Guidelines for Renal Anemia in Chronic Kidney Disease

36 Pages·2010·0.59 MB·English

tap_836240..275
TherapeuticApheresisandDialysis14(3):240–275
doi:10.1111/j.1744-9987.2010.00836.x
©2010TheAuthors
Journalcompilation©2010InternationalSocietyforApheresis
2008 Japanese Society for Dialysis Therapy: Guidelines for
Renal Anemia in Chronic Kidney Disease
Yoshiharu Tsubakihara,1 Shinichi Nishi,2 Takashi Akiba,3 Hideki Hirakata,4
Kunitoshi Iseki,5 Minoru Kubota,6 Satoru Kuriyama,7 Yasuhiro Komatsu,8 Masashi Suzuki,9
Shigeru Nakai,10 Motoshi Hattori,11 Tetsuya Babazono,12 Makoto Hiramatsu,13
Hiroyasu Yamamoto,14 Masami Bessho,15 and Tadao Akizawa16
1DepartmentofKidneyDiseaseandHypertension,OsakaGeneralMedicalCenter,Osaka,2BloodPurification
Center,NiigataUniversityMedicalandDentalHospital,9KidneyCenter,ShinrakuenHospital,Niigata,
3DepartmentofBloodPurification,KidneyDiseaseGeneralMedicalCenter,11DepartmentofPediatric
Nephrology,KidneyCenter,and12DepartmentofMedicine,DiabetesCenter,TokyoWomen’sMedical
University,6OjiHospital,7DivisionofNephrology,SaiseikaiCentralHospital,8KidneyCenter,St.Luke’s
InternationalHospital,14DivisionofKidneyandHypertension,DepartmentofInternalMedicine,Jikei
UniversitySchoolofMedicine,16DivisionofNephrology,DepartmentofMedicine,ShowaUniversitySchoolof
Medicine,Tokyo 4KidneyUnit,FukuokaRedCrossHospital,Fukuoka,5DialysisUnit,UniversityofThe
Ryukyus,Okinawa,10DivisionofClinicalEngineeringTechnology,FujitaHealthUniversityCollege,Aichi,
13DepartmentofNephrology,OkayamaSaiseikaiGeneralHospital,Okayama,and15Departmentof
Hematology,SaitamaMedicalSchool,Saitama,Japan
Abstract: The Japanese Society for Dialysis Therapy associatedwithrenaldisordersistheprimarycauseofrenal
(JSDT) guideline committee, chaired by Dr Y. Tsubaki- anemia, and that renal anemia refers to a condition in
hara, presents the Japanese guidelines entitled “Guide- whichthereisnoincreasedproductionofEPOandserum
lines for Renal Anemia in Chronic Kidney Disease.” EPOlevelsremainwithinthereferencerangeforhealthy
These guidelines replace the “2004 JSDT Guidelines for individualswithoutanemia,irrespectiveoftheglomerular
Renal Anemia in Chronic Hemodialysis Patients,” and filtration rate (GFR). In other words, renal anemia is
contain new, additional guidelines for peritoneal dialysis clearly identified as an“endocrine disease.”It is believed
(PD), non-dialysis (ND), and pediatric chronic kidney that defining renal anemia in this way will be extremely
disease (CKD) patients. beneficialforNDpatientsexhibitingrenalanemiadespite
Chapter 1 presents reference values for diagnosing having a high GFR.We have also emphasized that renal
anemiathatarebasedonthemostrecentepidemiological anemiamaybetreatednotonlywithESAtherapybutalso
data from the general Japanese population. In both men with appropriate iron supplementation and the improve-
and women,hemoglobin (Hb) levels decrease along with ment of anemia associated with chronic disease,which is
anincreaseinageandthelevelfordiagnosinganemiahas associated with inflammation, and inadequate dialysis,
beensetat<13.5g/dLinmalesand<11.5g/dLinfemales. anothermajorcauseofrenalanemia.
However,theguidelinesexplicitlystatethatthetargetHb InChapter2,whichdiscussesthetargetHblevelsinESA
levelinerythropoiesisstimulatingagent(ESA)therapyis therapy, the guidelines establish different target levels
different to the anemia reference level. In addition, in for hemodialysis (HD) patients than for PD and ND
defining renal anemia, the guidelines emphasize that the patients, for two reasons: (i) In Japanese HD patients,
reduced production of erythropoietin (EPO) that is Hb levels following hemodialysis rise considerably above
their previous levels because of ultrafiltration-induced
hemoconcentration;and(ii)asnotedinthe2004guidelines,
although10to11g/dLwasoptimalforlong-termprognosis
ReceivedJanuary2010. iftheHblevelpriortothehemodialysissessioninanHD
AddresscorrespondenceandreprintrequeststoDrYoshiharu
patienthadbeenestablishedatthetargetlevel,ithasbeen
Tsubakihara,Department of Kidney Disease and Hypertension,
reportedthat,basedondataaccumulatedonJapanesePD
OsakaGeneralMedicalCenter,3-1-56Bandaihigashi,Sumiyoshi-
andNDpatients,inpatientswithoutseriouscardiovascular
ku,Osaka558-8558,Japan.Email:[email protected]
PublishedinJJpnSocDialTher2008;41:661–716(inJapanese). disease,higherlevelshaveacardiacorrenalfunctionpro-
ReprintedwithpermissionfromtheJournaloftheJapaneseSociety tective effect, without any safety issues.Accordingly, the
forDialysisTherapy. guidelines establish a target Hb level in PD and ND
240
2009JDSTAnemiaGuidelines 241
patientsof11g/dLormore,andrecommend13g/dLasthe theexpertopinionthatevidenceobtainedfromstudiesin
criterionfordosereduction/withdrawal.However,withthe which an ESA cost-savings effect had been positioned
resultsof,forexample,theCHOIR(CorrectionofHemo- as the primary endpoint should not be accepted
globinandOutcomesinRenalInsufficiency)studyinmind, unquestioningly.
the guidelines establish an upper limit of 12g/dL for In Chapter 4, which discusses ESA dosing regimens,
patientswithseriouscardiovasculardiseaseorpatientsfor andChapter5,whichdiscussespoorresponsetoESAs,we
whom the attending physician determines high Hb levels gave priority to the usual doses that are listed in the
wouldnotbeappropriate. package inserts of the ESAs that can be used in Japan.
