Anemia Management in Chronic Kidney Disease and End

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Anemia Management in Chronic Kidney Disease and End-

Stage Renal Disease: Clinical Case Studies CME/CE

This activity is intended for nephrologists, primary care providers, nurses, and nurse practitionerswho manage patients with anemia associated with chronic kidney disease (CKD).

Goal

The goal of this activity is to summarize and interpret recent clinical data on the use of currenterythropoiesisstimulating agents (!"#s) in patients with CKD and endstage renal disease(!"$D) who have anemia, including the role of iron supplementation and emerging treatmentoptions. Decisionmaking that is %ased on uptodate clinical data and evidence on managementinterventions will %e encouraged.

Learning Objectives

&pon completion of this activity, participants will %e a%le to'

. $eview the rationale for the recommended hemoglo%in targets in patients with CKD andstrategies to minimize hemoglo%in cycling

. Consider the %enefits and challenges of !"# therapy in hospitalized patients with !"$D

*. Descri%e the efficacy, safety, %enefits, and limitations of current and emerging !"#therapies for patients with !"$D, including the role of iron therapy

+. dentify strategies for incorporating current !"# therapies in the management of patientswith !"$D and anemia

Credits Available

Physicians ma-imum of .AMA PRA Category 1 Credit(s)

Nurses .ANCC Contact Hour(s)(. contact hours are in the area of pharmacology)

#ll other healthcare professionals completing continuing education credit for this activity will %eissued a certificate of participation.

/hysicians should only claim credit commensurate with the e-tent of their participation in theactivity.

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Author's(

&aniel )* Coyne+ ,&

/rofessor of 0edicine, $enal Diseases, ?ashington &niversity4 "taff /hysician, AarnesBewish

@ospital, "t. 1ouis, 0issouri

Disclosure' Daniel ?. Coyne, 0D, has disclosed the following relevant financial relationships'

"erved as an advisor or consultant for' #%%ott 1a%oratories4 /harmacosmos4 sanofiaventis4

?atson /harmaceuticals, nc.4 2!;""erved as a speaker or a mem%er of a speakers %ureau for' #%%ott 1a%oratories4 /harmacosmos4

?atson /harmaceuticals, nc.

;wns stock, stock options, or %onds from' 0erck Co., nc.

Dr. Coyne does not intend to discuss off-labeluses of drugs, mechanical devices, %iologics, or

diagnostics approved%y the 5D# for use in the &nited "tates.

Dr. Coyne does intend to discuss investigational drugs, mechanical devices, %iologics, or

diagnostics not approved%y the 5D# for use in the &nited "tates.

)riter's(

$obert ,ar- &ana+ ,A
http://get.adobe.com/flashplayer/http://office.microsoft.com/en-us/powerpoint/http://get.adobe.com/reader/http://get.adobe.com/reader/http://get.adobe.com/reader/http://get.adobe.com/flashplayer/http://office.microsoft.com/en-us/powerpoint/http://get.adobe.com/reader/http://get.adobe.com/reader/


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0anaging /rincipal, "cientific Communications "ervices, !-ton, /ennsylvania

Disclosure' Disclosure' $o%ert 0ark Dana, 0#, has disclosed the followingrelevant financial relationships'"erved as an advisor or consultant for' /fizer nc.;wns stock, stock options, or %onds from' /fizer nc.4 0erck Co., nc.

.ames A* Shiffer+ $P!

0edical writer, 0arlton, 2ew Bersey

Disclosure' Bames #. "hiffer, $/@, has disclosed no relevant financial relationships.

/ditor's(

Anne G* Le+ Pharm&+ $Ph

"cientific Director, 0edscape, 11C

Disclosure' #nne . 1e, /harmD, $/h, has disclosed no relevant financial relationships.

C,/ $evie"er

Nafee0 1a"ahir+ ,&

C0! Clinical Director, 0edscape, 11C

Disclosure' 2afeez Eawahir, 0D, has disclosed no relevant financial relationships.

Nurse Planner

Laurie /* Scudder+ &NP+ NP

2urse /lanner, Continuing /rofessional !ducation Department, 0edscape, 11C4 Clinical #ssistant

/rofessor, "chool of 2ursing and #llied @ealth, eorge ?ashington &niversity, ?ashington, DC

Disclosure' 1aurie !. "cudder, D2/, 2/, has disclosed no relevant financial relationships.

From ,edscae /ducation Nehrology

Anemia Management in Chronic Kidney Disease and End-Stage Renal Disease: Clinical Case Studies CME/CEDaniel ?. Coyne, 0D

C0!7C! $eleased' F7F7F4 Galid for credit through F7F7F

The following testandteach case is an educational activity modeled on the interactive grand

rounds approach. The 6uestions within the activity are designed to test your current knowledge.

#fter each 6uestion, you will %e a%le to see whether you answered correctly and will then read

evidence%ased information that supports the most appropriate answer choice. /lease note that

these 6uestions are designed to challenge you4 you will not %e penalized for answering the

6uestions incorrectly. #t the end of the case, there will %e a short posttest assessment %ased on

material covered in the activity.
http://www.medscape.org/nephrologyhttp://www.medscape.org/nephrology


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Case Study 234 &iagnosis and 5reatment of Anemia in Predialysis Chronic

6idney &isease 77 Patient !istory

@T is a =yearold woman with previously diagnosed longterm type dia%etes and su%se6uently

diagnosed chronic kidney disease (CKD), hypertension, and anemia. "he is in the office for a

periodic followup and has %een compliant with her medications for hypertension, dia%etes, and

hypercholesterolemia. "he denies cardiovascular (CG) symptoms, including angina or dyspnea

during e-ertion. @ome measurements indicate that her %lood pressure is well controlled. "he has

%een postmenopausal for years and reports no orthostatic hypotension, gastrointestinal ()%leeding, or melena. "he had a normal colonoscopy + years ago. "he reports recurring fatigue

during the past * months that has made it increasingly difficult to perform her work as a sales

clerk. @er hemoglo%in (@%) values have slowly declined from F.H g7d1 a year ago to I. g7d1

despite treatment with an oral iron supplement for = months, which was discontinued months

ago. ;ther la%oratory values are as follows' sodium, + mmol714 potassium, +.H mmol714 car%on

dio-ide (C;), + mmol714 %lood urea nitrogen (A&2), +H mg7d14 creatinine, *. mg7d14 estimated

glomerular filtration rate (e5$), m17min4 white %lood cell (?AC), . million7J14 hematocrit,

I.4 and platelets, H,FFF7J1.

