Management Anemia in CKD

7/25/2019 Management Anemia in CKD

http://slidepdf.com/reader/full/management-anemia-in-ckd 1/15

Treatment Issues in Anemia of Chronic Kidney Disease CLINICAL REVIEW, NEPHROLOGY

Wissam Saliba, MD, Samer Antonios, MD, and Joseph Abdallah, MD

From the University of Kansas School of Medicine, Wichita, KS.

ABSTRACT

• Obective! To review the pathophysioloy a!" approa#h to $a!ae$e!t o% #hro!i# &i"!ey "isease

'C()*+relate" a!e$ia

• Methods! Review o% the literat-re

• "es#lts! C() is a! i!#reasi!ly #o$$o! $e"i#al #o!"itio! i! the.NITE) /TATE/ I t is

asso#iate" with a $yria" o% #o$pli#atio!s, a$o! whi#h a!e$ia is perhaps the $ost treata0le

A!e$ia has a hih i$pa#t o! the $or0i"ity a!" $ortality o% patie!ts with C(), $ai!ly 0y i!"-#i! le%t

ve!tri#-lar hypertrophy C()1relate" a!e$ia is pri$arily "-e to erythropoieti! i!s-%%i#ie!#y, 0-t

a0sol-te a!" %-!#tio!al iro! "e%i#ie!#y, iro! restri#tio!, a!" erythropoieti! resista!#e are also %a#tors

I! re#e!t years, hep#i"i! has e$ere" as a! i$porta!t player i! iro! ho$eostasis a!" the

pathophysioloy o% iro! restri#tio! a!" represe!ts a pote!tial taret %or %-t-re therape-ti# approa#hes

Early "ia!osis a!" eval-atio! o% a!e$ia are %-!"a$e!tal i! the $a!ae$e!t o% patie!ts with C()

a!" sho-l" i!#l-"e iro! stat-s assess$e!t Treat$e!t relies o! a #o$0i!atio! o% erythropoieti! a!"

iro! s-pple$e!tatio!, 0-t the opti$al he$olo0i! taret a!" threshol" at whi#h to treat are still

"e0ate"

• $oncl#sion! E%%e#tive treat$e!t o% C()1relate" a!e$ia #a! re"-#e #ar"iovas#-lar #o$pli#atio!s,

slow proressio! o% re!al %ail-re, a!" i$prove 2-ality o% li%e

http://www.jcomjournal.com/treatment-issues-in-anemia-of-chronic-kidney-disease/

http://www.jcomjournal.com/category/clinical-review/

http://www.jcomjournal.com/category/nephrology/

http://www.jcomjournal.com/treatment-issues-in-anemia-of-chronic-kidney-disease/#17982103

http://www.jcomjournal.com/category/clinical-review/

http://www.jcomjournal.com/category/nephrology/


http://www.jcomjournal.com/treatment-issues-in-anemia-of-chronic-kidney-disease/



The prevale!#e o% e!"1stae re!al "isease 'E/R)* i! the.NITE) /TATE/ is i!#reasi! C-rre!tly,

a0o-t 344,444 patie!ts have E/R), a!" this !-$0er is e5pe#te" to rea#h 674,444 0y 8497 :9; This

#oi!#i"es with a! i!#rease i! the prevale!#e o% #hro!i# &i"!ey "isease 'C()*, !ota0ly stae < I!

844<, 9=9 $illio! A$eri#a!s ha" C() 'a0o-t 99> o% the pop-latio!* :8; C-rre!t #lassi%i#atio! o%

C() i!#l-"es pare!#hy$al "a$ae %or staes 9 a!" 8 a!" "e#rease o% lo$er-lar %iltratio! rate

'G?R* rear"less o% pare!#hy$al "a$ae %or staes < a!" hiher :<; 'Table 1* The si!i%i#a!t

!-$0er o% C() patie!ts i$poses a hih #ost 0-r"e! o! the health #are syste$

O!e o% the $ost #halle!i! pro0le$s i! this patie!t pop-latio! is a!e$ia C()1relate" a!e$ia is

"e%i!e" 0y the Natio!al (i"!ey ?o-!"atio! 'N(?* as a he$olo0i! 'H0* level o% less tha! 9<7 @"L i!

