Guidelines for Renal Anemia in Chronic Kidney Disease

46 Pages·2017·2.03 MB·English

by  Hiroyasu Yamamoto

Yamamotoetal.RenalReplacementTherapy (2017) 3:36
DOI10.1186/s41100-017-0114-y
POSITION STATEMENT Open Access
2015 Japanese Society for Dialysis Therapy:
Guidelines for Renal Anemia in Chronic
Kidney Disease
Hiroyasu Yamamoto1*, Shinichi Nishi2, Tadashi Tomo3, Ikuto Masakane4, Kazuhide Saito5, Masaomi Nangaku6,
Motoshi Hattori7, Takahiro Suzuki8,9, Satoshi Morita10, Akira Ashida11, Yasuhiko Ito12, Takahiro Kuragano13,
Yasuhiro Komatsu14, Ken Sakai15, Yoshiharu Tsubakihara16,17, Kazuhiko Tsuruya18, Terumasa Hayashi19,
Hideki Hirakata20,21 and Hirokazu Honda22
Abstract
Renal anemia is a complication of chronic kidney disease. Guidelines for safe and effective treatment inpatients
withrenal anemia are needed. The JapaneseSociety for Dialysis Therapy (JSDT) published guidelines for the
treatment ofrenal anemia inchronic hemodialysis patients in2004 and inhemodialysis, peritoneal dialysis,
predialysis, and pediatric patients in2008. These two publications provide excellent guidance withrespect to
clinical practice issues, including thedefinitionand diagnosis of renal anemia, thecriteria for the initiation of
treatment, target hemoglobin levels,iron supplementation therapy, blood transfusion, and side effects. The
guidelines significantly improved thetreatment of renal anemia in Japan. However, since 2008, many studies have
assessed the treatment ofrenal anemia, and erythropoiesis-stimulating agents (ESAs) are now available. Therefore,
theExecutiveBoard of the JSDT decided that it was time to revise the guidelines to makethem more appropriate
to thesituationof chronic kidney disease patients inJapan.This is the third edition of theguidelinesfor renal
anemia published by the JSDT. The purpose is to improve the prognosis ofchronic kidney disease patients,
including after renal transplantation, through thetreatmentof renal anemia. The intended users ofthe guidelines
are allhealthcare professionals engaged inthe treatment ofchronic kidney disease. Regarding thetreatmentof
adult dialysis and predialysis patients, statements and commentary are provided in the context of answers to
clinical questions inChapter 2 (Target Hb leveland criteria for starting renalanemia treatment) and Chapter 4
(Evaluation of iron status and iron therapy). Furthermore, the essential information is provided alongside the critical
issues in Chapter 1(Diagnosis ofrenal anemia), Chapter 3 (Administrationof ESAs—administration route and dose),
Chapter 5(ESA hyporesponsiveness), Chapter 6(Side effects and concomitant symptoms ofESAs), and Chapter 7
(Red blood cell transfusion).In addition, thetreatmentof pediatric patientsand post-renal transplant patients is
discussed inChapter 8 and Chapter 9, respectively.
Keywords: Guideline, Anemia, Chronic kidney disease,Erythropoietin-stimulating agents, Iron
*Correspondence:[email protected]
ThisarticleistranslatedfromJapanesewithpermissionfromtheJapanese
SocietyforDialysisTherapy.Theoriginalarticlewaspublishedas“Guidelines
forRenalAnemiainChronicKidneyDisease2015”intheJournalofthe
JapaneseSocietyforDialysisTherapy,49:89–158,2015.Theoriginalworkisat
https://www.jstage.jst.go.jp/browse/jsdt/49/2/_contents/-char/ja/©Japanese
SocietyforDialysisTherapy.
1DepartmentofInternalMedicine,AtsugiCityHospital,1-16-36,Mizuhiki,
AtsugiCity,Kanagawa243-8588,Japan
Fulllistofauthorinformationisavailableattheendofthearticle
©JapaneseSocietyforDialysisTherapy.2017OpenAccessThisarticleisdistributedunderthetermsoftheCreative
CommonsAttribution4.0InternationalLicense(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricteduse,
distribution,andreproductioninanymedium,providedyougiveappropriatecredittotheoriginalauthor(s)andthesource,
providealinktotheCreativeCommonslicense,andindicateifchangesweremade.TheCreativeCommonsPublicDomain
Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,
unlessotherwisestated.
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page2of46
Scope they would be more appropriate to the situation of
Background CKD patients in Japan. The Working Group (WG) on
Renal anemia is a complication of chronic kidney the Revision of Guidelines for Renal Anemia in
disease (CKD). The features of CKD are as follows: the Chronic Kidney Disease (hereafter, the third WG),
frequency and severity of renal anemia increase with whose aim was to prepare the revised third edition of
the progress of renal insufficiency, and the progress of the guidelines, was established in November 2012.
anemia is accompanied by not only the deterioration in Anemia in post-renal transplantation patients was
quality of life but also organ damage, such as deterior- included in these guidelines for the first time in Japan.
ation of renal function or cardiac function due to The third WG started preparing guidelines for the
chronic ischemia. Previously, the treatment of renal treatment of renal anemia in all CKD patients,
anemia relied on blood transfusion because no other ef- including HD patients, PD patients, predialysis CKD
fective treatment was available. In the 1980s, however, patients, pediatric patients, and post-renal transplant-
the treatment of renal anemia drastically changed with ation patients.
the development of recombinant human erythropoietin
(rHuEPO). Since 1990, when it became possible to use
Cooperationwithrelatedorganizationsinthepreparation
rHuEPO in hemodialysis (HD) patients in Japan,
oftheguidelines
therapeutic intervention has been promoted for renal
The members of the third WG were selected not only
anemia. Before this time, there were no guidelines for
from the JSDT. Those with expertise in the treatment of
the management of renal anemia, and decisions regard-
predialysis CKD patients, pediatric patients, and post-renal
ing the timing, method, and target of therapeutic inter-
transplantation patients were invited from the Japanese
vention were made according to trial and error.