?hat key clinical chemistry value or assessment information does the clinician need

%efore proceeding to therapy with an erythropoiesisstimulating agent (!"#) in this

patientL

Creactive protein

!C for left ventricular hypertrophy (1G@)

rondeficiency studies (serum ferritin, transferrin saturation MT"#TN)


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#c

Prevalence and Conse%uences of Anemia in C6&

The kidneys produce appro-imately IF of all !/;, the hormone that stimulates the %one marrow

to produce red %lood cells. Thus, patients with !"$D or CKD stage O * usually develop anemia

due to impaired renal secretion of !/;. #nemia can occur insidiously soon after onset of CKD,

even prior to the 5$ P =F m17min diagnostic threshold of stage * (moderate) CKD. #nemia

%ecomes progressively worse as kidney function declines and progresses to !"$D. # recent

largescale study of predialysis CKD patients (2 Q ) in the &nited "tates found that +R.R had

@% levels S g7d1 (the upper limit of normal) and H.I had levels S F g7d1. MN# multinational

survey of predialysis patients (2 Q +***) found that =H had a @% concentration S .F g7d1. MN

/revalence of CKD and attendant or coincidental anemia increases with age. 5or e-ample, the

2ational @ealth and 2utrition !-amination "tudy (2@#2!" ) study found that more than F of

#mericans = years of age and older are anemic, representing perhaps * million individuals, with

H. of the cases due to renal insufficiency and an additional + due to CKD plus anemia of

chronic disease.M*Niven the aging &" population and rapid increase in diagnoses of type

dia%etes, the overall prevalence of CKD is likewise increasing.

Aesides su%normal production of !/;, a common cause of anemia in cases of CKD or !"$D is

iron deficiency resulting from any of several causes, as discussed later in this article. nade6uate

iron or decreased iron availa%ility has %een shown to %e a significant predictor of !"# resistance

or nonresponsiveness.M+NThus, for purposes of this initial assessment of our patient, @T, clinicians

should o%tain a complete %lood count with differential and platelet count, @% concentration, mean

corpuscular volume, mean corpuscular @% concentration, and tests for iron deficiency' serum

ferritin level and serum T"#T level. The serum ferritin assay reflects the %ody3s iron stores, while

the T"#T assesses the availa%ility of iron for erythropoiesis. These standard tests may %e

supplemented with an assay for reticulocyte hemoglo%in content (C@r), an early, direct

determination of iron availa%le for @% synthesis.

n treating CKDassociated anemia in this patient, what symptoms or clinical risks are

most likely to improveL

Save and Proceed


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$egression of 1G@

$eduction in heart failure risk

$eduction in stroke risk

$eduction in fatigue

There are multiple, wellknown conse6uences of untreated anemia in the !"$D setting. 0ost

nota%ly are CG complications resulting from the added %urden that CKD and anemia place on the

heart. #nemia in !"$D patients has %een shown to %e an independent risk factor in de novo

cardiac failure and mortality.MN!ven in patients with mildtomoderate renal insufficiency, studies

have shown a * increase in 1G@ risk for each F.g7d1 decrease in @%. M=N#nemic !"$D patients

also e-perience fatigue, e-ercise intolerance, cognitive impairment, and reduced immune function.!"$D patients treated with !"#s have shown significant improvement in 6uality of life (;1) into

the nearnormal activity range as measured %y increased Karnofsky /erformance "tatus "cale

scores, reflecting the adverse impact of anemia on activities of daily living. MRN# recent clinical trial

has shown that intravenous (G) iron therapy significantly improved ;1 scores in irondeficient,

stage O * CKD patients not on dialysis, even in the a%sence of !"# therapy.MHN n a persuasive

testimony to the de%ilitating effects of CKDassociated anemia, a patient not receiving dialysis who

had a 5$ of m17min noted that none of the effects of his disease truly slowed him down

>e-cept anemia, which in recent years has forced me toward retirement and had prevented me

from virtually all e-ercise, even walking *F minutes per day to protect my heart.>MINn effect, anemia

acts as a riskmultiplier in CKD patients, e-acer%ating e-isting ;1 limitations and contri%uting to

comor%idities such as hypertension and other forms of CG disease and dia%etes.

Case 3 'cont(

The clinician reviews @T3s medical history with her, specifically asking a%out past occurrence of

stroke or other throm%otic events and cancer. The clinician counsels @T a%out the practical

aspects of !"# therapy, including the necessity for fre6uent parenteral administration and the

inconvenience associated with regular monitoring. #n occult fecal %lood test is performed on site. #

%lood sample is o%tained to determine iron status.

#ll of the following clinical information is important in deciding whether to use an !"# in

@T, a CKD patient, except'

Save and Proceed


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/rior history of !"# use

@istory of stroke

/atient3s willingness to accept inconvenience and discomfort of regular treatment

and monitoring$uling out iron deficiency as a primary cause of anemia

$ationale and /vidence for 5reatment of Anemia

#nemia is easily diagnosed and relatively easy to correct, even in patients with advanced kidney

disease. n doing so, clinicians should %e aware of relevant treatment considerations. The first is

that circulating @% concentration, the principal %iomarker for anemia, has a narrow reference range

that is often an elusive therapeutic target. Thus, maintaining @% at target levels is dependent on

careful monitoring and dose ad:ustment of ironreplacement therapy or !"#s. # second

consideration is that the optimal @% target in CKDassociated anemia has %ecome somewhat

controversial %ecause of the outcomes of several largescale randomized clinical trials ($CTs) that

evaluated treatment of anemia in CKD patients. The upshot of these studies, which will %e

discussed %elow, is that the @% level achieved %y anemia therapy may %e a source of %oth %enefit

and CG risk. Despite these therapeutic challenges, appropriate treatment of CKD and anemia

together can su%stantially reduce CG risk, decrease transfusion re6uirements, and improve ;1.