Chapter 3 discusses the criteria for iron supplementa- However,ifthemaximumdoseofdarbepoetinalfathatcan
tion. The guidelines establish reference levels for iron currentlybeusedinHDandPDpatientsweretobeused,
supplementationinJapanthatarelowerthanthoseestab- thenthemajorityofpoorresponderswouldberescued.
lished in the Western guidelines.This is because of con- Blood transfusions are discussed in Chapter 6. Blood
cerns about long-term toxicity if the results of short-term transfusions are attributed to the difficulty of managing
studies conducted byWestern manufacturers,in which an renalanemianotonlyinHDpatients,butalsoinend-stage
ESA cost-savings effect has been positioned as a primary ND patients who respond poorly to ESAs. It is believed
endpoint,are too readily accepted.In other words,if the thatthenumberofpatientsrequiringtransfusionscouldbe
serum ferritin is <100ng/mL and the transferrin satura- reducedfurtheriftherewerenovellong-actingESAsthat
tion rate (TSAT) is <20%, then the criteria for iron couldbeusedforNDpatients.
supplementation will be met;if only one of these criteria Chapter 7 discusses adverse reactions to ESA therapy.
is met, then iron supplementation should be considered Ofparticularconcernistheemergenceandexacerbationof
unnecessary. hypertension associated with rapid hematopoiesis due to
Although there is a dearth of supporting evidence for ESAtherapy.
these criteria,there are patients that have been surviving ThetreatmentofrenalanemiainpediatricCKDpatients
onhemodialysisinJapanformorethan40years,andsince is discussed in Chapter 8;it is fundamentally the same as
there are approximately 20000 patients who have been that in adults. Key Words: Chronic dialysis, Erythropo-
receiving hemodialysis for more than 20years,which is a iesis stimulating agent, Guidelines, Hemoglobin, Non-
situationthatisdifferentfromthatinmanyothercountries. dialysis Chronic kidney disease, Pediatric chronic kidney
Asthereareconcernsaboutadversereactionsduetothe disease,Quality of life,Renal anemia,Serum erythropoi-
overuseofironpreparationsaswell,wethereforeadopted etinconcentration.
Renal anemia is a major complication in patients theguidelinesofdifferentcountriesandregionscite
with chronic kidney disease (CKD), particularly virtuallyidenticalevidence,differencesmaybeseen.
dialysis patients,and is a problem that has yet to be In all of the guidelines outside of Japan, the target
conquered. However, the feeling has been that this Hb levels for ESA therapy in hemodialysis (HD),
problem had been solved by the development of peritoneal dialysis (PD), and ND patients are
recombinant human erythropoietin (rHuEPO), almost identical.
which became available for use by dialysis patients In 2001, there was a groundswell of momentum
in Japan in 1990,and immediately began to be used for the preparation of guidelines in Japan as well,
by approximately 80% of patients with unprec- and the First Renal Anemia Treatment Guideline
edented efficacy.Then,in 1994,an additional indica- Preparation Working Group (WG) of the Japanese
tion was approved for non-dialysis (ND) CKD Society for Dialysis Therapy (JSDT), chaired by
patients, yielding a dramatic reduction in blood Professor F. Gejyo, was formed.The working group
transfusions given when starting dialysis and afford- first assessed the Western guidelines that had
ing various other beneficial effects, including sup- already been prepared, as well as the evidence
pression of the progression of renal failure and an on which they had been based, and then explored
improvement in patient quality of life (QOL). An what data were available in Japan. However, since
improved vital prognosis following the start of there was virtually no evidence that was suitable
dialysis was also reported.Moreover,new problems forcitinginJapan,theuseoftheWesternguidelines
were identified with the target hemoglobin (Hb) was one option that was considered. On the
levels in ESA therapy and also with the criteria for other hand,given that the dialysis and blood collec-
the concomitant use of iron preparations. In order tion methods that are used in the West in HD
to find solutions to these problems, clinical studies patients are different than those used in Japan, the
were conducted,and guidelines based thereon were working group decided against adopting the
formulated and revised in various countries and Western guidelines in their present form.There was
regions around the world.Although the majority of also considerable debate about whether or not to
©2010TheAuthors
Journalcompilation©2010InternationalSocietyforApheresis TherApherDial,Vol.14,No.3,2010
242 YTsubakiharaetal.
handle PD and ND patients in the same way as including those of JSDT members, reported the
HD patients, whose Hb values change markedly overall framework at the JSDT Annual Meeting in
from before to after hemodialysis. In the end, June 2008, obtained approval, and published the
renal anemia treatment guidelines were established guidelines in that same year,in the October issue of
only for HD patients. The working group also J Jpn Soc Dial Ther, the Japanese-language journal
proposed preparing its own evidence on HD of the JSDT.
patients.Although this is not usually how guidelines Intheseguidelines,thecitedpapersaredividedinto
are prepared, there was no other way of preparing three levels, A, B, and C, in order of decreasing
Japan-specific guidelines,and this plan was accepted strengthoftheevidencecontainedtherein.Sothatthe
by all the members of the working group. In recommendations shown in the boxes in the guide-
order to prepare the evidence, the results of the lines are easier to understand, they have also been
statistical surveys conducted by the JSDT Commit- divided into three levels: Strong Recommendation;
tee of Renal Data Registry (CRDR) at the end of Moderately Strong Recommendation; and Opinion
each year at all dialysis facilities in Japan were ana- (recommendation as the committee’s opinion).Fur-
lyzed retrospectively. Based on the evidence thermore,evidencefromJapanandrecommendation
obtained, finally, in 2004, the “Guidelines for Renal levels that are based on evidence from Japan are
Anemia in Chronic Hemodialysis Patients” were indicatedbyasterisks.
completed. Itisoursincerehopethattheseguidelinescontrib-
Thefollowingyear,inDecember2005,inaddition ute to the improved treatment of anemia in CKD
to revising the 2004 guidelines, the Second Renal patients in Japan. In the future, these guidelines
Anemia Treatment Guidelines Working Group, should be revised as necessary as new evidence is
chaired by Dr Y. Tsubakihara, was formed for the obtained, and after giving due consideration to the
purpose of preparing renal anemia treatment guide- opinionsofJSDT,JSN,JSPD,andJSPNmembersand
lines for PD,ND,and pediatric CKD patients.Most otherrelevantparties.
of the members of the first working group were
retained, and JSDT CRDR members and hematol-
ogy specialists were added. In addition, in order to CHAPTER1
prepare guidelines for ND, PD, and pediatric CKD
Diagnosis,criteria,andtreatmentofrenalanemia
patients, the cooperation of the Japanese Society
of Nephrology (JSN), the Japanese Society of Peri- 1. Hemoglobin(Hb)levelsinhealthyadultsdependonage,
gender,andrace.Therefore,thecriteriaforanemiamustbe
toneal Dialysis (JSPD), and the Japanese Society
establishedconsideringthesefactors.(Table1-1).
for Pediatric Nephrology (JSPN) was obtained. 2. “Hb levels” should be used as reference values for
Each society was invited to send a representative diagnosisofanemia(Strongrecommendation).