Society of Nephrology, the Japanese Society for Pediatric
Guidelines for the safe and effective treatment for the
Nephrology, and the Japanese Society for Clinical Renal
majority of patients with renal anemia were therefore
Transplantation, respectively. Those with expertise in
needed. In the late 1990s, various guidelines were
hematologyandmedicalstatisticswerealsoinvitedtojoin
prepared based on the clinical studies and statistical
thethirdWG.
surveys accumulated in Europe and the USA. Since
then, these guidelines have been revised or new guide-
Purposeoftheguidelines
lines have been published.
Thepurposeoftheguidelinesistoimprovetheprognosis
of CKD patients in Japan through the treatment of renal
Preparationofguidelines
anemia. The first issue discussed by the third WG was
In Japan, the Japanese Society of Dialysis Therapy
what information to include in the guidelines. This infor-
(JSDT) published the Guidelines for Renal Anemia in
mationshouldbereliableandusefulinclinicalpractice.It
Chronic Hemodialysis Patients (Chairman, Fumitake
wasalsoimportanttoclarifyhowtodeterminethegrades
Gejyo) for the first time in 2004. In 2008, the JSDT
of recommendation of the medical practices that seem to
published the Guidelines for Renal Anemia in Chronic
bemostappropriate.Inaddition,themembersagreedthat
Kidney Disease (Chairman, Yoshiharu Tsubakihara),
the interpretation and evaluation of many lines of evi-
the target of which was expanded to include peritoneal
dence accumulatedto date are veryimportantfor prepar-
dialysis (PD) patients, predialysis CKD patients, and
ing treatment guidelines suitable for CKD patients in
pediatric patients. These two guidelines provided ex-
Japan. Based on the above, the principles and procedures
cellent information related to the issues of clinical
for the revision of the guidelines were established as de-
practice, including the definition and diagnosis of renal
scribedbelow.
anemia, the criteria for the initiation of treatment, tar-
get hemoglobin (Hb) level, iron supplementation ther-
apy, blood transfusion, and side effects. The guidelines Principlesforthepreparationoftheguidelines
significantly improved the treatment of renal anemia
in Japan. However, since 2008, there have been many Targets The guidelines targeted all CKD patients, in-
studies on the treatment of renal anemia, rHuEPO has cluding HD patients, PD patients, predialysis CKD pa-
been markedly improved over the more than 30 years tients, pediatric patients, and post-renal transplantation
since its development, and erythropoiesis-stimulating patients. Post-renal transplantation patients were added
agents (ESAs), including long-acting agents, have be- as targets in the guidelines. The intended users of the
come available. Therefore, the need for new guidelines guidelines are all healthcare professionals engaged in the
was discussed, and, in October 2012, the Executive treatment of CKD. Please note that the guidelines are
Board and the Academic Committee of the JSDT de- designed for use in clinical practice and not as materials
cided that it was time to revise the guidelines so that formedicallawsuits.
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page3of46
Style a) The most critical issues in the treatment of of HD patients in Japan is better than that in Europe
renal anemiawereraised asclinicalquestions(CQs) and the USA. Although racial characteristics seem to
and werediscussedwithrespecttoeach typeof contribute to this difference, it is also pointed out
patient. that this difference results from the differences in the
b) Basicinformation wasprovidedtocomplementthe dialysis therapy provided in Japan and abroad, includ-
answerstoCQs sothattheguidelines couldbemore ing the purity of dialysate, the dialyzers used, and the
usefulandeasytounderstand. arteriovenous fistula utilization rate. Such differences
in medical conditions should be fully taken into
Literature search Research papers in the literature re- consideration when interpreting various lines of evi-
lated to CQs and basic information written in English dence collected worldwide. Recently, there have been
or Japanese and published in PubMed or Igaku Chuo differences between evidence and clinical outcomes in
Zasshi (ICHUSHI) during the period from 2003 to Japan and other countries. The reasons for such
June 2014 were searched. Important research papers differences were examined objectively after being dis-
published before or after this period were manually cussed in the plenary meeting. Furthermore, although
searched and added to the target. The keywords for the JSDT’s statistical surveys are classified as observa-
the literature search included anemia, kidney, renal, tional studies, the data collected by those surveys
iron, overload, deficiency, and transplantation. Reports were regarded as direct evidence because they
on animal experiments and genetic research were ex- provided valuable information about a large number
cluded from analysis. of HD patients in Japan. Although all of the treat-
ments mentioned in the revised guidelines are as-
Determination of statements and grades of recom- sumed to be covered by health insurance in Japan,
mendation Statements related to CQs and the grades of those treatments were not evaluated in terms of
recommendation of the statements were discussed and health economics.
determined in the plenary meeting of the WG. Care was
taken to ensure that no bias was introduced while deter-
miningthe target of analysis while collectively evaluating CriticalissuesinclinicalpracticeandCQs
the relevant literature. If no consensus was reached, the Various issues arise, in daily clinical practice, with
CQs and grades of recommendation were adopted ac- respect to treatment for renal anemia in Japan.
cording to the agreement of more than two thirds of the However, if all such issues were considered critical in
members. When no CQs were raised but basic points the guidelines, it would be difficult to distinguish
alone were provided, the basic points were used not as which are the core principles for the treatment of
statements but considered to represent the opinion of renal anemia. Therefore, only the issues related to the
theWGwith respecttothe issue. following four items were considered as “critical” in
clinical practice:
External review An External Review Committee was
established independent of the third WG and was tasked 1) Atwhich Hblevelshouldthe treatment ofrenal
toreview thedraft guidelines. anemia bestarted?
2) Whatisthe Hblevelthatshouldbemaintained
Literatureevaluation duringthe treatment ofrenalanemia?