5or patients with stage * CKD and !"$D, !"#s are a cornerstone of treatment. #vaila%ility of

!"#s with differing pharmacokinetic profiles ena%les individualized treatment, specifically

regarding dose size and dosing intervals. #pproved initial and maintenance dosing intervals are

shown in Ta%le . n practice, clinicians deviate widely from these recommendations in nondialysis

CKD patients in order to individualize treatment. 5or e-ample, epoetin is commonly given at

weekly or %iweekly intervals. Dar%epoetin alfa is often given at intervals ranging from %iweekly to,

in some cases, monthly intervals on an offla%el %asis.

Table 1. Profile of FDA-Arove! Erythrooietin-"ti#ulating Agents $1%&

Phar#aco'ineticProerties

(enericna#e

Tra!ena#e

FDA-Arove!!osingfre)uency

Co##onClinical*se

A!#inistration route

T+ , T+ ,"C T#a0

epoetinalfa

/rocritU,!pogenU

nitial' * timesweekly

0aintenance'individualized

nitial'weekly

0aintenance'

G or "C +.F.F

I.F.*

=.F+.F

Save and Proceed


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weekly to *times weekly

individualized weekly to%iweekly

dar%epoetin alfa

#ranespU

nitial' weeklyor %iweekly

0aintenance'individualizedweekly to%iweekly

nitial'weekly or

%iweekly0aintenance' one doseevery +weeks

G or "C .* +H.H=I.=

+.F

SC = subcutaneous !" = intravenous #$ = p%as&a 'a%%ie #&ax = ti&e to &axi&u& p%as&a

'a%%ie

"u%cutaneous ("C) administration of approved !"#s allows for e-tended dosing intervals that

help reduce the inconvenience associated with in:ecta%le !"# therapy. 5or e-ample, e-tended

dosing intervals for epoetin ranging from once weekly to once every + or more weeks have %een

successful in maintaining @% levels V .F g7d1 in some patients. MFNThe recommended approach is

to rule out iron deficiency as a primary cause of anemia prior to !"# therapy, or to treat irondeficiency concurrently with !"# therapy.

/SA Convenience Issues

Certain aspects of !"# therapy re6uire the for%earance of %oth clinicians and !"$D patients. &"

5ood and Drug #dministration (5D#)approved !"#s (Ta%le ) are photosensitive, highly la%ile

synthetic agents, re6uiring that they %e stored under refrigeration and without shaking. 0ore

pro%lematic is the fre6uency of dosing needed for CKD therapy. #s dosing fre6uency increases,

compliance inevita%ly declines. !poetin is approved for administration * times weekly, though

dosing weekly or %iweekly is common in clinical practice. Dar%epoetin has a longer halflife and

re6uires in:ection less fre6uently, at weekly or %iweekly intervals depending on dialysis status.

Dar%epoetin is also occasionally used offla%el as a monthly treatment. t should %e noted thatstudies have found that H of predialysis CKD patients were a%le to maintain @% at O .F

g7d1 when epoetin was given at e-tended intervals from to more than + weeks. MFN#n e-tended

dosing interval may %e of particular %enefit to patients who selfadminister an !"#. !ach of the

three approved !"#s is indicated for selfadministration in patients not on dialysis, a scenario that

makes it difficult to monitor compliance.

5he 5rial to $educe Cardiovascular /vents "ith Aranes 5heray '5$/A5( and

Correction of !emoglobin and Outcomes in $enal Insufficiency 'C!OI$( Studies

The T$!#T study was an ongoing randomized, dou%le%lind, multinational trial designed to

determine whether anemia therapy with dar%epoetin would reduce mortality and CG events in

predialysis CKD patients with type dia%etes. 0ore than +FFF patients with %aseline @% I.F.F

g7d1 not receiving !"# therapy were randomly assigned to achieve a target @% of * g7d1 with

dar%epoetin therapy or place%o, with rescue dar%epoetin given for @% P I g7d1. The primary

outcome was a composite endpoint of death, myocardial infarction, acute myocardial ischemia,

congestive heart failure, and stroke. T$!#T was designed to provide clinical guidance for the

future management of anemia in a highCGrisk population. t is the largest $CT of anemia and

CKD conducted to date.

The primary results of T$!#T, reported in FFI, indicated that use of dar%epoetin in patients with

dia%etes, CKD, and moderate anemia did not reduce risk for the primary outcomes' death or a CG

or renal event.MN#dditionally, the annualized risk for stroke (@$ .I4 I C, .*H.=H4 P P .FF)

was nearly dou%le in dar%epoetintreated patients vs the place%o group, . vs .. #

su%se6uent analysis %y T$!#T investigators found that those patients who had a poor initial


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hematopoietic response to dar%epoetin had higher rates of CG events. MNn contrast, those patients

with a good initial response to dar%epoetin did not have increased CG events compared with the

place%o group, though they also did not show any reduction in CG events. The T$!#T study and

the recent analysis confirm that treatment with !"# does not reduce CG risk in nondialysis patients

and may increase the risk for some CG events. #lthough cancer mortality was not significantly

different %etween dar%epoetin and place%o groups, T$!#T patients with cancer history at %aselinehad a significantly greater cancer mortality rate vs patients without a history of malignancy (+7HH

vs 7=F4P Q .FF).MN

Current data %roadly indicate that CG disease is the leading cause of death in CKD patients. The

C@;$ study,M*Na previous largescale $CT involving predialysis CKD patients treated with epoetin

to achieve target @% levels of either .* g7d1 or *. g7d1, found an increased risk with higher @%

target in a composite CG endpoint of death, stroke, myocardial infarction (0), and heart failure.

The increased CG risk in the C@;$ study was driven %y a higher rate of death and heart failure

associated with higher @% targeting. Thus, while these large trials differ in design and the o%served

CG risks from !"# use designed to achieve higher @% levels, they are harmonious on the point

that targeting higher @% does not reduce risks.