$ales a!" less tha! 98 @"L i! %e$ales :; The Natio!al Health a!" N-tritio! E5a$i!atio! /-rveys

%ro$ 9=== to 8448 reporte" that a!e$ia was $ore #o$$o! i! %e$ales, A%ri#a! A$eri#a!s, ol"er

patie!ts '!ota0ly ae B 64 years*, a!" patie!ts with C() staes < a!" a0ove :7; It is well &!ow! that

a!e$ia "evelops earlier i! "ia0eti# patie!ts with C() A0o-t 3> o% stae C() patie!ts with

"ia0etes $ellit-s have a!e$ia, 0-t o!ly a0o-t <> o% stae C() !o!"ia0eti# patie!ts are a!e$i#

:3; I! this arti#le, we review the pathophysioloy a!" #a-ses o% a!e$ia relate" to C() a!" provi"e a

syste$ati# approa#h %or its $a!ae$e!t

PATHOPHSIO!O"

#ormal $rythro%oiesis

.!"ersta!"i! !or$al erythropoiesis helps el-#i"ate the pathophysioloy o% C()1relate" a!e$ia

Healthy re" 0loo" #ell 'RDC* pro"-#tio! re2-ires 0oth erythropoieti! 'EPO* a!" iro! :6; EPO

pro"-#tio! 0y the &i"!ey i!#reases with #ell hypo5ia EPO wor&s early i! the #y#le o% RDC $at-ratio!





0y sti$-lati! the erythroi" 0-rst1%or$i! -!its a!" #olo!y1%or$i! -!its I! #o!trast, iro! is re2-ire"

later i! the #y#le %or the tra!s%or$atio! o% erythro0lasts i!to reti#-lo#ytes

The averae h-$a! 0o"y #o!tai!s a0o-t o% iro!, "istri0-te" 0etwee! the he$olo0i! '8 * a!"

the reti#-lo1e!"othelial syste$ '9 * Aro-!" 84 $ o% iro! %low i!to the plas$a pool "aily %ro$

"estr-#tio! o% se!es#e!t RDCs a!" are -se" 0y the 0o!e $arrow %or pro"-#tio! o% !ew erythro#ytes

I! #o!trast, o!ly a0o-t 9 to 8 $ o% iro! are a0sor0e" every "ay i! the pro5i$al "-o"e!-$ to repla#e

the iro! lost thro-h "es2-a$atio! o% i!testi!al $-#osa #ells :; H-$a! physioloy "oes !ot allow

iro! e5#retio! Iro! a0sorptio! is the sole $e#ha!is$ 0y whi#h iro! stores are physioloi#ally

#o!trolle" :=; .!%ort-!ately, the $e#ha!is$ o% i!testi!al iro! a0sorptio! a!" its re-latio! are poorly

-!"erstoo"

H-$a! #ells #a! ta&e -p iro! thro-h "i%%ere!t $e#ha!is$s :94; '&i'ure 1* ost #ells -se the

tra!s%erri! re#eptor %or -pta&e o% iro! i! the %or$ o% iro!1sat-rate" tra!s%erri! Other #ells -se the

"ivale!t $etal tra!sporter 9 ')T9* %or -pta&e o% %ree iro! a#rophaes -se the iro! provi"e" 0y

phao#ytosis o% se!es#e!t RDCs The $aFority o% #ells -se iro! %or their ow! p-rposes, s-#h as

sy!thesis o% he$olo0i!, e!y$es, a!" other protei!s However, %ew #ells are spe#ialie" iro!

e5porters these i!#l-"e the "-o"e!al e!tero#ytes, hepato#ytes, $a#rophaes, a!" e$0ryo!i# or

pla#e!tal #ells )espite the vario-s $e#ha!is$s %or iro! -pta&e, iro!1e5porti! #ells have o!ly o!e

way to e5port iro! a 98 tra!s$e$0ra!e1se$e!t protei! #alle" %erroporti! :99; ?erroporti! is the o!ly

&!ow! iro!1e5porter i! verte0rates It is i!hi0ite" 0y hep#i"i!, #-rre!tly #o!si"ere" as the $aster o%

iro! ho$eostasis



Hep#i"i! was "is#overe" i! 8444 It is a s$all pepti"e hor$o!e pro"-#e" 0y the liver 'Hep1* a!" has

0a#teri#i"al properties '1#i"i!* Rivera et al :98; showe" that $i#e that were i!traperito!eally i!Fe#te"

with hep#i"i! a#2-ire" e5tre$ely low plas$a iro! level %or -p to ho-rs a%ter i!Fe#tio! Hep#i"i!