3. In diagnosing anemia, various disorders causing anemia
to join the working group as a member, and a
mustbedifferentiated.Meancorpuscularvolume(MCV)is
working group with 16 members was thereby ausefulindex(Opinion).
formed. In January 2006, at a meeting with the US 4. The primary cause of renal anemia is decreased
erythropoietin (EPO)-producing capacity associated with
National Kidney Foundation Kidney Disease Out-
renaldisorder.Thediagnosisofrenalanemiaismadefor
comes Quality Initiative (NKF K/DOQI) Guideline the first time when no other diseases causing anemia are
Preparation Committee members, we were found.Insomenon-dialysis(ND)patients,measurementof
serumEPOlevelmaybeuseful(Opinion*).
reminded anew of the differences in the patient
backgrounds between the patient populations in the
large-scale clinical studies conducted in the US and 1. Generaldiagnosticcriteriaforanemia
the patients that we see in the clinical setting in
ThereferencevaluesfordiagnosisofanemiainJapaneseare
Japan.We therefore determined that,as a matter of Hblevelsof<13.5g/dL(hematocrit[Ht]levels<40%)inadult
policy, as had been done by the First Working males and <11.5g/dL in adult females (Ht levels <35%)
(Recommendation*).
Group, we would emphasize Japanese evidence
wherever possible.
We then initiated a search of the literature and (1) Definitionofanemia. Anemiaisnotadisease
communications amongst ourselves, held 13 meet- name but a condition in which the Hb level is
ings of the working group,exchanged opinions with decreased. Hb transports oxygen to each body
the Japan Bio-Iron Society (JBIS) regarding the use tissue; therefore, when anemia occurs, oxygen
of iron preparations, held a public hearing with supply to tissues is reduced, and the physical func-
JSDT members, posted the draft guidelines on the tion is influenced in accordance with the severity of
JSDT home page, compiled numerous opinions, anemia.
©2010TheAuthors
TherApherDial,Vol.14,No.3,2010 Journalcompilation©2010InternationalSocietyforApheresis
2009JDSTAnemiaGuidelines 243
TABLE1-1. MeanhemoglobinlevelsinJapanesemalesandfemalesandthe
criteria
foranemia
MiwaHematology, Chronological
3rdedition(1) scientific(2)
19–60years 60–69years 70–79years
Maleg/dL(Mean(cid:2)SD) 15.3(cid:2)0.9 13.8(cid:2)0.9 13.5(cid:2)1.2
Femaleg/dL(Mean(cid:2)SD) 13.3(cid:2)0.9 12.5(cid:2)1.0 12.2(cid:2)0.9
ReferenceLevelsforDiagnosis
Maleg/dL(Mean-2SD) 13.5 12.0 11.1
Femaleg/dL(Mean-2SD) 11.5 10.5 10.4
SD,standarddeviation.
(2) Diagnosticcriteria. Therehavebeenfewtext- Hemodialysis Patients” (2004 Guideline) (5) also
books which provide diagnostic criteria for anemia specified the diagnostic reference values, but they
based on measurement results in healthy Japanese. were revised as shown in Table1-1 and 1-2
Whenmean-2SD(standarddeviation)valuesofHb because of revisions to the supporting data. The
or Ht levels in Japanese judged to be healthy by provided age-specific Japanese diagnostic reference
certainstandardsaredefinedasreferencevaluesfor values for both males and females aged 60years or
diagnosis of anemia, the values are as shown in oldertendtobelowerthanthoseinEuropeandthe
Table1-1and1-2(1,2)(LevelB*).Asindicatedinthe US.
tables, the reference values for diagnosis of anemia Inbloodtestswithanautomaticanalyzerwhichis
differbetweenmalesandfemalesandamongtheage now commonly used, the red blood cell count, Hb
groups. Table1-3 lists common reference values for level,andMCVareobtainedasmeasuredvalues,and
diagnosis of anemia in Europeans and Americans the Ht level as a calculated value.Unlike Hb levels
which are provided in the European Best Practice which remain relatively constant after blood sam-
Guidelines(EBPG)(3)andUS(K/DOQI)(4)guide- pling, the values of MCV and Ht change due to
linesforrenalanemia(hereinafterabbreviatedasthe variousinfluencesoccurringwithtimeaftersampling
EuropeanandUSguidelines). (3) (Level A).Therefore, unless Ht levels are mea-
In Japan, the “2004 Japanese Society for Dialysis sured directly, the use of Hb levels in diagnosing
Therapy Guideline for Renal Anemia in Chronic anemiaisrecommended.
TABLE1-2. MeanhematocritlevelsinJapanesemalesandfemalesandthe
criteriaforanemia
MiwaHematology, Chronological
3rdedition(1) scientific(2)
19–60years 60–69years 70–79years
Male%(Mean(cid:2)2SD) 45.0(cid:2)2.5 42.0(cid:2)2.8 40.9(cid:2)3.6
Female%(Mean(cid:2)2SD) 40.0(cid:2)2.5 37.6(cid:2)3.1 36.9(cid:2)2.9
ReferenceLevelsforDiagnosis
Male%(Mean—2SD) 40.0 36.4 33.7
Female%(Mean—2SD) 35.0 31.4 31.1
TABLE1-3. EuropeanBestPracticeGuidelines(EBPG)(3)andKidney
DiseaseOutcomesQualityInitiative(K/DOQI)(4)criteriaforanemia
EBPG K/DOQI
Adultmale Hblevel<13.5g/dL Hblevel<13.5g/dL
Adultfemale Hblevel<11.5g/dL Hblevel<12.0g/dL
Maleaged>70years Hblevel<12.0g/dL
Hb,hemoglobin.