"ome %enefits do appear to accrue from anemia treatment in CKD, including improvements in

fatigue in select patients and a reduction in likelihood of transfusion. Dar%epoetintreated patients

in the T$!#T study had a ++ lower risk for %lood transfusions vs the place%o group, +.H vs

+. (@$ F.=4 I C, F.+IF.=4 P P .FF).MN Dar%epoetintreated patients also had a week

improvement in their 5#CT5atigue score of +. W F. points vs .H W F.* points (PQ .FF)

compared with the place%o group. #n increase of * or more points, considered to %e clinically

relevant, occurred in +.R of dar%epoetintreated patients vs +I. of place%o patients (PQ .

FF), @owever, other ;1 factors related to energy and physical functioning were not significantly

different %etween groups.

#le-ander /risant, a healthcare policy advisor and the CKD patient 6uoted in the preceding

section, provided an elo6uent commentary on the pitfalls of overreliance on onesizefitsall

guidelines derived from evidence%ased trials such as T$!#T. #fter %eing placed on a regimen of

FF Jg of "C dar%epoetin administered %iweekly, >the results have %een electrifying,> he reported

in a recent issue of theA&erican *ourna% o +idney ,iseases.MIN 5ollowing treatment, his @% level

rose to V g7d1 for the first time in more than years, allowing him to e-ercise * times weekly

and virtually eliminating H years of sta%le angina. Commenting specifically on the implications of

T$!#T, he offered the following recommendation to clinicians' treat the patient as an individual.

@is response was e-ceptional, as evidenced %y the %linded trial results in the T$!#T and C@;$

studies, %ut led to an important point' ?hether e-amining trial results like T$!#T or guidelines

recommendations like those from the Kidney Disease ;utcome uality nitiative (KD;) or

Kidney Disease' mproving lo%al ;utcomes (KD;), clinicians should consider the particular

patient3s risks and %enefits of !"# therapy. f choosing to treat with an !"#, monitor individual

response to determine whether further treatment is really providing a lasting %enefit.

C@;$ was an $CT that evaluated the a%ility of epoetin to correct anemia in more than +FF CKD

patients. /articipating patients were treated at epoetin doses designed to achieve an @% level of

either *. g7d1 or .* g7d1 during a median treatment period of = months. The group assigned

to the @% target level of *. g7d1 had a significantly higher risk for CGassociated events (@$

.*+4 I C, .F*.R+4 P Q .F*).M*N!-cess CG events included mortality and heart failure %ut not

stroke. mprovements in ;1 were similar in %oth treatment groups. 1imitations of C@;$ were its

openla%el design and high rate (*H.*) of early withdrawal for reasons other than primary

endpoints.M+N"tudy investigators concluded that an @% target of .* g7d1 rather than *. g7d1 is

an appropriate target to correct anemia in CKD patients. This is consistent with the .F.F g7d1


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range recommended %y the KD; guidelines and the 5D#approved goal of maintaining @%

%etween F.F and .F g7d1 when using an !"#. # su%se6uent metaanalysis of $CTs of !"#

usage in CKD patients with anemia concluded that patients in the higher @% target group had a

significantly greater risk for allcause mortality ($$ .R4 I C, .F.*4 P Q .F*).MN

5he Normal !ematocrit Study 'N!S(

The 2@" preceded T$!#T and C@;$ and differed from the later $CTs in that it evaluated

anemia treatment in chronic dialysis patients (2 Q **) with pree-isting CG disease. #ll

participants had a %aseline hematocrit of at least *F and were then randomly assigned to receive

epoetin to maintain hematocrit of *F or raise it to +. /atients randomly assigned to the lower

hematocrit target had a *F lower risk for mortality and nonfatal heart attacks. 2@" for the first

time contradicted the conventional wisdom that aggressive correction of anemia in patients

receiving dialysis was %oth %eneficial and without risk.M=N

6&O8I and F&A Guidelines for !emoglobin 5arget

$esults of the preceding trials are generally interpreted as indicating that () adherence to the 5D#guideline of maintaining @% levels S g7d1 is advisa%le for minimizing risk for CG complications

from anemia therapy in CKD, and () little or no incremental improvement in ;1 occurs %y

targeting a higher @% level. nformed %y largescale $CT results, the KD; ?ork roup has

issued an evidence%ased clinical practice recommendation that CKD patients %oth on and not on

dialysis who are receiving !"# therapy should generally have an @% target in the range of .F

.F g7d1. &se of the word >generally> can %e interpreted as allowing some latitude for

individualization of therapy. #dditionally, the guidelines acknowledged that use of !"# was a

patientspecific decision. The ?ork roup has also issued a clinical practice guideline stating that

CKD patients %oth on and not on dialysis who are receiving !"# therapy should have an @% target

S *.F g7d1 in the a%sence of sufficient evidence of %enefit from maintaining higher @% levels. MRN#n

interesting perspective on the KD; guidelines is the o%servation that some ?ork roupmem%ers represent corporate interests and may have a proindustry %ias that favors increased use

of !"#s.MFN

The 5D# @% targetrange lower limit for approved !"#s differs somewhat from the KD; range

and recommendations. 1a%eling for 5D#approved !"#s recommends >individualized dosing to

achieve and maintain hemoglo%in levels within the range of F to g7d1.>MHFN The 5D# la%eling

also states that for patients una%le to achieve an @% of F.F.F g7d1 after * months of increasing

!"# dose, clinicians should reduce the !"# dose to the lowest necessary to avoid transfusions.

Case 3 'cont(

Discontinuance of oral iron therapy coincided with the patient3s symptoms of fatigue and declining@% level. @T was found to have a serum iron of H+ Jg7d1, a serum ferritin level of + ng7m1 and a

T"#T of . Dar%epoetin therapy was initiated at a dosage of * Jg "C weekly, consistent with

the product3s recommended starting dose of F.+ Jg7kg.