The following were some of the factors considered in 3) Isitrecommendedtoadministeriron
the evaluation of reports in the literature selected as supplementationpriortoESAtherapy?
the target of analysis. It is usually expected that the 4) What are the criteria for the initiation of iron
contents of several guidelines are almost the same supplementation therapy? Should there be any
when those guidelines are prepared based on the upper limits?
same literature. However, when the context, ethnicity
of subjects, and medical practices described in the Specific CQs were raised focusing on these critical
literature vary, it is also important to determine issues. Regarding the treatment of adult HD and PD
whether the information is applicable to patients who patients and predialysis CKD patients, statements and
are the targets of the guidelines being prepared. The commentary are provided in answers to the CQs in
differences in the background of the literature and Chapter 2 (Target Hb level and criteria for starting
the results were examined in the plenary meeting so renal anemia treatment) and Chapter 4 (Evaluation of
that no bias was introduced into the evaluation of the iron status and iron therapy). Furthermore, the basic
literature. Part of the discussion at the plenary meet- pointsthatareessentialtothesafeandeffectivetreatment
ing was as follows. It is known that the life prognosis of renal anemia are provided complementary to the
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page4of46
critical issues in Chapter 1 (Diagnosis of renal Processofpreparationofguidelines
anemia), Chapter 3 (Administration of ESAs—admi- In accordance with the principles described above for
nistration route and dose), Chapter 5 (ESA the preparation of the guidelines, the third WG held
hyporesponsiveness), Chapter 6 (Side effects and con- 10 meetings, including ad hoc meetings, and drafted
comitant symptoms of ESAs), and Chapter 7 (Red the revised version of the guidelines. We sincerely
blood cell transfusion). In addition, the treatment of thank all committee members for their effort in
pediatric patients and post-renal transplantation pa- collecting and comprehensively evaluating numerous
tients is discussed in Chapter 8 (Renal anemia in research studies, exchanging opinions in earnest
pediatric patients) and Chapter 9 (Post-transplant discussions, and drafting the guidelines despite their
anemia in renal transplant recipients), considering the busy schedules.
characteristics of the target patients. The style of de-
scription in these two chapters is similar to that in Externalreview
the chapters on the treatment of adult patients. To increase the validity and transparency of the
guidelines, an External Review Committee was
Indicationanddeterminationofstatementsandgradesof established independent of the third WG and was
recommendation requested to review the draft of the guidelines. The
The answers to CQs were provided in the form of state- External Review Committee consisted of 22 members in-
ments with grades of recommendation. The grades of cluding Noritomo Itami (Chairman) and Takayuki
recommendationwereindicatedbythecombinationofthe Hamano (Vice Chairman), who were requested by the
strength of recommendation and the strength of evidence JSDTtofillthesepositions.
withreferencetoMinds2014.Asdescribedintheprinciples
for the preparation of the guidelines, decisions were made ReviewbytheExternalReviewCommittee
by voting when no consensus was reached. Most of the The first meeting of the External Review Committee
statements were adopted unanimously. Only part of the was held on January 15, 2014, and the committee
statement regarding CQ3, “What are the criteria for start- spent 1 year reviewing the guidelines drafted by the
ing and stopping iron therapy?” was adopted by the agree- third WG. The main points raised by the review were
ment of more than two thirds of all members. Because as follows:
there was still room for discussion about this issue, an as-
terisk(*)wasattachedtothisstatement. 1) Theappropriateness oftheestablishedCQsand the
principlesofthe preparationofthe guidelines
Strengthofrecommendation 2) Theappropriateness ofthenumberofresearch
reports selected asthetargetofanalysis
1: Recommend 3) Theappropriateness oftheevaluationand
2: Suggest interpretation oftheliterature
4) Theappropriateness ofthestatementsand
*If a statement cannot be expressly recommended, it is commentary
indicatedas“not graded.” 5) Theappropriateness ofthegradesof
Strengthofevidence(examples) recommendation
A (Strong): High confidence in the estimate (e.g.,
meta-analyses) The External Review Committee provided feedback
B (Medium): Moderate confidence in the estimate fourtimestothethirdWG,whichexaminedthefeedback
(e.g., randomizedcontrolled trials) and modified the drafted guidelines. Although it was the
C(Weak):Limited confidence inthe estimate (e.g., ob- first time that such a review process was adopted by the
servational studies) JSDT,theobjectivefeedbackprovidedbytheExternalRe-
D(Veryweak):Littleconfidenceintheestimate(others) view Committee was helpful for the preparation of the
The grades of recommendation in the revised version guidelines.WesincerelythankallmembersoftheExternal
of the guidelines were determined by strictly following ReviewCommittee.
the procedure described above. However, because the
procedure to determine the grade of recommendation FinalreviewbytheExecutiveBoardandAcademic
was not exactly the same as that used in the 2008 ver- CommitteeoftheJSDT
sion of the guidelines, there may be differences between The Executive Board and the Academic Committee of
thegradesofrecommendationofthestatementsindicated the JSDTconstituted the supervisory committee for the
in the 2008 version of the guidelines and the revised preparation of the guidelines and reviewed the drafted
version of the guidelines. guidelines prepared by the process described above.
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page5of46
Afterthedraftguidelineswereapprovedbythiscommit- currentstateofrenalanemiainJapan,althoughitwasnot
tee, they were published on the website of the JSDT. easy to deal with all pathological conditions in CKD
Then, a public hearing was held and the draft guidelines patients. We hope that the guidelines are helpful to
were reviewed and modified based on the opinions healthcare professionals engaged in the treatment of
expressed at the public hearing to establish the final ver- patientswithrenalanemiawiththeaimofimprovingtheir
sionoftheguidelines. prognoses.