0i!"s to %erroporti! i! iro!1e5porti! #ells a!" #a-ses its i!ter!aliatio! a!" "estr-#tio!, preve!ti!

the e%%l-5 o% iro! i!to the plas$a iro! pool There%ore, whe! sti$-late" 0y hep#i"i!, the e!tero#ytes,

the hepato#ytes a!" the $a#rophaes #a!!ot e5port iro! Hep#i"i! itsel% is sti$-late" 0y

i!%la$$atory states a!" iro! loa" a!" i!hi0ite" 0y erythropoieti# si!als :9<; '&i'ure (*

$rythro%oiesis in Renal &ailure

As the &i"!ey %-!#tio! "e#li!es, the "isease" &i"!eys 0e#o$e -!a0le to pro"-#e s-%%i#ie!t 2-a!tities

o% erythropoieti! EPO "e%i#ie!#y is well "o#-$e!te" i! C() patie!ts :9;, 0-t its $a!it-"e "oes !ot

appear to 0e relate" to the level o% &i"!ey %-!#tio! A!e$ia o% C() is $-lti%a#torial Altho-h tr-e

EPO "e%i#ie!#y is prese!t i! $ost patie!ts with C(), several other %a#tors #o!tri0-te to the a!e$ia

Reti#-lo1e!"othelial 0lo#&a"e It is well &!ow! that C() is a low1ra"e #hro!i# i!%la$$atory state "-e

to i$0ala!#e o% pro1o5i"a!ts a!" a!tio5i"a!ts :97; ar&ers o% i!%la$$atio! s-#h as C1rea#tive



protei! a!" i!terle-&i!13 levels are o%te! elevate" This lea"s to sti$-latio! o% hep#i"i! pro"-#tio! 0y

the hepato#ytes The "e#rease" re!al #leara!#e o% hep#i"i! "-e to %aili! &i"!eys i!#reases its ser-$

level eve! %-rther This i!#rease i! hep#i"i! levels #a-ses EPO resista!#e a!" iro! restri#tio!, as

e5plai!e" a0ove This is o%te! re%erre" to as reti#-lo1e!"othelial 0lo#&a"e

A0sol-te iro! "e%i#ie!#y A0sol-te iro! "e%i#ie!#y is o%te! prese!t i! patie!ts i!itiati! he$o"ialysis,

a!" reple!ishi! iro! stores is #r-#ial i! the $a!ae$e!t o% their a!e$ia A0sol-te iro! "e%i#ie!#y

"evelops i! C() patie!ts "-e to $-ltiple %a#tors i!#l-"i! "e#rease i! i!testi!al a0sorptio! o% iro!,

o##-lt astroi!testi!al 0lee"i! "-e to platelet $al%-!#tio! a!" i!#rease" i!#i"e!#e o% arterio1ve!o-s

$al%or$atio!, a!" 0loo" loss %ro$ repetitive la0oratory testi! ?-rther$ore, the i!itiatio! o%

erythropoieti!1sti$-lati! ae!ts 'E/A* re2-ires lare a$o-!ts o% store" iro! :93; I! %a#t, raisi! H0

%ro$ 94 @"L to 9< @"L re2-ires the %or$atio! o% 974 o% H0 'esti$ate" total 0loo" vol-$e J 7 L*

/i!#e H0 is 4<> iro!, the %or$atio! o% 974 o% H0 wo-l" re2-ire 794 $ o% iro!, whi#h is $ore tha!

hal% o% the iro! store" i! the reti#-lo1e!"othelial syste$

?-!#tio!al iro! "e%i#ie!#y ?-!#tio!al iro! "e%i#ie!#y or i!e%%e#tive erythropoiesis is #hara#terie" 0y

the prese!#e o% a"e2-ate iro! stores 0-t a slow iro! $o0iliatio! rate i!to the site o% erythropoiesis

whe! E/A is starte" I! other ter$s, iro! tra!sporters %ail to &eep -p with the i!#rease" rate o%

erythropoiesis It is parti#-larly i$porta!t to "i%%ere!tiate 0etwee! %-!#tio!al iro! "e%i#ie!#y a!" iro!

restri#tio! thro-h reti#-lo1e!"othelial 0lo#&a"e, as the %or$er is respo!sive to iro! therapy while the

latter is !ot This will 0e "is#-sse" later i! the arti#le

Other %a#tors $ay #o!tri0-te to C()1relate" a!e$ia s-#h as the prese!#e o% -re$i# i!hi0itors,

vita$i! D98 or %oli# a#i" "e%i#ie!#y, a!" re"-#e" RDC li%e

O)TCO*$S

A!e$ia is asso#iate" with a! i!#rease i! $ortality a!" $or0i"ity o% patie!ts with C() /y$pto$s are

si$ilar to those %o-!" i! the !or$al pop-latio! a!" i!#l-"e a!ore5ia, %ati-e, "e#rease" #o!itio! a!"