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?hat is the %est option for @T who is on !"# therapy %ut whose @% level increases

a%ove the normal range to *.H g7d1L

Keep the !"# dose at the current level for an additional weeks

"top !"# therapy4 resume at a lower dose when @% is P g7d1

$educe the !"# dose %y F

$educe the !"# dose %y

Challenges Associated )ith Current 5reatment Otions

# fundamental challenge facing clinicians in the management of patients with renal insufficiency is

that, in general, controlled @% levels vary significantly over time despite continuous !"# treatmentand ade6uate iron availa%ility. This is principally %ecause intercurrent events and varying sensitivity

to !"# alter @% levels %eyond our narrow therapeutic target range. !-cessive alterations in !"#

dose, inade6uate time %etween !"# dose changes, and fluctuating iron ade6uacy may also

contri%ute to this varia%ility. This phenomenon is termed @% cycling (shortterm varia%ility in @%

level) and can %e e-acer%ated %y using currently availa%le in:ecta%le !"#s at long dosing

intervals. t should %e noted that @% varia%ility is more fre6uent and pronounced in dialysis

patients, such as the individual who will %e discussed in case , than in CKD stage * and +

patients not on dialysis.

!emoglobin 5arget $ange and Cycling

There is wide varia%ility of @% levels around the target range of .F.F g7d1 and S * g7d1 in

!"#treated patients. 5or e-ample, a recent study found that more than =F of !"#treated

patients receiving hemodialysis re6uired %etween = and I dose ad:ustments per year to maintain

an @% target range of .F.F g7d1. MRN# trial of patients on hemodialysis who were treated with

dar%epoetin found that !"# dose ad:ustments (increases or decreases) were re6uired %y RF of

patients receiving dialysis during a Fweek titration period and %y F during an Hweek

maintenance period.MRN# 5resenius 0edical Care 2orth #merica largescale study of !"$D

patients (2 V =,FFF) found that only *H.+ of participants had @% levels %etween .F and .F

g7d1.MNThe recommended approach to managing varia%le @% levels in CKD patients is to

administer !"# dose titrations in increments of and to monitor @% levels at least once

monthly after each ad:ustment.

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The great ma:ority of patients on dialysis who are receiving !"# therapy e-perience hemoglo%in

cycling or periodic changes V . g7d1 in @% levels, followed %y reversion to the appro-imate

prefluctuation level over a period of H weeks or more. n one study of patients receiving

hemodialysis, the mean num%er of @% e-cursions was *. W . per year, with a mean @%

amplitude of . W F.HI g7d1 per e-cursion. MN0ore than IF of patients in the study e-perienced

at least @% cycle. The aforementioned 5resenius study found that I of !"$D patients movedfrom %elow to a%ove the @% target range or vice versa during the *month tracking period. MNn

other words, the @% level in most !"$D patients is 6uite varia%le due to physiologic factors (eg,

inflammation, chronic infection, %lood loss, iron status, dietary intake, !/; resistance) or

iatrogenic causes (eg, effects of !"# or iron therapy, including dose ad:ustments and withholding,

hospitalization, inade6uate dialysis, dialysis volume removal). /erhaps the most clinically relevant

concern associated with @% cycling is treatmentrelated >overshoots,> a rapid rise in @% defined %y

the 5D# as V g7d1 within a week period. The failure to find incremental %enefit of @% levels V

g7d1 and the potential risks of @% levels outside the KD; target range place added emphasis

on fre6uent monitoring and therapeutic dose ad:ustment on an individualized %asis to offset the

impact of @% cycling.

#n important caveat applies to !"# dose ad:ustments' #de6uate time must have elapsed %etween

ad:ustments to determine their ultimate effect on @% level. $eacting to an overshoot %y a%ruptly

discontinuing treatment, for e-ample, can result in an a%rupt drop in @% concentration to a level

well %elow the target range. # good rule of thum% is that !"# dose should %e decreased %ut not

withheld when the @% level e-ceeds .F g7d1, dose ad:ustments should %e in increments or

decrements, a +week interval should %e allowed to elapse %etween dose ad:ustments, and

monitoring should %e done on at least a monthly %asis. &sing this approach, it is not uncommon for

=H weeks to elapse %efore the desired @% level is reached while at the same time e-cessive

e-cursions outside the target range are minimized. Ta%le summarizes !"# dosead:ustment

guidelines in CKDassociated anemia.

Table . (ui!ance for E"A Dose A!2ust#ents in C3D or E"4D Patients

#d:ust the !"# dose to maintain the @% level within the desired range %ut not V .F

g7d1

#d:ust !"# dose in increments or decrements to avoid overcompensating for @%

levels outside the target range

#llow a +week interval %etween !"# dose ad:ustments for hematopoietic response to

occur

0onitor @% level on at least a monthly %asis to maintain target @% level4 more fre6uent

monitoring may %e indicated after !"# dose changes


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?hich statement a%out iron deficiency in a CKD patient with anemia such as @T is trueL

#ll CKD patients with anemia have iron deficiency

;ral iron therapy should always %e administered %efore G iron is given

Correction of iron deficiency will increase the response to !"# therapy

ron therapy and !"#s should not %e given concurrently

Iron 5heray

0any CKD patients have a%solute iron deficiency, usually defined as serum ferritin levels P FF

ng7d1 and T"#T P F. This can result from any of several causes, including inade6uate dietary

intake, %lood loss, occult gastrointestinal malignancy, or chronic inflammation. CKD is a

proinflammatory disease often due to chronic in:ury to the kidneys, dia%etesassociated vascular

in:ury, malignancy, autoimmune disease, or infection. f an iron deficiency e-ists, it must %e

corrected %efore a patient with CKD or on dialysis can respond to !"# therapy. nitial treatment for

iron deficiency is usually with oral iron therapy for * months or more. G iron therapy is generally

given as a single initial dose followed %y testing for ferritin levels and T"#T and retreatment as

necessary. !"# therapy can %egin when la%oratory values indicate that the iron deficiency has%een treated successfully (5igure ).

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Figure 1. $ecommended use of erythropoietinstimulating agents to manage anemia in patients

with chronic kidney disease.

"ome patients do not respond even after several months of !"# therapy with increment dose

increases. n the Dialysis /atients3 $esponse to G ron with !levated 5erritin (D$G!) trial,

hemodialysis patients with refractory anemia had a faster and larger @% response when treated

with mg of G ferrous gluconate for H consecutive hemodialysis sessions. M*NThus, concurrent

G iron therapy can %e %eneficial in anemic patients on dialysis who are receiving recommended

!"# dosages (5igure ).