December 2015
Promotionoftheuseoftheguidelinesinclinicalpractice HiroyasuYamamoto,Chairman
The following efforts aimed at improving the conveni- Working Group on Revision of Guidelines for Renal
ence for users and promoting the use of the Anemia inChronicKidneyDisease
guidelines:
Guideline Preparation Committee
– Theguidelines werepublishedonthewebsite ofthe JapaneseSociety forDialysisTherapy
JSDT. Working Group on Revision of Guidelines for Renal
– Specificnumericalvalueswereprovided (e.g.,target Anemia inChronicKidneyDisease
Hblevel). Chairman: HiroyasuYamamoto, DepartmentofInternal
– Allmedical treatmentsmentionedinthe guidelines Medicine,AtsugiCityHospital.
arecoveredbyhealthinsurance. Vice Chairman: Shinichi Nishi, Division of Nephrology
and Kidney Center, Kobe University Graduate School of
Futurerevisionoftheguidelines Medicine.
The first and second editions of the guidelines for the Member and Chairman of Academic Committee:
treatment of renal anemia, were published by the Tadashi Tomo, Blood Purification Center, Oita Univer-
JSDT in 2004 and 2008, respectively, and in 2015, the sityHospital.
third edition was published. It will be important to Member and Chairman of Guideline Preparation
review the treatment guidelines along with the Subcommittee: Ikuto Masakane, Department of Nephrol-
development of novel drugs and the accumulation of ogy,YabukiHospital.
new evidence. Member (Japanese Society for Clinical Renal Trans-
plantation): Kazuhide Saito, Department of Urology,
Editorialindependence Niigata University Graduate School of Medical and
The total cost of preparing the guidelines was covered Dental Sciences.
by the JSDT. No other organizations, institutions, or Member (Japanese Society of Nephrology): Masaomi
companiesprovidedfinancialsupport. Nangaku, Division of Nephrology and Endocrinology,
TheUniversityofTokyo.
Conflictofinterestandsecuringofuniversality Member (Japanese Society for Pediatric Nephrology):
Motoshi Hattori, Department of Pediatric Nephrology,
1) AllmembersofthethirdWGandtheExternalReview Tokyo Women’sMedicalUniversity.
Committee submitted a self-report on conflicts of Member (invited): Takahiro Suzuki, Division of
interest to the Conflict of Interest Committee of Hematology, Jichi Medical University (Present Address:
the JSDT. KitasatoUniversitySchoolofMedicine).
2) Toensuretheabsenceofbiasinthecontentofthe Member (invited): Satoshi Morita, Department of Bio-
guidelines,the membersofthe thirdWGwere medical Statistics and Bioinformatics, Kyoto University
invitedmembersnotonlyoftheJSDTbutalso of GraduateSchool ofMedicine.
theJapanese Society ofNephrology,the Japanese Member: Akira Ashida, Department of Pediatrics,
SocietyforPediatricNephrology,and theJapanese Osaka Medical College.
SocietyforClinicalRenalTransplantation. Member: Yasuhiko Ito, Department of Renal Replace-
Furthermore,those with expertise inhematology ment Therapy, Nagoya University Graduate School of
and medical statisticswereinvitedinordertoensure Medicine.
theuniversalityoftheguidelines. Member: Takahiro Kuragano, Division of Nephrology
andDialysis,DepartmentofInternalMedicine,HyogoCol-
As described above, the Guidelines for Renal legeofMedicine.
Anemia in Chronic Kidney Disease were revised using Member: Yasuhiro Komatsu, Division of Nephrology,
a new procedure for preparing evidence-based and re- DepartmentofMedicine,St.Luke’sInternationalHospital.
liable treatment guidelines. The utmost effort was made Member: Ken Sakai, Department of Nephrology, Toho
to make the guidelines as suitable as possible for the UniversityFacultyofMedicine.
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page6of46
Member: Yoshiharu Tsubakihara, Department of Cardiovascular Risk Reduction by Early Anemia
Comprehensive Kidney Disease Research, Osaka Treatment with Epoetin Beta (CREATE) trials were
University Graduate School of Medicine (Present published 6 months later. Since then, there has been
Address: Master Course of Management in Health a growing emphasis on transparency, neutrality, and
Care Sciences, Graduate School of Health Care validity in the preparation of guidelines. If the state-
Sciences, Jikei Institute). ments are prepared by conducting a literature search
Member: Kazuhiko Tsuruya, Department of Integrated aimed at finding answers to clinical questions (CQs)
Therapy for Chronic Kidney Disease, Kyushu University and by evaluating evidence, almost identical contents
GraduateSchool ofMedical Sciences. of the statements will be obtained. If there are differ-
Member: Terumasa Hayashi, Department of Kidney ences between guidelines drafted by the Guideline
DiseaseandHypertension,OsakaGeneralMedicalCenter. Preparation Committee and the opinions of the
Member: Hideki Hirakata, Division of Nephrology and External Review Committee under the same CQs, the
Dialysis Center, Japanese Red Cross Fukuoka Hospital examination of such differences will be helpful in
(PresentAddress:FukuokaRenalClinic). enhancing the objectivity of the guidelines. This is
Member: Hirokazu Honda, Division of Nephrology, why the External Review Committee was established.
Departmentof Medicine, Showa University Koto Toyosu
Hospital. Committeemembers
(Japanesesyllabaryorder;honorifics omitted) Among the nominated young researchers with an
interest in renal anemia, Noritomo Itami, who was
Records of committee meetings and interim commissioned by the Japanese Society for Dialysis
reporting Therapy (JSDT) to serve as Chairman, selected 21
First meeting:November30,2012 members who were specialists in internal medicine,
Secondmeeting: April18,2013 pediatrics, and urology. He appointed Takayuki
Thirdmeeting:June14,2013 Hamano to serve as Vice Chairman. The members
Fourth meeting: November 24,2013 were approved by the Executive Board.
Fifthmeeting:January17,2014
Sixth meeting: April 18,2014 Methods
Seventhmeeting: May16,2014 Because the Guideline Preparation Committee had
Adhocmeeting: June13,2014 achieved a consensus on the draft guidelines at the An-
Eighth meeting: July3,2014 nual Meeting of the JSDT in 2013, the External Review
Ninth meeting: August15,2015 Committee followed the example of the Kidney Disease:
Committee-sponsored symposium at the 58th Annual Improving Global Outcomes (KDIGO) anemia guidelines
MeetingoftheJSDT:June21,2013(Fukuoka) publishedin2012,onwhichcommentswereexpressedby
Committee-sponsored consensus conference at the severalcountries.
