybelowerthan>500–800ng/mL
inHDpatientswithapparentinflammation,Furtherstudieswouldbenecessarytodeterminewhatare
truelevelsofupperserumferritintargetstopredictironoverloadinCKDpatientswhenconcomitant
inflammationispresent.
6. ImpactofInflammationonTherapeuticStrategywithIronSupplementationinCKD
Ironsupplementationhasbeenusedin57.3–78.0%ofdialysischildren[103–105]anditsuseis
lessprevalentinthosenotreceivingthaninthosereceivingESA[104,105]. Thus,irontherapyislikely
tobemorefrequentlyusedinsevereanemicCKDchildrenreceivingESA.Thereisasimilartrendin
CKDadults;irontherapyhasbeenusedin48.1–56.3%ofND-CKD[4,106],68.0%ofperitonealdialysis
(PD)and76.0–84.4%ofHDadults[104,107]. TheuseofIIThasrecentlybeenincreasedto>70%ofHD
adults[108]andserumferritintargetsandIVirondoseshavebeenincreasedinHDadults[108,109].
MaintenanceIITcanimprovetheresponsetoESAwithareductionofESAdoseandearlysurvivalin
ND-CKD[73]andHDadults[110]. However,Hblevelsof>13g/dLfollowingIITisassociatedwith
worseoutcomeinCKDpatients[111]. Thus,thetargetHb(tHb)of10–13g/dLisrecommendedfor
themanagementofIDAinCKDpatients[112–114]. Wehereindiscusstheimpactofinflammationon
sometherapeuticissuestomaintaintHbforthemanagementofIDAinCKDpatients.
6.1. InflammationandtheResponsetoIronSupplementationinCKD
IIT is generally superior to OIT to improve IDA in children and adults with CKD [115,116],
whilesomepatientsfailtorespondtoirontherapy. Insupportofthis,Qunibietal. showedthatthe
tHblevelsweremoremaintainedinND-CKDpatients(60.4%)afterIVferriccarboxymaltosethanin
those(34.7%)receivingOIT[117]. OneofthereasonsaccountingforsuperiorityofITToverOITto
maintaintHbinCKDpatientsmaybedifferenceintheefficacyofIITandOITinCKDpatientsinthe
presenceofconcomitantinflammationthatincreasesferritinandhepcidin. Table3summarizesdata
regardingtheimpactofinflammationontheeffectofOITversusIITforIDAinCKDpatients,inwhom
thedataforCRPareavailable. TheefficacyofIITisgenerallybetterthanOITforthemanagement
of IDA in inflamed ND-CKD patients with positive CRP [98,118–122]. Stoves et al. showed no
significantdifferenceintheHblevelsattheendofOITandIITinND-CKDadultswithpositiveCRP,
whilethelevelsofHbachievedtendedtobehigherintheIITgroupthanthoseintheOITgroup[123].
Incontrast,inHDpatientswithnormalCRP,OITisaseffectiveasIIT[124–126]. HDadultsresponding