©2010TheAuthors
Journalcompilation©2010InternationalSocietyforApheresis TherApherDial,Vol.14,No.3,2010
244 YTsubakiharaetal.
TABLE1-4. Differentialdiagnosisofanemia
Microcytic iron-deficiencyanemia,ACD,sideroblasticanemia,thalassemia,atransferrinemia
Normocytic renalanemia,hemolyticanemia,aplasticanemia,PRCA,myelodysplasticsyndrome,
ACD,leukemia
Macrocytic renalanemia,megaloblasticanemia(VitaminB12deficiency,folicaciddeficiency),
hepatopathy,hypothyroidism,aplasticanemia,myelodysplasticsyndrome,and
drug-relateddisordersinDNAsynthesis
ACD,anemiaofchronicdisease;PRCA,pureredcellaplasia.
2. Differentialdiagnosisofanemiaandexamination EPO-producing capacity of the kidney which is not
items attributabletocausesotherthanrenaldisease(Level
B*)(6,7).However,inbroadly-definedrenalanemia,
Indiagnosinganemia,variousdisorderscausinganemiamust
causes other than the decreased EPO-producing
be differentiated.In the differential diagnosis of anemia,the
typeofanemiashouldbeclassifiedintomicrocytic,normocytic, capacity due to renal disease (such as shorter life
andmacrocyticcategoriesbasedonMCV.(Opinion). spanofredbloodcells)arealsotakenintoconsider-
ation. In Japan, it is reasonable to regard values in
In diagnosing renal anemia, differentiation of
Table1-1 and 1-2 as the reference values of Hb
variousdiseasescausinganemiaisneeded.Tomakea
dependingonthesexandage.
differential diagnosis of anemia in clinical practice,
Referencevaluesofadecreaseinglomerularfiltra-
classification of microcytic, normocytic, and macro-
tion rate (GFR) at which the incidence of renal
cytic categories based on MCV is clinically useful.
anemia abruptly increases are approximately serum
ThedisordersclassifiedaccordingtoMCVvaluesare
creatinine (Cr) of 2mg/dL or more, or creatinine
showninTable1-4.
clearance(Ccr)oflessthan20to35mL/min(chronic
The examination items necessary for the differen-
kidneydisease[CKD]stage4to5)(8–10)(LevelC).
tiation of the individual diseases are summarized in
Inpatientswithdiabeticnephropathy,renalanemiais
Table1-5.The items include a peripheral blood test,
knowntooccuratanearlierstagethaninthosewith
parametersofironmetabolism,biochemistry,asero-
non-diabeticnephropathy,andtheroughindicationof
logicaltest,serumEPOlevel,bonemarrowexamina-
such occurrence is Ccr of less than 45mL/min (3)
tion, and vitamin/hormone measurements. It is
(LevelC).
important to select the examination items in accor-
However,the presence of renal anemia cannot be
dancewithdisorderstobedifferentiated.
ruledouteveninpatientswithrelativelyhigherGFR.
Given that “renal anemia is an endocrine disease”,
3. Definitionofrenalanemia factors responsible for anemia other than decreased
renal EPO production due to renal disease must be
1. Renalanemiareferstoanemiacausedbydecreasedrenal
EPO-producingcapacityduetorenaldisease. excludedbeforediagnosingrenalanemia.Neverthe-
2. Othercausesofrenalanemiaincludeshorterlifespanofred less, in most cases, renal anemia may be diagnosed
blood cells, hypo-responsiveness of erythroid progenitor
when a decrease in GFR is within the ranges
cellstoEPO,malnutrition,andresidualbloodinthedialysis
bloodcircuitinhemodialysis(HD)patients. describedaboveandnoothercausesofanemia(par-
ticularly,irondeficiencyanemia,etc.)arefound.
In a limited sense,renal anemia refers to a condi- AlthoughmeasurementofserumEPOleveliscon-
tion in which the Hb level cannot be maintained sideredtobeoflessdiagnosticsignificanceinpatients
above the reference value because of decreased with end stage renal failure (3–5),it should be con-
TABLE1-5. Usefulexaminationitemsforthedifferentialdiagnosisofanemia
1. RBC,Hb,Ht,andMCV 8. Bonemarrowtest
2. Reticulocytes 9. VitaminB ,folicacid,Zn,andCu
12
3. Parametersofironmetabolism(Fe,UIBC,Ferritin,andTSAT) 10. Coombs’testandhaptoglobin
4. Leukocytecount,WBCfraction,andplateletcount 11. Bloodaluminumlevel
5. Occultbloodinstool 12. Thyroidfunction
6. Bloodbiochemistry,CRP,andproteinfraction 13. Parathyroidfunction(intactPTH)
7. SerumEPOlevel 14. Others
TSAT(%)=[serumiron(mg/dL)/TIBC(mg/dL)]¥100;CRP,C-reactiveprotein;EPO,erythropoietin;Hb,hemoglobin;Ht,hematocrit;
MCV,meancorpuscularvolume;PTH,parathyroidhormone;RBC,redbloodcell;TSAT,transferrinsaturation;UIBC,unsaturatediron
bindingcapacity;WBC,whitebloodcell.
©2010TheAuthors
TherApherDial,Vol.14,No.3,2010 Journalcompilation©2010InternationalSocietyforApheresis
2009JDSTAnemiaGuidelines 245
sidered when no other causes of anemia are found 4. Treatmentofrenalanemia
despite a relatively mild decrease in GFR (3,6)
1. Whenadefinitediagnosisofrenalanemiaisreachedand
(Level B). The national health insurance in Japan
criteria for treatment are met, ESA therapy should be
covers such measurement when conducted before started(Strongrecommendation).
thestartoftreatmentwitherythropoiesisstimulating 2. Treatment with iron preparations required for
erythropoiesis should be used concomitantly (Strong
agents (ESAs). Renal anemia can be diagnosed
recommendation).
when,although the GFR is relatively preserved,the 3. In maintenance HD patients, efforts should be made to
Hblevelislowandnoothercausesofanemiaorno purify the dialysate, and adequate dialysis should be
conducted(Strongrecommendation).
increased serum EPO level is observed.Re-analysis
4. In patients with malnutrition or inflammation,aggressive
ofdatafromJapaneseclinicalstudiesofrecombinant treatment for them should be conducted (Strong
human erythropoietin (rHuEPO) in ND patients recommendation).