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Figure . !valuation and treatment of iron deficiency for chronic kidney disease patients receiving

erythropoiesisstimulating agents.

Clinicians should note that peripheral iron indices such as serum ferritin and T"#T only have

moderate accuracy in predicting response to iron therapy.M+Nf %oth T"#T and ferritin levels are low,

the likelihood of iron deficiency is high. #t higher levels, these values have a relatively poorer

correlation with iron deficiency and response to !"# therapy. ;nly when the T"#T is truly high, ie,

at the F level, can iron deficiency %e definitively ruled out. Thus, some patients with a ferritin

level in the FF*FF ng7m1 range and a T"#T level in the F*F range may still %e iron

deficient and capa%le of %enefitting from a dose of G iron.

Case 34 Conclusion and &iscussion

The patient had an @% level of F.H g7d1 within weeks after initiating !"#, and reported that her

fatigue was much reduced. @er ferritin level increased to *RF mg7m1 and her T"#T level increased

to *F at + weeks after %eginning !"# therapy. "he maintained an @% level %etween F.H and

g7d1 for the ne-t = months of treatment with no e-cursions a%ove g7d1. G iron treatment was

not used %ecause her pretreatment iron levels were accepta%le and consistent with ade6uate iron

stores. ;ver time while on !"# therapy, @T may %ecome iron deficient, characterized %y higher

!"# dose re6uirements or lower @% and falling T"#T or ferritin level. &se of oral or G iron at that

time may %e appropriate.

/merging /SA 5heraies

!poetin was the original synthetic endogenous !/; approved %y the 5D# as an !"# in IHI.

Dar%epoetin, the secondgeneration !"# introduced in FF, has a similar mode of action and


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safety and efficacy profiles, %ut it re6uires much less fre6uent dosing due to its longer halflife,

particularly following "C administration (Ta%le ). These !"#s have replaced transfusions as first

line therapy for treatmentresponsive anemia in patients with CKD. Aesides avoiding transfusion,

!"# therapy3s demonstrated %enefits include improved ;1 and survival. n addition, there is

some evidence that !"#s may slow progression of renal disease and provide cardioprotection

when @% levels are maintained within the F.F.F g7d1 treatment target range.MFN#lthough theseearly !"#s are the current standard of care and have transformed treatment of anemia in CKD,

the following e-perimental or newly emerging agents promise to further increase our a%ility to

manage this aspect of renal insufficiency.

f our patient, @T, developed anti%odymediated pure red cell aplasia (/$C#) related to

her !"# therapy, which of the following investigational agents appears to %e most

promising for treatment of anemiaL

Continuous erythropoietin receptor activator (C!$#)

@ypo-iainduci%le factor (@5) sta%ilizers

@epcidin activators

/eginesatide

Peginesatide

/eginesatide (@ematideX) is an investigational !"# now %eing tested in phase * clinical trials

involving patients with chronic renal failure, including trials in patients receiving dialysis

(!0!$#1D and ) and in patients not receiving dialysis (/!#$1 and ). MN/eginesatide is a

novel, synthetic !"# that is immunologically unrelated to endogenous human !/;. /ure red cell

aplasia (/$C#) is a rare %ut potential side effect of currently availa%le !"#s, where%y the patient

develops neutralizing anti%odies to the recom%inant !/; analogs. This nullifies the activity of the

!"# as well as endogenously produced !/;, leaving the individual severely anemic and

dependent on %lood transfusions. !/; anti%odies do not crossreact with peginesatide. #s a

result, peginesatide has shown the a%ility to increase and maintain @% levels in patients with

/$C#, avoiding a rare %ut serious adverse effect of !"#s that contain synthetic !/; analogs. n

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addition, peginesatide has the advantages of oncemonthly administration, greatly reducing the

fre6uency and inconvenience of treatment, as well as storage at room temperature.

n a phase trial, peginesatide maintained @% levels in patients with CKD previously treated with

dar%epoetin. n the /!#$1 studies of patients not receiving dialysis, peginesatide had mi-ed

results. #lthough peginesatide had e6uivalence to dar%epoetin in increasing @%, higher rates ofmortality and CG events were reported, and /!#$1 showed a higher percentage of patients

receiving transfusions. n the !0!$#1D studies of patients receiving dialysis, peginesatide had

safety and efficacy e6uivalence to epoetin, including transfusion rates.

Continuous /rythrooietin $ecetor Activator

Continuous erythropoietin receptor activator (C!$#) is the generic designation for a third

generation !"# class in which the !/; analog is pegylated, a drug delivery formulation that alters

pharmacokinetics so that the clinically active agent has an e-tended halflife. n the case of

C!$#s, pegylation allows e-tended dosing intervals. 0etho-y polyethylene glycolepoetin %eta is

the firstinclass C!$#, licensed as 0iceraU%y $oche in FFH for oncemonthly treatment of CKD

associated anemia, including in patients receiving dialysis. n a recent phase * study, metho-y

polyethylene glycolepoetin %eta maintained target @% levels more successfully than dar%epoetin

at oncemonthly dosing intervals, despite dose increases with dar%epoetin. M=N# noteworthy aspect

of the study was that the early withdrawal rate was + in the metho-y polyethylene glycol

epoetin %eta group vs +F for dar%epoetin, with the difference primarily due to a higher rate of

insufficient therapeutic response in the dar%epoetin patients. The !"#s had compara%le safety

profiles. 0etho-y polyethylene glycolepoetin %eta is approved for use in the !uropean &nion %ut

has yet to %e marketed commercially in the &nited "tates due to patent disputes. #n interesting

aspect of C!$# therapy is that some clinicians may actually prefer shorteracting !"#s so that the

dose response can %e more closely controlled in order to minimize the potential for adverse side

effects.