59thAnnual MeetingoftheJSDT:June15,2014(Kobe) With respect to the four CQs raised by the Guide-
BriefreportonGuidelinesforRenalAnemiaatthe60th line Preparation Committee, the External Review
AnnualMeetingoftheJSDT:June26,2015(Yokohama) Committee searched and analyzed research papers
DraftguidelinesapprovedbytheAcademic Committee that were written in English or Japanese and pub-
oftheJSDT:May1,2015 lished in PubMed or Igaku Chuo Zasshi from 2003 to
Draft guidelines published on the website of the JSDT: June 2014. The committee members were divided into
July27,2015 five teams assigned to the themes of pediatric
Publichearingonguidelines: August 15,2015(Tokyo) patients, renal transplantation, blood transfusion,
Guidelines approved by the Executive Board of the target Hb level, and iron therapy, for conducting the
JSDT:December 4,2015 literature search. They examined whether the statements
correctly answered the CQs and assessed the strength of
Summary of reviews by the External Review evidence for the statements by reviewing the relevant
Committee research papers. The strength of evidence was graded as
Background follows, in a similar way as in the draft guidelines: A
The target hemoglobin (Hb) level suggested in the (strong; high confidence in the estimate), B (moderate;
2006 revised edition of the Kidney Disease Outcomes moderate confidence in the estimate), C (weak; limited
Quality Initiatives (KDOQI) anemia guidelines needed confidenceintheestimate),D(veryweak;littleconfidence
to be modified immediately after publication, when in the estimate), and not graded (a statement cannot be
the results of the Correction of Hemoglobin and expresslyrecommended).Therewerealimitednumberof
Outcomes in Renal Insufficiency (CHOIR) and research papers from Japan that presented strong
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page7of46
evidence. However, the External Review Committee Fourth meeting: August10,2014
agreed with and followed the policy adopted by the Fifthmeeting:November1,2014
Guideline Preparation Committee that the data col- Sixth meeting: January 25,2015
lected from JSDT statistical surveys represent strong
evidence, although those surveys were classified as External Review Committee
observational studies. Moreover, at plenary meetings, Chairman: Noritomo Itami, Kidney Center, Nikko Me-
the External Review Committee examined and con- morial Hospital (Present Address: Department of Neph-
firmed whether the research papers were properly rology, ItamiKidneyClinic).
cited in the commentaries and whether the observa- Vice Chairman: Takayuki Hamano, Department of
tions in such studies were accurately reflected in the ComprehensiveKidneyDiseaseResearch,OsakaUniversity
commentaries. The results of the plenary meetings GraduateSchoolofMedicine.
were reported to the Guideline Preparation Commit- Members:
tee in the form of “Agreed” or “Modifications Takaya Abe, Department of Urology, Iwate Medical
required” (with the reasons explained). In total, the University.
External Review Committee re-examined the modifi- Hiroaki Ueda, Department of Pediatrics, Osaka City
cations of the draft guidelines shown by the Guideline GeneralHospital.
Preparation Committee and provided feedback four Akira Okada, Division of Nephrology and Endocrin-
times. The final draft of the guidelines was completed ology,The University ofTokyo.
after six meetings of the External Review Committee. Tadashi Okada, Department of Nephrology, Hakuyu
ChiyodaClinic.
Conclusions Daisuke Katagiri, Division of Nephrology and Endo-
In contrast to the evidence review team for the KDIGO crinology/Division of Hemodialysis and Apheresis, The
guidelines, the External Review Committee did not con- UniversityofTokyo(PresentAddress:studyingabroad).
duct a thorough systematic review. However, the com- Takayuki Katsuno, Department of Nephrology, Nagoya
mittee members of each team earnestly searched the UniversityGraduateSchool ofMedicine.
literature and exchanged opinions at plenary meetings. Sawako Kato, Department of Nephrology, Nagoya
Dr. Hamano is greatly appreciated for his leadership as University Graduate School of Medicine.
the chairman of the meetings. The strength of evidence Noritaka Kawada, Department of Nephrology, Osaka
of52statementswasevaluatedasfollows:0=A(strong), Minato Central Hospital (Present Address: Osaka Bay
3=B(medium),9=C(weak),8=D(veryweak),and32= CentralHospital).
not graded. There was no statement with the strength of Eiichiro Kanda, Department of Nephrology, Tokyo
evidence grade A, and grade B accounted for 5.7% of all KyosaiHospital.
statements. As the Chairman of the External Review Kan Kikuchi, Department of Nephrology, Shimoochiai
Committee, Dr. Itami is responsible for all of the results Clinic.
andinadequaciesoftheassessmentbythecommittee. Toshihiro Sawai, Department of Pediatrics, Shiga
In the KDIGO guidelines, the strength of evidence was University of Medical Science.
graded as A for 5.4% of all statements. It seems that the TakaichiSuehiro,DepartmentofNephrology,Harasanshin
amount of strong evidence for the treatment of renal Hospital (Present Address: Social Insurance Nakabaru
anemiaislimitedworldwide.Theamountofdatacollected Hospital).
from JSDT statistical surveys and the number of reports Yuki Tsuruta, Department of Nephrology and Blood
onJapanesepatientsincreasedintherevisededitionofthe Purification, Tokyo Metropolitan Geriatric Hospital
guidelines comparedwith those in the original version.In (at present: Department ofNephrology,TsurutaItabashi
the future, it will still be necessary to accumulate more Clinic).
evidenceonthetreatmentofrenalanemiainJapan. Hyogo Nakakura, Department of Pediatrics, Osaka
Finally, we hope that these guidelines will contribute Medical College (Present Address: Department of
to improvements in the prognosis of all patients with HemodialysisandApheresis,ArisawaGeneralHospital).
chronic kidneydisease. Toshihide Naganuma, Department of Urology, Osaka
NoritomoItami,ChairmanofExternalReviewCommittee City University Medical School.