(conducted by Chugai Pharmaceutical Co.,Ltd.and
Kirin Pharma Company, Ltd.; both studies included The first-line treatment of renal anemia is ESAs.
patientswithCrof2mg/dLormore,orCcrof30mL/ Anabolic steroids covered by the national health
min,orlessandHboflessthan10g/dL)revealedthat insurance in Japan should not be used because of
the mean(cid:2)standard deviation (SD) of serum EPO adverse reactions (4) (Level A). In special cases,
levelin422patientswas22.7(cid:2)12.1mIU/mL(range including those where no ESA preparations can be
5.0 to 151.0mIU/mL) and that the mean+2SD was used, anabolic steroids should be used after
46.9mIU/mL (7). In ND patients with Hb levels of adequate informed consent is obtained. Causes of
less than 10g/dL and lower serum EPO levels than renal anemia include uremic toxin or endotoxin,
this value, renal anemia is suspected irrespective of malnutrition,shorterlifespanofredbloodcellsdue
GFR(LevelC*). to inflammation and other factors, poor responsive-
In Japan, most laboratory testing companies use ness of erythroid progenitor cells to EPO, and
the radioimmunoassay (RIA) method to measure residual blood in the hemodialysis circuit of HD
the EPO level,while the enzyme-linked immunoas- patients. The EBPG recommends that adequate
say (ELISA) method is mainly used in Europe and dialysis doses should be Kt/V of 1.2/week or more
the US. Since there have been no studies which for HD patients and 1.8/week or more for PD
addressed cross validation of these methods, data patients (3) (Level B). However, the more recent
obtained from the different methods cannot be PD guidelines published in Europe and the US
simply compared. The values previously described (11,12) recommend Kt/V of 1.7 or more as the
are based on RIA. The method used for measure- minimum target.
ment should be confirmed prior to outsourcing the In HD patients, purification of the dialysate and
test. In the laboratory testing companies below, all long-term dialysis are effective not only in treating
use the identical reagent (Recombigen EPO kit*). renal anemia but also in improving survival progno-
Slight differences in their reference values (healthy sis (3) (Level B). Since malnutrition and inflam-
individuals without anemia) are considered to cause mation are also among the causative factors of
no problem in measurement (as of September renal anemia, treatment for these events should be
2008). conducted in combination with ESA therapy (3)
(Level B). In addition, hemodiafiltration (HDF) is
1. SRL,Inc.(Tokyo,Japan): 8–36mIU/mL
believed to be more effective than ordinary HD (3)
2. Mitsubishi Chemical Medience Corp. (Tokyo,
(Level B).
Japan): 9.1–32.8mIU/mL
3. BML,Inc.(Tokyo,Japan): 29.0mIU/mL
orlower
4. FALCObiosystemsLtd.(Tokyo,Japan): CHAPTER2
9.1–32.8mIU/mL
TargetHblevelandcriteriaforstartingESA
5. Health Sciences Research Institute,Inc.(Tokyo,
therapy
Japan): 8–36mIU/mL
6. Koto Biken Medical Laboratory (Ibaraki, HDpatients
1. WerecommendthatESAtherapyinpatientsundergoing
Japan): 8.0–36.0mIU/mL
HD should target an Hb level of 10 to 11g/dL in blood
samplescollectedinthesupinepositionbeforeHDatthe
*Manufactured and distributed by: Mitsubishi
beginning of the week (2days from the last dialysis)
KagakuIatron,Inc. (Moderately strong recommendation*). Hb levels
Reference material for calibration:WHO 2nd IRP exceeding12g/dLshouldbethecriteriafordosereduction
orinterruptionofESAs(Opinion*).
(HUM,urinary/Bioassay67/343(194).
©2010TheAuthors
Journalcompilation©2010InternationalSocietyforApheresis TherApherDial,Vol.14,No.3,2010
246 YTsubakiharaetal.
very little information on PD or ND patients.Com-
2. WhentheHblevelislessthan10g/dLinseveraltestresults
pared to anemia treatment in Europe and the US,
followingadiagnosisofrenalanemia,ESAadministration
shouldbeinitiated.(Opinion*). circumstances such as limitations of types and doses
3. Inrelativelyyoungpatientswithhighactivitylevels,anHb of ESAs covered by the national health insurance
levelof11to12g/dLshouldbemaintained.(Opinion*).Hb
resulted in markedly lower Hb levels (17). Further-
levels exceeding 13g/dL should be the criteria for dose
reduction or interruption of ESAs (Opinion*).When the more there were no large-scale studies to set the
Hb level is less than 11g/dL in several test results,ESA targetHblevel.After2004,thetargetHblevelinthe
administrationshouldbeinitiated.(Opinion*).
US K/DOQI guidelines was revised twice. In the
PDandNDpatients
1. WerecommendthatESAtherapyinPDandNDpatients update in 2006 (4),the upper limit of Hb levels was
shouldtargetanHblevelof11g/dLorhigher(Moderately removed as in the EBPG (3) (although it included
strongrecommendation*).IftheHblevelexceeds13g/dL,
the statement that there is no evidence to recom-
dose reduction or interruption should be considered
(Opinion*). mend that Hb levels be maintained at 13g/dL or
2. WhentheHblevelislessthan11g/dLinseveraltestresults higher). In 2007, the guideline was revised again
followingadiagnosisofrenalanemia,ESAadministration
based on the results of large-scale,randomized,con-
shouldbeinitiated.(Opinion*).
3. If the patient has a history of serious cardiovascular trolled trials (RCTs), including the Correction of
disease or complications or if it is medically necessary, Hemoglobin and Outcomes in Renal Insufficiency
dosereductionorinterruptionshouldbeconsideredifthe
(CHOIR)studyinNDpatientspublishedattheend
Hb level exceeds 12g/dL (Moderately strong recommen-
dation*). of 2006 (18) in addition to consideration of the US
Food and DrugAdministration (FDA) alert (13).In
1. BackgroundofsettingthetargetHblevel(Ht this update, given the Hb target should be set by
level)forESAtherapy taking the conditions of individual patients into
Although the Europe and US guidelines for renal account, it was specified that the Hb target should
anemia (3,4) provide identical target Hb levels for generallybeintherangeof11to12g/dLandshould
HD, PD, and ND patients, the 2004 Guideline (5) notbegreaterthan13g/dL.TheEBPGrecommends
restricted its application to HD patients, and the that the target Hb level should be higher than 11g/
setting of Hb levels for PD and ND patients was dL,without setting the upper limit.However,it also
postponed.This was primarily because Hb levels in states that the target Hb level for patients with con-
HD patients vary depending on hemoconcentration gestive heart failure and severe cardiovascular
duetofluidremovalcausedbyHD(13,14).IntheUS, diseaseshouldbe11to12g/dL(3)(LevelA).