$e!tal a#-ity, sleep "ist-r0a!#es, i!#rease" ris& o% hospitaliatio!, a!" prolo!e" hospital le!th o%

stay I! a""itio!, a!e$ia is a! i$porta!t #a-se o% le%t ve!tri#-lar hypertrophy 'LVH* a!" #o!estive

heart %ail-re "-e to hypo5ia a!" i!#rease" heart strai! :96; A "e#rease o% H0 0y 9 $@"L $ay #a-se

a 84> to 4> i!#rease i! le%t ve!tri#-lar "ilatatio! LVH $ay "evelop i! patie!ts with H0 levels as low

as 98 $@"L oreover, oha!ra$ et al :9; i"e!ti%ie" a!e$ia as a! i!"epe!"e!t ris& %a#tor %or

proressio! o% "ia0eti# !ephropathy to E/R), with a! a"F-ste" haar" ratio o% 9== i! patie!ts with

H0 K 99< @"L



$+A!)ATIO#

A##or"i! to the (i"!ey )isease O-t#o$es -ality I!itiative '(@)OI* -i"eli!es :;, a!e$ia

s#ree!i! sho-l" 0e "o!e i! all patie!ts with C() rear"less o% stae or etioloy H0 levels sho-l" 0e

$eas-re" at least a!!-ally The eval-atio! o% patie!ts with a!e$ia a!" C() sho-l" i!#l-"e

$eas-re$e!t o% RDC i!"i#es, reti#-lo#yte #o-!t, %e#al o##-lt 0loo" test, a!" assess$e!t o% iro!

stat-s

Iro! $a!ae$e!t is a &ey to s-##ess%-l a!e$ia treat$e!t, 0e#a-se it has 0ee! show! to i!#rease H0

level a!" "e#rease EPO resista!#e a!" EPO "ose I! %a#t, the a""itio! o% iro! to EPO therapy was

asso#iate" with a !et savi! o% M9<=4 per 9 @"L i!#rease i! H0 over a 981wee& perio" :9=; ?erriti!

a!" tra!s%erri! sat-ratio! 'T/AT* are the $ost wi"ely -se" iro! $ar&ers Doth are easy to -se, o%

$o"erate #ost, a!" wi"ely availa0le However, they have a hih varia0ility a!" a poor a##-ra#y

&erritin

?erriti! provi"es a! i!"ire#t $eas-re o% the iro! store" i! the reti#-lo1e!"othelial syste$ I! patie!ts

with !o C(), a %erriti! level K 97 !@$L is i!"i#ative o% iro! "e%i#ie!#y a!e$ia ?erriti! is also a!

i!te!se positive a#-te phase rea#ta!t I! C() patie!ts or patie!ts with i!%la$$atory or i!%e#tio-s

#o!"itio!s, a %erriti! level -p to 344 !@$L $ay 0e prese!t i! the setti! o% iro! "e%i#ie!#y a!e$ia

This has a#t-ally 0ee! ill-strate" i! several st-"ies where the se!sitivity o% %erriti! %or iro! "e%i#ie!#y

a!e$ia i! C() patie!ts was less tha! 74> :84,89; However, the sa$e st-"ies showe" a very hih

spe#i%i#ity This $ea!s that iro! "e%i#ie!#y a!e$ia is al$ost always prese!t i! patie!ts with low %erriti!

level

TSAT

Tra!s%erri! sat-ratio! is #al#-late" as the plas$a iro! level "ivi"e" 0y total iro! 0i!"i! #apa#ity

'TIDC* It provi"es a $eas-re o% #ir#-lati! iro! T/AT has poor to $o"erate a##-ra#y as well "-e to

the hih varia0ility o% ser-$ iro! I! a""itio!, TIDC is a !eative a#-te phase rea#ta!t a!" its level

"e#reases i! i!%la$$atory #o!"itio!s It is also a%%e#te" 0y !-tritio!al stat-s a!" $ay 0e low i!

patie!ts with $al!-tritio!