Masahiko Nagahama, Division of Nephrology, St.
Records of meetings of the External Review Luke’sInternationalHospital.
Committee Hiroki Nishiwaki, Division of Nephrology, Department
First meeting:January25,2014 ofMedicine,ShowaUniversityFujigaokaHospital.
Secondmeeting: April12,2014 Kiichiro Fujisaki, Kidney Care Unit, Kyushu University
Thirdmeeting:May 24,2014 Hospital.
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page8of46
Yukio Maruyama, Division of Kidney and Hyperten- TakayukiHamano:Receivedanhonorariumforgivinga
sion, the Jikei University Kashiwa Hospital (Present lecture and research grants from, and belongs to a project
Address: Division of Kidney and Hypertension, the Jikei endowedby,BayerYakuhin,Ltd.(acompanythatdevelops,
UniversityHospital). imports, produces, and sells pharmaceuticals, medical
YukihiroWada,DepartmentofNephrology,Department devices, and veterinary products), Kyowa Hakko Kirin Co.,
ofMedicine,ShowaUniversityHospital. Ltd.(acompanythatproducesandsellsprescriptiondrugs),
(Japanesesyllabaryorder;honorifics omitted) ChugaiPharmaceuticalCo.,Ltd.(acompanythatproduces,
sells, and imports/exports prescription drugs), Glaxo-
Information about conflicts of interest SmithKline K.K. (a company that conducts research and
InorderfortheWGmemberstomaintainaneutralandfair development and imports, produces, and sells prescription
perspectiveinthepreparationofclinicalpracticeguidelines, drugs and general pharmaceuticals), Furuno Electric Co.,
theJSDTmakeseveryefforttoavoidanyconflictofinterest Ltd. (a company that produces, sells, and imports/exports
that exists or that could arise in the future. All WG mem- medical instruments), Asahi Kasei Pharma Corporation (a
bers are required to submit a signed document agreeing to company that produces and sells prescription drugs, diag-
disclose information about conflicts of interest that exist or nostic enzymes, diagnostic agents, and liquid food), Otsuka
could arise, and this form needs to be updated every year Pharmaceutical Co., Ltd. (a company that produces, sells,
and modified whenever the situation changes. The submit- andimports/exportspharmaceuticals,clinicaltestingequip-
ted information is listed in the “Disclosure of conflicts of ment, medical devices, and food products), and Baxter (a
interest in the External Review Committee” below, and the companythatimports,produces,andsellsdialysisproducts,
records of the facts that support such information are kept plasmaproteinproducts,anddrugadministrationsystems).
bytheSecretariatoftheJSDT. (The members not listed above have no conflict of
Reference interesttoreport.)
*)JSDT: JSDT Guideline on Conflict of Interest (COI)
in Medical Research. 2011: http://www.jsdt.or.jp/jsdt/
1370.html Chapter 1. Diagnosis of renal anemia
Disclosure of conflicts of interest in the External
ReviewCommittee 1)Renalanemiaoccurswhentheamountoferythropoietin(EPO)
Noritomo Itami: Received an honorarium for giving a producedinthekidneysisinsufficienttocompensateforthedecrease
inhemoglobin(Hb)level.Thediagnosisofrenalanemiaismade
lecture from Otsuka Pharmaceutical Co., Ltd. (a com-
whenchronickidneydisease(CKD)aloneistheprimarycauseof
pany that produces, sells, and imports/exports pharma- anemiaandtherearenootherdiseasespresentthatcauseanemia.
ceuticals, clinical testing equipment, medical devices, ThemeasurementofserumEPOlevelisusefulforthediagnosisof
renalanemiainpredialysisCKDpatients.
andfood products).
Sawako Kato: Received research grants from Sanwa 2)ThecausesofanemiaotherthandecreasedEPOproduction
capacityincludethesuppressionoferythropoiesis,shortenedred
Kagaku Kenkyusho Co., Ltd. (a company that conducts
bloodcell(RBC)survivaltime,disordersofironmetabolism,residual
research and development, and produces and sells medical bloodinthedialysiscircuit,bleeding,andmalnutritiondueto
products and diagnostic agents), Kyowa Hakko Kirin Co., variousfactors.Thesefactors,however,arenotyetfullyunderstood.
Ltd.(acompanythatproducesandsellsprescriptiondrugs), 3)Hblevelshouldbeusedasareferenceforthediagnosisofanemia.
ThefollowingareappropriatereferenceHblevelsforthediagnosisof
OtsukaPharmaceuticalCo.,Ltd.(acompanythatproduces,
anemiaintheJapanesepopulationaccordingtoageandgender.
sells, and imports/exports pharmaceuticals, clinical testing Thesereferencevaluesarealsousedforthediagnosisofrenalanemia.
equipment,medicaldevices,andfoodproducts),andSumi- However,decisionsregardingthetreatmentofrenalanemiashouldbe
madebasedontherecommendationsorsuggestionsineachchapter.
tomo Dainippon Pharma Co., Ltd. (a company that pro-
ducesandsellsprescriptiondrugsanddiagnosticagents).
Kan Kikuchi: Receivedanhonorariumforgivingalec-
ture from Chugai Pharmaceutical Co., Ltd. (a company
that produces, sells, and imports/exports prescription
drugs)andDaiichiSankyoCo., Ltd.(acompanythatcon- 4)Inthediagnosisofrenalanemia,itisnecessarytodifferentiate
ducts research and development, and produces and sells renalanemiafromvarioushematologicaldiseasesthatcancause
anemia.Thefollowingareusefulcriteriafordifferentiatingblood
prescriptiondrugs).
diseases:
ToshihiroSawai:ReceivedtravelexpensesfromAlexion (1)Presenceorabsenceofabnormalitiesofleukocytesand
Pharma(acompanythatproduces,sells,andimportsphar- platelets(abnormalitiesinfractionation,morphology,andcount,
andthepresenceofmyeloblasts)
maceuticalsinJapanandabroad).