an increase of 1 to 3g/dL of Hb levels after HD has Looking back on changes in Japanese anemia
beenreported(13)(LevelB).Inaddition,itisknown treatment after the publication of the 2004 Guide-
thatthedryweight(DW)ofJapaneseHDpatientsis lines,theresultsofthestatisticalsurveysbytheJSDT
lessthanthatofWesternersandthatmanyJapanese at the end of 2005 and 2006 (19,20) revealed that
patients have high weight gain rates (15) (Level B). approximately 40% of HD patients still had Hb
Therefore,itisexpectedthatthechangeofHblevels levelsoflessthan10g/dLasthelowerlimitoftheHb
between pre-HD and post-HD is larger in Japanese target recommended by the 2004 Guidelines (Level
patients than in Europeans and Americans. Taking A*).This implied that the 2004 Guidelines had not
such changes of Hb levels into consideration, the been understood or adequately penetrated.In addi-
EuropeandUSguidelinesrecommendthatsampling tion,inassociationwiththerevisionofmedicaltreat-
for Hb levels in HD patients should be conducted mentfeesforHDpatientsin2006,thecostofESAs
midweek as the weight gain is smaller (4).However wasincludedinaflatpaymentsystem.Becauseofthis
inJapan,mostinstitutionsconductbloodsamplingat event, the survey results at the end of 2006 showed
the beginning of the week,and the statistical survey that as compared to the survey at the end of 2005
data by the Japanese Society for Dialysis Therapy (19), the used dose of rHuEPO had decreased (20)
(JSDT) are also based on this sampling schedule. andthatpatientswithsevereanemiatendedtohave
Therefore, the increase in Hb after HD cannot be higher iron stores. Given such influence of this flat
disregarded.Attheendof1997,thestatisticalsurvey payment system,more efficient ESA therapy will be
results by the JSDT showed that the percentage of pursued further in the future. On the other hand, a
patients with Ht levels of 40% or higher reached long-acting ESA, darbepoetin alfa (DA), has been
12.7% after HD compared to 2.0% before HD (16) approved also in Japan for the treatment of renal
(LevelA*). anemiainHDandPDpatientsandclinicalstudiesin
For these reasons, the 2004 Guidelines in Japan ND patients are being conducted presently.In addi-
restricteditsapplicationtoHDpatients(5).Another tion,clinicalstudiesofanotherlong-actingESA,con-
majorreasonforsucharestrictionwasthattherewas tinuous erythropoietin receptor activator (CERA),
©2010TheAuthors
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2009JDSTAnemiaGuidelines 247
arealsoongoinginHD,PD,andNDpatients.Before TABLE2-1. Influenceofthehematocrit(Ht)levelprior
publication of the 2004 Guidelines, the Japanese tohemodialysis(HD)attheendof1995onthe5-year
survivalrate(5)(correctedbyage,gender,underlying
targetHblevelsforHD,PD,andNDpatientswereall
disease,Kt/Vurea,andpercentweightlossduringHD)
approximately 10g/dL (Ht: approximately 30%),
which was the target Hb level specified in the Htlevelprior
package insert of rHuEPO.The same criteria were toHD(%) RR(95%CI) P-value
also recommended in the report on HD patients by <24 1.714(1.610–1.82) 0.0001
the 1990 Health Sciences Research Committee 24(cid:3)<27 1.219(1.159–1.28) 0.0001
27(cid:3)<30 1.026(0.980–1.07) 0.2722
(chairperson;YoshiheiHirasawa)(21).However,the 30(cid:3)<33 1.000(control) control
Japanese clinical studies of DA provided higher 33(cid:3)<36 1.112(1.050–1.178) 0.0003
target Hb levels than before separately in HD, PD 36(cid:3)<39 1.254(1.156–1.362) 0.0001
39(cid:3) 1.306(1.185–1.440) 0.0001
andNDpatientsbasedontheEuropeandUSguide-
lines.Inthesestudies,nosafetyissueswereobserved, CI,confidenceinterval;RR,relativerisk.
and favorable results were reported in QOL and
cardiac function.As a result, an increased Hb (Ht) between 27 and 33% was lowest when adjusted by
targetofapproximately11g/dL(33%)wasprovided age,sex,primary disease,weight gain rate,and Kt/V
in the package insert of DA. The results of these (Table2-1).Analysesbyageandprimarydiseasealso
studies targeting higher Hb levels are important for indicatedthatsurvivalprognosiswasmostfavorable
they were obtained from Japanese patients with in the group with Ht levels between 30 and 33%,
chronickidneydisease(CKD).Therefore,thisGuide- although a slight difference was observed between
lineacknowledgedthesefindingstochangethecrite- theresultsoftheseanalyses(5)(LevelB*).
ria for ESA dose reduction or interruption in HD Hirasawa etal. retrospectively investigated a
patients and also to set target Hb levels for PD and 3-yearprognosisin2654Japanesemaintenancedialy-
NDpatients. sis patients receiving rHuEPO at 22 institutions,
based on mean Ht levels divided into 3% intervals.