!yo9ia7Inducible Factor Stabili0ers

@5 is a key regulator of !/; gene e-pression. @5 responds to changes in cellular or circulating

o-ygen levels. f %lood o-ygen levels decline, as in anemia or at highaltitude environments, @5 is

activated from renal cells and !/; production rapidly increases. $ecently, @5 has %ecome a

therapeutic target for treatment of anemia in CKD patients. &nder normal conditions, @5 is

meta%olized %y prolylhydro-ylase. &nder hypo-ic conditions, prolylhydro-ylase is inhi%ited

%ecause it uses o-ygen, thus sta%ilizing @5 e-pression. 5= and 5+I MRN(developed %y

5i%roen, nc) are oral @5 sta%ilizers that function as prolylhydro-ylase inhi%itors (/@s) and

are %eing evaluated in phase trials as oral agents given or * times weekly. $esponse time

occurs in * weeks. ;f particular interest was the a%ility of 5= to stimulate erythropoiesis

compara%le to dar%epoetin therapy, %ut with only modest increases in plasma !/; levels. MHNThis

was attri%uted to /@ upregulation of other erythropoiesis pathways, particularly iron mo%ilization.

This activity would potentially allow erythropoiesis even in !"$D patients with negligi%le kidney

function. ;ne safety concern with this class of drugs is whether they would e-acer%ate cancer

%ecause @5 is angiogenic and is constitutively e-pressed %y some cancers.

5heraeutic $ole of !ecidin

The hormone hepcidin is the predominant negative regulator of iron a%sorption from the intestine

and iron release from macrophages for purposes of o-ygen transport. This homeostatic

mechanism ena%les tight control of iron, simultaneously avoiding to-ic effects of iron overload

while meeting physiologic demands for iron use. nflammation, hypo-ia, and anemia all suppresshepcidin production, removing its inhi%itory effect on iron a%sorption and iron release from


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macrophages.MIN &nderstanding hepcidin synthesis pathways may contri%ute to an alternative

treatment of anemia, specifically %y means of hepcidin antagonists, which would increase iron

availa%ility. This would provide a therapeutic option separate from !"# treatment, thus avoiding

the occasional adverse side effects of !"#s, such as hypertension and anti!/; immune

response.

/PO&:$/ ;ioum

Treatment of anemia in patients with CKD typically involves "C administration of !"#s at regular

intervals followed %y fre6uent la%oratory tests to monitor @% concentration. The !/;D&$!

Aiopump (0edgenics4 Gienna, Girginia) is a sustained !/; drug delivery system for CKD patients.

!/;D&$! is an autologous dermal %iopump capa%le of sustained secretion of !"#s at

therapeutic levels. # small tissue e-plant is harvested directly from the patient3s dermis under local

anesthetic. The %iopump is produced %y e- vivo introduction of the !/; gene into cells of the

e-plant, which then e-presses and secretes !/;. The %iopump is su%se6uently implanted

su%cutaneously %ack to the patient in order to provide continuous delivery of a known amount of

!/;. /hase and clinical trials, as yet unpu%lished, have demonstrated sustained !"# therapy

for greater than months in CKD patients implanted with the %iopumps. M*FN

Case


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;n the %asis of the information provided, what is the most likely e-planation for 0/3s

anemiaL

nade6uate !"# therapy

nfectionrelated inflammation

;ccult %lood loss

nterventionalprocedure related %lood loss

#ll of the a%ove

Anemia ,anagement in !ositali0ed Patients on &ialysis

@ospitalization is common in patients on dialysis and fre6uently e-acer%ates CKDassociated

anemia. @ospitalization rates vary depending on the severity of CKD and certain comor%idities. 5or

e-ample, 0edicare patients with stage * CKD had allcause hospitalization rates that were I

higher than those of patients with stage CKD. 0edicare patients with CKD also had hospital

admission rates for all causes, CG disease, and infection that were *H+= higher than for non

CKD patients.M*N

/atients on dialysis who have prehospitalization @% levels within the KD; target range often

have depressed @% levels during or after hospitalization. The posthospitalization decrease in @%

levels can %e significant and prolonged. 5or e-ample, one study found that hospitalized dialysis

patients (2 Q =) had @% levels at discharge and for months thereafter that were significantly

lower (F.R W F. vs .+ W F. g7d14 PP .F) than at months prior to admission.M*NThe

prolonged decrease in @% levels occurred despite an increase in mean epoetin dosage (H vs

H &7kg7week4 P P .FFF) during the month period after discharge.

5actors associated with su%normal or declining @% levels after hospitalization include pree-isting

anemia, high prehospitalization !/; re6uirements, inade6uate or interrupted !"# administrationduring hospitalization, e-tended stays, and diagnosis of congestive heart failure or other CG

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disease. ;ther causes of anemia in hospitalized patients on dialysis include fre6uent or high

volume %lood sampling, %leeding, surgery or other sources of %lood loss, inflammation or

infection of arteriovenous grafts or fistulas, and poor wound healing. n older patients on dialysis,

%lood loss can often result from lesions such as gastric ulcers, diverticulitis, colonic

hemorrhoids, or fissures. Treatment with anticlotting agents such as clopidogrel can increase %lood

loss from these sources of lowgrade occult %leeding. nflammation may also occur duringillnesses. This can lead to increased hepcidin levels which in turn reduce iron %ioavaila%ility. M**N

nflammation may also hinder the response to !"# therapy. #ny of these pree-isting conditions

can %e predictive of the need for increased !"# dosing during or after hospitalization.

Case < 'cont(

&pon return to his dialysis unit + weeks later, 0/3s epoetin dose is increased from ,FFF to

H,RF unit7week, a dose increase. The dosing fre6uency for the FFmg G iron therapy is

increased to once weekly. # hemoccult test performed to determine whether there was occult

%lood loss is negative. @emoglo%in, serum ferritin, and T"#T levels are determined + weeks after

discharge to assess anemia status. The @% level at that time is F.+ g7d1, ferritin level is I+

ng7m1, and T"#T level is +.

#ssuming that your @% target is g7d1, what would %e the most appropriate

intervention for 0/ at this pointL

#dminister FFF mg oral iron over * weeks

ncrease his !"# dose another

Aoth of the a%ove

Continue present therapy and reevaluate in + weeks

?hen preadmission @% levels are within the KD; target range, patients receiving dialysis clearly

are at a lower risk of having @% concentration fall precipitously %elow the g7d1 anemia threshold

during and after hospitalization. Thus, it is advisa%le to maintain @% in the target range for dialysis

patients through prudent use of !"# and iron therapy. iven the long interval %etween !"# dose

Save and Proceed


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changes and hematopoietic response, a dose increase should generally occur only once during

most hospitalizations, and only after a +week interval has elapsed since the last increase.