(2)Cytometriccategoriesbymeancorpuscularvolume(MCV)
Hiroki Nishiwaki: Received research grants from (microcytic,normocytic,andmacrocytic)
Kyowa Hakko Kirin Co., Ltd. (a company that produces (3)Increaseanddecreaseinreticulocytecount
(4)SerumEPOlevel
andsellsprescription drugs).
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page9of46
Rationale there may be other factors contributing to the devel-
opment of anemia in these cases. Some pathological
1)RenalanemiaoccurswhentheamountofEPOproducedinthe
conditions associated with CKD may be related to the
kidneysisinsufficienttocompensateforthedecreaseinHblevel.
ThediagnosisofrenalanemiaismadewhenCKDaloneisthe development of anemia, but their details are not yet
primarycauseofanemiaandtherearenootherdiseasespresent fully understood.
thatcancauseanemia.ThemeasurementofserumEPOlevelis
usefulforthediagnosisofrenalanemiainpredialysisCKDpatients.
Rationale
2)ThecausesofanemiaotherthandecreasedEPOproduction
capacitymaybethesuppressionoferythropoiesis,shortenedRBC
EPO-producing cells in the kidneys are fibroblast-like
survivaltime,disordersofironmetabolism,residualbloodinthe
cells in the peritubular interstitium of the proximal tubule dialysiscircuit,bleeding,andmalnutritionduetovariousfactors.
that produce EPO in response to a low partial pressure of Thesefactors,however,arenotyetfullyunderstood.
oxygen [1]. The partial pressure of oxygen surrounding
EPO-producingcellsisdeterminedbythebalancebetween
the supply of oxygen from arteries and the oxygen con- Ithasbeenreportedthatvariousfactorscontributetothe
sumptionoftissues.Thesupplyofoxygenisdeterminedby development of anemia, in addition to the relative decrease
renal blood flow and Hb level, whereas oxygen consump- inEPOproductioncapacityinthekidneys,inCKDpatients.
tionisdeterminedmainlybytheNare-absorptioncapacity (1)Suppressionoferythropoiesis
oftheproximaltubule[2]. It has been pointed out that the levels of various uremic
In CKD patients, the supply of oxygen to tissues is sup- toxins are elevated in the blood of CKD patients and may
pressed dueto decreased renal blood flow and, atthe same suppresstheformationoferythroblasts[7,8].However,the
time, local oxygen consumption decreases due to tubular uremic toxins that suppress the formation of erythroblasts
defects.Asaresult,itisassumedthatthepartialpressureof havenotbeenidentified,andtheirroleshavenotbeensuffi-
oxygen surrounding the proximal tubule often remains ciently clarified. Because the levels of inflammatory cyto-
withinthe normal range. In such cases,stimulation of EPO kinessuchasinterferonandtumornecrosisfactor-α(TNF-
productioncapacityto compensateforthelowpartialpres- α), which decrease the sensitivity of erythroblasts to EPO,
sure of oxygen is inappropriate. Therefore, when Hb level increase in some CKD patients [9, 10], abnormal cytokine
decreases for some reason, anemia persists because EPO levelsmayberelatedtoanemiainCKDpatients.
production is not sufficientlyinduced. Renal anemia canbe (2)ShortenedRBCsurvivaltime
explained as anemia that becomes apparent when the It has been reported that RBC survival time is short-
amount of EPO produced in the kidneys is insufficient to ened by 30–60% in CKD patients, although the rate of
compensateforthedecreaseinHblevel(relativedeficiency). shortening varies between reports. In a recent analysis
Therehavebeenanumberofreportsontherelationship usingradioisotopes,theRBCsurvivaltimeinhemodialysis
between Hb level and serum EPO levels. In these reports, (HD) patients was shortened by ~20% [11]. Osmotic fra-
mostpatientswithhematopoieticdisorderssuchasaplastic gility, RBC deformability, and RBC metabolism disorders
anemia and myelodysplastic syndromes (MDS) with Hb due to red cell membrane dysfunction are considered to
levels of <10 g/dL showed serum EPO levels of >50 mIU/ causetheshorteningofRBCsurvivaltime,butthemecha-
mL [by radioimmunoassay or the chemiluminescent en- nismsarenotyetfullyunderstood.
zymeimmunoassay(CLEIA)][3,4],whereasmostCKDpa- (3)Disordersofironmetabolism
tients showed serum EPO levels of <50 mIU/mL [by Serum hepcidin levels increase in CKD patients be-
enzyme-linked immunosorbent assay (ELISA) or the cause of the enhanced synthesis of hepcidin in the liver,
CLEIA method] [5, 6] (different measurement methods mediated by an inflammatory cytokine, interleukin-6,
may affect the measured value of EPO, but such an effect and due to the attenuated clearance of hepcidin in the
has not been examined). Moreover, it has been reported kidneys [12]. Hepcidin is a peptide hormone that sup-
that the increase in EPO level in response to the decrease pressesthereleaseofironfromcellsintotheblood.Thein-
in Hb level is suppressed at more advanced stages of CKD crease in hepcidin levels leads to decreased serum iron
[6]. As a result, upregulation of EPO in response to the levelsandincreasedintracellularironlevels(ferritinlevels),
samedegreeofanemiaisinsufficientinCKDpatientscom- causing defective iron utilization in the bone marrow and
paredtothosewithnormalrenalfunction. anemia (functional iron deficiency). It has been found that
SerumEPOlevelismaintainedwithinthereferencerange theincreaseinhepcidinlevelisamajorcauseofanemiaas-
regardless of Hb level in most CKD patients [5, 6]. This sociated with chronic inflammation and that a similar
findingindicatesthatEPOproductionisnot sufficientlyin- pathologicalconditionisalsoobservedinCKDpatients.