2. TargetHblevelforHDpatients Evaluation of the survival prognosis using the Ht
In the Europe and US guidelines, the target Hb levelsadjustedbyage,sex,primarydisease,concomi-
levelsaresetat11to12g/dLorhigher,basedonthe tant disease, albumin (Alb) level, and other param-
results of several endpoints, including survival rate, etersrevealedthattheprognosiswasmostfavorable
morbidity,leftventricularmassindex(LVMI),QOL, in the group with Ht levels between 30 and 33%
physical activity level, number (length) of hospital- (Table2-2)(23)(LevelB*).
izations,othercognitiveabilities,metabolicfunction, Taken together, the results described above sug-
andsleeppattern(3,4)(LevelB). gested that the target Hb level for rHuEPO therapy
On the other hand, a slight ethnic difference is is10to11g/dL(Htlevel:30to33%)(5)whenevalu-
observedinthenormalHb(Ht)levelbetweenJapa- ated in terms of survival prognosis, (Level B*).
nese and Westerners, and it is slightly lower in the However,when limited to younger individuals aged
Japaneseelderly(seeChapter1).However,thereare 35 to 45years, analysis of 5-year survival using the
only a few studies that address the setting of Hb statistical data by the Japanese Society for Dialysis
target for rHuEPO therapy in Japanese that are Therapy revealed that the RR in the group with Ht
worthciting.Intheannualstatisticalsurveyresultsby levels of 33 to 36% was as low as 0.78,with no sig-
theJSDT,evaluationofindependentfactorsaffecting nificant difference compared to the group with Ht
1-yearsurvivalrevealedthattheoptimalHtlevelwas levels between 30 and 33% because of the limited
30 to 35%. However, this evaluation was limited to number of patients.Therefore, the 2004 Guidelines
the short-term prognosis of 1-year survival and the recommendedtheHblevelof11to12g/dL(Htlevel
evaluated Ht range was divided into intervals as of33to36%)onlyforrelativelyyounger,activeindi-
broadas5%.Forthesereasons,theHtlevelwithan viduals with fewer arteriosclerotic lesions (5) (Level
intervalof5%isconsideredinappropriateforrecom- C*).
mendation. It was presumed that the difference in the target
In this context,using the statistical survey data by Hb level (Ht level) between the Japanese and
theJSDT,westratifiedHtlevelsobtainedattheend Europe or US guidelines could be explained by dif-
of 1995 (55855 patients, including non-rHuEPO ferencesintheethnicity,dayofbloodsampling,body
users) into 3% intervals as in Europe and the US to positionduringbloodsampling,andotherfactors.To
examinetheeffectofHtlevelson5-yearsurvival.The test this hypothesis, two types of additional studies
resultrevealedthattherelativerisk(RR)ofHtlevels belowwereconducted.
©2010TheAuthors
Journalcompilation©2010InternationalSocietyforApheresis TherApherDial,Vol.14,No.3,2010
248 YTsubakiharaetal.
TABLE2-2. Influenceofthehematocrit(Ht)level/patientcharacteristicsonthe1-yearand3-yearmortalityrates
1-yearmortalityrate 3-yearmortalityrate
Backgroundfactor RR 95%CI P-value RR 95%CI P-value
Group1(Ht(cid:4)36%) 0† 0† 0.9694 0.915 0.405–2.072 0.8321
Group2(33%(cid:3)Ht<36%) 0.605 0.320–1.146 0.1231 1.111 0.816–1.514 0.5036
Group3(30%(cid:3)Ht<33%) 0.447 0.290–0.689 0.0003 0.677 0.537–0.855 0.001
Group4(27%(cid:3)Ht<30%) 1
Group5(Ht<27%) 1.657 1.161–2.367 0.0054 1.604 1.275–2.019 <0.0001
Age:1-yearincrease 1.029 1.016–1.043 <0.0001 1.048 1.039–1.056 <0.0001
Gender:Female 0.85 0.620–1.167 0.3159 0.758 0.629–0.913 0.0036
Underlyingdisease
Diabeticnephropathy 0.958 0.671–1.368 0.815 1.354 1.114–1.647 0.0024
Complications
Heartfailure 1.224 0.883–1.696 0.2256 1.596 1.319–1.932 <0.0001
Occlusivearteriosclerosis 1.281 0.844–1.944 0.2456 1.639 1.302–2.063 <0.0001
Cerebrovasculardiseases 1.683 1.142–2.480 0.0085 1.522 1.211–1.913 0.0003
Digestivedisorders 1.190 0.870–1.628 0.2759 0.907 0.753–1.093 0.3051
Hepatobiliarysystemdisorders 1.438 0.978–2.117 0.0651 1.264 0.997–1.603 0.0528
Cancer 1.725 0.943–3.156 0.0768 2.716 1.910–3.862 <0.0001
Alb
<3.5g/dL 1
(cid:4)3.5g/dL 0.424 0.307–0.585 <0.0001 0.603 0.501–0.726 <0.0001
†NodeathsamongN=36.ThistableisquotedfromthestudydescribedbyHirasawaetal.(23).Alb,albumin;CI,confidenceinterval;RR,
relativerisk.
In the JSDT survey of the current status,most of greaterdecreaseinHtlevelsthaninhealthyindividu-
the Ht levels were obtained at the beginning of the als (24). In Europe and the US, many HD patients
week,while in Europe and the US,results of blood receive dialysis while sitting in a chair bed,whereas
sampled at midweek are used. Therefore, it is those in Japan receive dialysis in a supine position.
expectedthatthereisaninfluencefromadifference Thus,thebodypositionduringbloodsamplingisdif-
in the weight gain rate between Japan and Western ferent. In this context, in 99 HD patients with little
countries. In this context, a comparison between residual renal function who were receiving dialysis
peripheral blood data obtained on Monday and three times weekly at four institutions, peripheral
Wednesday from the same patient was conducted in bloodwastakenwhiletheywereinasittingposition
247 Japanese patients undergoing HD three times shortly after admission to the laboratory test room.
weekly(Monday,Wednesday,andFriday)atasingle Data on these peripheral blood samples were com-
institution. The result showed that the Ht level on paredtothoseobtainedaftertheyrestedinasupine
Monday corresponded to 99.1% of that onWednes- position for approximately 10min. The result
day(Table2-3)(5)(LevelC*). revealed that the Ht level of the blood samples in a
In addition, it is known that the patient’s body supinepositionwas94.3%ofthatinasittingposition
positionduringbloodsamplingaffectstheHtlevel.A (Table2-4)(5)(LevelC*).
study conducted in Japan has shown that in HD Asimplecalculationwiththetwofactorsdescribed
patients’ blood sampled in a supine position had a aboverevealedthatHtlevelsof33to36%inEurope
and the US correspond to those of 30.8 to 33.6% in
Japan.
TABLE2-3. Differencesbetweenthedaysofblood
However, the studies on the survival prognosis
collection(5).(Comparisonofthehematologicaldata
mentionedabovewereallretrospectiveandbasedon
betweenMondayandWednesdayofthesameweekin247
patientsundergoingdialysisonMonday,Wednesdayand Htlevelsduringacertainperiod.
Friday) In order to set target Hb levels, large-scale, pro-
spectiveRCTswithendpointssuchassurvivalprog-
Monday Wednesday Difference
nosisandQOLwillbeneededinthefuture.