Case


23/25

. 5oley $2, /arfrey /", @arnett BD, et al. The impact of anemia on cardiomyopathy,

mor%idity, and and mortality in endstage renal disease. #m B Kidney Dis. II=4H'*=.

#%stract

=. 1evin #, Thompson C$, !thier B, et al. 1eft ventricular mass inde- increase in early renal

disease' impact of decline in hemoglo%in. #m B Kidney Dis. III4*+'*+.#%stract

R. 0oreno 5, #racil 5B, /[rez $, et al. Controlled study on the improvement of 6uality of life

in elderly hemodialysis patients after correcting endstage renal diseaserelated anemia

with erythropoietin. #m B Kidney Dis. II=4R'+H=.#%stract

H. #garwal $, $izkala #$, Aastani A, et al. # randomized controlled trial of oral versus

intravenous iron in chronic kidney disease. #m B 2ephrol. FF=4='++++.#%stract

I. /risant #. T$!#T versus treatment' # patient3s view of a scientific interpretation. #m B Kid

Dis. FF4'#*#*.

F. ?ish BA, Coyne D?. &se of erythropoiesisstimulating agents in patients with anemia of

chronic kidney disease' overcoming the pharmacological and pharmacoeconomic

limitations of e-isting therapies. 0ayo Clin /roc. FFR4H'*R*HF.#%stract

. /feffer 0#, Aurdmann !#, Chen C


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I. #ranespU(dar%epoetin alfa) 5or n:ection. /rescri%ing information. #mgen nc. $evised

0ay FF.

F. !/;!2U(!poetin alfa) 5;$ 2B!CT;2. /rescri%ing information. #mgen nc. $evised

5e%ruary FF.

. 1acson ! Br, ;fsthun 2, 1azarus B0. !ffect of varia%ility in anemia management on

hemoglo%in outcomes in !"$D. #m B Kidney Dis. FF*4+'+.#%stract

. 5ish%ane ", Aerns B". @emoglo%in cycling in hemodialysis patients treated with

recom%inant human erythropoietin. Kidney nt. FF4=H'**R*+*.#%stract

*. Coyne D?, Kapoian T, "uki ?, et al. 5erric gluconate is highly efficacious in anemic

hemodialysis patients with high serum ferritin and low transferrin saturation' results of the

Dialysis /atients3 $esponse to G ron with !levated 5erritin (D$G!) "tudy. B #m "oc

2ephrol. FFR4H'IRIH+.#%stract

+. "tancu ", A^rsan 1, "tanciu #, et al. Can the response to iron therapy %e predicted in

anemic nondialysis patients with chronic kidney diseaseL Clin B #m "oc 2ephrol.

FF4'+FI+=.

. #ffyma- and Takeda announce phase * trials meet primary endpoints for investigational

drug, hematide(T0)7peginesatide, to treat anemia in chronic renal failure with some

differences noted in secondary analyses. Bune , FF. M/ress release.N #vaila%le at'

http'77www.takeda.com7press7article]*=.html#ccessed Banuary H, F.

=. Carrera 5, 1ok C!, de 5rancisco #, et al. 0aintenance treatment of renal anaemia in

haemodialysis patients with metho-y polyethylene glycolepoetin %eta versus dar%epoetin

alfa administered monthly' a randomized comparative trial. 2ephrol Dial Transplant.

FF4'+FFI+FR.#%stract

R. Aesara% #, @ulter @2, Klaus ", et al. 5+I, a novel oral @5 prolyl hydro-ylase

inhi%itor, elevates hemoglo%in in anemic stage *7+ CKD patients. /rogram and a%stracts

of the +*rd #nnual 0eeting "cientific !-position of the #merican "ociety of 2ephrology

(#"2) $enal ?eek4 2ovem%er =, FF4 Denver, Colorado. /oster "#5C+=.

H. Aunn @5. 2ew agents that stimulate erythropoiesis. Alood. FFR4FI'H=HHR*.#%stract

I. /ak 0, 1opez 0#, a%ayan G, anz T, $ivera ". "uppression of hepcidin during anemia

re6uires erythropoietic activity. Alood. FF=4FH'*R*F*R*.#%stract

*F. Aesara% #, 2issenson #$, "chwartz D, et al. !rythropoiesis sustained months %y the

!/;D&$! %iopump in patients with chronic kidney disease' further results of phase 7

proof of concept trial. /rogram and a%stracts of the +*rd #nnual 0eeting "cientific

!-position of the #merican "ociety of 2ephrology (#"2) $enal ?eek4 2ovem%er =,

FF4 Denver, Colorado. /oster 5 5CRF.

*. &nited "tates $enal Data "ystem. FF #tlas of CKD and !"$D. Gol , #tlas of CKD,

Chapter +, 0or%idity and 0ortality. #vaila%le at' http'77www.usrds.org7atlas.htm. #ccessed

Decem%er , FF.
http://www.medscape.org/medline/abstract/12500228http://www.medscape.org/medline/abstract/12500228http://www.medscape.org/medline/abstract/16105069http://www.medscape.org/medline/abstract/17267740http://www.takeda.com/press/article_36525.htmlhttp://www.medscape.org/medline/abstract/20522670http://www.medscape.org/medline/abstract/17032916http://www.medscape.org/medline/abstract/16882706http://www.usrds.org/atlas.htmhttp://www.medscape.org/medline/abstract/12500228http://www.medscape.org/medline/abstract/16105069http://www.medscape.org/medline/abstract/17267740http://www.takeda.com/press/article_36525.htmlhttp://www.medscape.org/medline/abstract/20522670http://www.medscape.org/medline/abstract/17032916http://www.medscape.org/medline/abstract/16882706http://www.usrds.org/atlas.htm


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Documents

Anemia Management in Chronic Kidney Disease and End