duced in CKD patients to reverse anemia. This suggests (4)Residualblood inthedialysiscircuitandbleeding
that, in addition to decreased EPO production capacity, (5)Malnutrition
Yamamotoetal.RenalReplacementTherapy (2017) 3:36 Page10of46
The risk of malnutrition is high in CKD patients, al- Table1HemoglobinlevelsintheJapanesepopulationbyage
though the degree of malnutrition varies from patient to andgender
patient.Thelackofnutrientsrequiredforerythropoiesis, Miwa’sHematology ChronologicalScientific
such as vitamins and folic acid, can also accelerate the 3rdedition[280] [281]
progressionofanemia. 19–60years(g/dL) 60–69years 70–79years
(g/dL) (g/dL)
It is assumed that the above factors associated with CKD
contributetothedecreaseinHblevelandthattheinsufficient Male(mean±SD) 15.3±0.9 13.8±0.9 13.5±1.2
EPO production capacity in the kidneys leads to the persist- Female(mean±SD) 13.3±0.9 12.5±1.0 12.2±0.9
ence of anemia. However, which factors and to what extent Male(mean−2SD) 13.5 12.0 11.1
theyarereallyrelatedtoanemiahavenotyetbeenelucidated. Female(mean−2SD) 11.5 10.5 10.4
Rationale Becausetherearevariousdiseasesthatcancauseanemia,
it is important to differentiate renal anemia from anemia
3)Hblevelshouldbeusedasareferenceforthediagnosisof causedbyhematologicaldiseases.Figure1showsthediffer-
anemia.ThefollowingaretheappropriatereferenceHblevelsfor
entiationchart.
thediagnosisofanemiaintheJapanesepopulationaccordingto
ageandgender.Thesereferencevaluesarealsousedforthe InCKDpatientswithrenalanemia,althoughEPOpro-
diagnosisofrenalanemia.However,decisionsregardingthe duction is suppressed, EPO levels oftenremain withinthe
treatmentofrenalanemiashouldbemadebasedonthe
reference range. Therefore, absolute EPO level is not a
recommendationsorsuggestionsineachchapter.
<60years,60–69years,≥70years clear indication of decreased EPO production capacity,
Male:Hb<13.5g/dL,Hb<12.0g/dL,Hb<11.0g/dL anditisnecessarytocompareEPOlevelswithHblevels.
Female:Hb<11.5g/dL,Hb<10.5g/dL,Hb<10.5g/dL
According to the re-analysis of data from Japanese
clinical studies of recombinant human erythropoietin in
Because the physiological Hb level in healthy individuals predialysis CKD patients (conducted by Chugai Pharma-
varies according to age, gender, and race, the criteria for ceutical Co., Ltd. and Kirin Pharma Co., Ltd.), the
anemia diagnosis should be determined while considering mean±SDserumEPOlevelwas22.7±12.1mIU/mL(5.0–
these factors. It seems appropriate to use the mean−2 151.0mIU/mL)andthemean+2SDsserumEPOlevelwas
standard deviations (SDs) of Hb level in Japanese individ- 46.9 mIU/mL [13] in 422 patients with a creatinine
ualswhowerejudgedtobehealthybycertainstandardsas levelof≥2mg/dLoracreatinineclearancerateof≤30mL/
referencevaluesforthediagnosisofanemia.Table1shows minandHblevelof<10g/dL.Similarresultswerealsoob-
theHblevelsintheJapanesepopulation,andTable2shows tainedinstudiesabroad,althoughtheEPOlevelsincreased
the criteria for anemia diagnosis used in other countries. up to ~100 mIU/mL in some patients with stage 3
Target Hb levels and the criteria for starting treatment CKD [5, 6]. In contrast, EPO levels were >50 mIU/mL in
should be determined based on the recommendations or mostpatientswithhematologicaldiseases[3,4].
suggestionsinthefollowingchapters. Considering the above, the measurement of EPO level is
In blood tests using an automatic analyzer, which is now usefulasanancillarytestinthediagnosisofrenalanemia.If
commonly used, RBC count, Hb level, and MCVare meas- CKD patients show anemia (Hb levels <10 g/dL) and have
urementvalues,andhematocrit(Ht)levelisacalculatedvalue. EPOlevelsof<50mIU/mL,theycanbediagnosedwithrenal
UnlikeHblevel,whichremainsrelativelyconstantafterblood anemia. In contrast, when EPO levels are >50 mIU/mL, the
sampling,MCVchangesduetovariousfactorsoccurringwith EPOproductioncapacityofthekidneysmightbemaintained
timeaftersamplingandHtlevelalsochangeswithchangesin and it may be necessary to consider the possibility of other
MCV. Therefore, unless Ht level is measured directly, it is diseases that can cause anemia. Particular attention is
recommendedtouseHblevelasthecriterionforanemia. requiredforpatientswithEPOlevelsof>100mIU/mL.
Reticulocyte count reflects the erythropoietic activity in
the bone marrow. Reticulocyte count increases when the
Rationale
formation of erythroblasts is enhanced due to hemolysis or
4)Inthediagnosisofrenalanemia,itisnecessarytodifferentiate
renalanemiafromvarioushematologicaldiseasesthatcancause
anemia.Thefollowingareusefulforthedifferentiationof
Table2EuropeanBestPracticeGuidelinesandKidneyDisease
hematologicaldiseases.
OutcomesQualityInitiativescriteriaforanemia
(1)Presenceorabsenceofabnormalitiesofleukocytesand
platelets(abnormalitiesinfractionation,morphology,andcount, EBPG[80](g/dL) KDOQI[282](g/dL)
andthepresenceofmyeloblasts)
Adultmale Hb<13.5 Hb<13.5
(2)CytometriccategoriesbyMCV(microcytic,normocytic,and
macrocytic) Adultfemale Hb<11.5 Hb<12.0
(3)Increaseanddecreaseinreticulocytecount
(4)SerumEPOlevel Male≥70years Hb<12.5