BW(kg) 53.1(cid:2)0.7 52.6(cid:2)8.9 0.6
Although not an RCT, there is a report on the
Hblevel(g/dL) 10.4(cid:2)1.0 10.5(cid:2)1.3 0.15
Htlevel(%) 32.3(cid:2)3.5 32.6(cid:2)4.4 0.36 results of a prospective, open-label clinical study in
TP(g/dL) 6.7(cid:2)0.5 6.7(cid:2)0.5 0.05 which DA was administered for approximately
Values are reported as Mean(cid:2)SD. BW, body weight; Hb, oneyear to 513 HD patients in maintenance phase
hemoglobin;Ht,hematocrit;TP,totalprotein. receivingrHuEPO(25).Inthisstudy,atargetHblevel
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2009JDSTAnemiaGuidelines 249
TABLE2-4. ComparisonoftheHtlevelbetweenthe Inthe2004Guidelines,theHbtargetswerestrictly
sittingpositionandthesupinepositioninpatients set within narrow ranges; 10 to 11g/dL and 11 to
undergoingHD(5)
12g/dL for active younger patients. However, Hb
Results Sittingposition Supineposition levels of patients vary by various factors, and the
variationrangeofapproximately1g/dLisconsidered
Crlevel(mg/dL) 10.9(cid:2)2.8 10.9(cid:2)2.8
BUN(mg/dL) 74.4(cid:2)12.4 74.0(cid:2)12.2 acceptable in clinical practice.Although it is impor-
Hblevel(g/dL) 10.7(cid:2)1.0 10.1(cid:2)0.9(94.4%) tant to pay attention to the upper limit of Hb levels
Htlevel(%) 33.2(cid:2)3.0 31.3(cid:2)2.9(94.3%)
during the ESA use, excessive adherence to this
TP(g/dL) 6.7(cid:2)0.5 6.3(cid:2)0.5(94.0%)
upperlimitmaycauseHblevelstobemaintainedat
ExaminationinOsakaprefectureHospitalandthreeotherhos- a relatively lower level. This probably leads to the
pitals. Examination was conducted in 99 patients with little
result mentioned above that the number of patients
residual renal function who were undergoing HD three times a
week in four hospitals, and from whom informed consent was with Hb levels of less than 10g/dL have not yet
obtained.We collected blood via the venous route in the sitting decreased. As described above, the clinical study
positionimmediatelyafterarrival,andviathearterialrouteabout
resultsofDAandCERAhaveshownnosafetyissues
10min after they were placed in the supine position.The levels
werecompared.ValuesarereportedasMean(cid:2)SD.BUN,blood withthehightherapyrangeofHbfrom10to13g/dL.
ureanitrogen;Cr,reatinine;Hb,hemoglobin;Ht,hematocrit;TP, Therefore,ascriteriafordosereductionorinterrup-
totalprotein.
tion, in addition to target Hb levels, we decided to
recommend Hb levels are more than 12g/dL, and
more than 13g/dL for active younger patients with
higherthanthatrecommendedbythe2004Guideline mildvascularlesions.
wasused;specifically,thestudyHbtargetwassetat11 A large-scale, prospective, observational study of
to12g/dL(10to13g/dLastherapeuticwindow).The rHuEPOisbeingconductedpresentlyinHDpatients
meanHblevelafterthestartoftheDAtreatmentwas to investigate Hb targets from the viewpoint of sur-
maintained at approximately 11g/dL, but no safety vivalprognosis(22).Thisresultisnotable,butaRCT
issues were observed.In addition,we compared the in HD patients to investigate Hb targets is also
medical outcomes study 36-item short-form health neededinJapan.
survey(SF-36)ofQOLassessmentatthestartofDA
treatmentandwhentheHblevelincreasedto11g/dL
orhigher.Theresultrevealedthatallscoresshoweda 3. TargetHblevelforPDandNDpatients
tendencytowardanincreaseaftertheDAtreatment. The Europe and US guidelines for renal anemia
Particularly in patients in whom the Hb level (3,13) provide the same Hb targets for HD,PD,and
increasedby1g/dLorgreaterandreached11g/dLor NDpatients.However,thereisnoscientificevidence
higher,the score of vitality significantly increased as for handling these patient subgroups equally, since
comparedtothoseinwhomtheHblevelincreasedby Hb levels of PD and ND patients are more stable
lessthan1g/dLandremainedlowerthan11g/dL(26) than those of HD patients which change before and
(LevelB*).TheseresultsmaysuggestthattargetHb after HD. However, only a few studies have been
levels for HD patients which are higher than the conducted regarding target Hb levels for PD or ND
conventional reference value cause no safety issues patientsinJapan.EarlierclinicalstudiesofrHuEPO
andaremoreuseful. in Japanese ND patients have suggested that an
Based on these clinical study results, the package increase in Hb levels to approximately 12g/dL or
insert of DA states the target Hb level of approxi- higherwouldbeusefulinimprovingcardiacfunction
mately11g/dL,whichishigherthantheconventional (28)orprotectingrenalfunction(29).Anincreasein
target of approximately 10g/dL. This explains the Htlevelstoarangeof32%to39%byadoseincrease
currentdoublestructureofJapanesetargetHblevel of rHuEPO has been reported to significantly
for ESA therapy in the package inserts, which con- improveLVMIwithoutsafetyissues(28)(LevelB*).
sists of approximately 10g/dL for rHuEPO and In other research which prospectively investigated
approximately11g/dLforDA. effectsontherenalfunctioninNDpatientsrandom-
Inaprospective,open-labelclinicalstudyinwhich ized to rHuEPO group or untreated group, it has
145 HD patients in maintenance phase on rHuEPO beenreportedthatdeteriorationoftherenalfunction
received CERA for approximately oneyear,the Hb (as evaluated by doubling of Cr) was significantly
targetwassetat10to12g/dL.Theresultshowedthat prevented in the rHuEPO group (the Ht level
the mean Hb level after the CERA administration increasedfrom27%to32%)comparedtothatinthe
was maintained at approximately 11g/dL, and no untreated group (29) (Level A*). Furthermore, in
safetyissueswereobserved(27)(LevelB*). postmarketing clinical studies of rHuEPO in ND
©2010TheAuthors
Journalcompilation©2010InternationalSocietyforApheresis TherApherDial,Vol.14,No.3,2010