/everal !ewer tests are #-rre!tly availa0le The reti#-lo#yte H0 #o!te!t 'CHr* test provi"es a "ire#t

$eas-re o% iro! at the level o% reti#-lo#ytes /everal st-"ies have show! CHr to 0e a $ore sta0le a!"



$ore se!sitive $ar&er o% iro! "e%i#ie!#y tha! %erriti! or tra!s%erri! i! EPO1treate" he$o"ialysis

patie!ts :88; However, the #li!i#al -tility o% CHr i! patie!ts with C() has !ot 0ee! esta0lishe" Other

tests s-#h as per#e!tae o% hypo#hro$i# RDCs a!" sol-0le tra!s%erri! re#eptor are still

i!vestiatio!al a!" their -se i! C() patie!ts is !ot yet i!"i#ate" A hep#i"i! level $ay pote!tially 0e

-se%-l i! iro! $a!ae$e!t i! C() patie!ts :8<; Theoreti#ally, it $ay "isti!-ish 0etwee! reti#-lo1

e!"othelial 0lo#&a"e 'hih hep#i"i! level* a!" %-!#tio!al iro! "e%i#ie!#y a!e$ia 'low hep#i"i! level*,

whi#h is o!e o% the $ost #halle!i! #o!"itio!s i! iro! stat-s assess$e!t However, o!ly li$ite" "ata

are #-rre!tly availa0le a!" $ore st-"ies are !ee"e" to assess the #li!i#al -tility o% this test

*A#A"$*$#T

Previo-sly, RDC tra!s%-sio! a!" a!"roe! therapy were theONLY OPTION/ %or a!e$i# C()

patie!ts The ./ ?oo" a!" )r- A"$i!istratio! '?)A* approval o% EPO revol-tio!ie" $a!ae$e!t

However, the ti$i! o% the treat$e!t, the H0 taret, the T/AT@%erriti! tarets a!" i!"i#atio!s %or RDC

tra!s%-sio!s are still hot topi#s a!" re#o$$e!"atio!s #ha!e every year C-rre!tly, the

$a!ae$e!t o% a!e$ia o% C() is #o$ple5 a!" #o!sists o% a #o$0i!atio! o% erythropoiesis1

sti$-lati! ae!ts 'E/A* a!" iro! therapies

$rythro%oiesis,Stimulatin' A'ents

The i"e!ti%i#atio! a!" #lo!i! o% the h-$a! erythropoieti! e!e le" to the pro"-#tio! o% re#o$0i!a!t

erythropoieti! 'EPO* It was approve" 0y the ?)A %or treat$e!t o% a!e$ia i! E/R) patie!ts i! 9==

/hortly a%ter, it was approve" %or C() patie!ts C-rre!tly, <4> o% pre"ialysis patie!ts -se a! E/A %or

a!e$ia treat$e!t However, -p to 37> o% C() patie!ts have a H0 K 99 @"L a!" $ay 0e elii0le %or

E/A -se :8; The -se o% E/A has res-lte" i! si!i%i#a!t #li!i#al 0e!e%its, i!#l-"i! #orre#tio! o%

a!e$ia, "e#rease o% the !ee" %or 0loo" tra!s%-sio!s, i$prove" 2-ality o% li%e a!" level o% e!ery,

"e#rease" LVH, a!" possi0ly "e#rease" $ortality E/A #a! 0e a"$i!istere" either i!trave!o-sly 'IV*

or s-0#-ta!eo-sly '/*, a!" the "ose $ay 0e ive! o!#e wee&ly or less %re2-e!tly Re#e!tly, several

st-"ies have show! that the -se o% E/A i! patie!ts with a#tive #a!#er $ay shorte! s-rvival a!"

i!#rease the ris& o% t-$or rowth This was espe#ially si!i%i#a!t with hea" a!" !e#& #a!#er :87;,

$etastati# 0reast #a!#er :83; a!" #ervi#al #a!#er :86;

The 8 $ost #o$$o!ly -se" E/As i! the.NITE) /TATE/ are epoieti! al%a a!" "ar0epoieti! al%a

The latter is #hara#terie" 0y a <1%ol" lo!er hal%1li%e a!" reater 0ioloi#al a#tivity a!" $ay 0e

a"$i!istere" less %re2-e!tly tha! epoieti! al%a However, "ar0epoieti! al%a is al$ost twi#e as

e5pe!sive as epoieti! al%a I! a st-"y o% 933 C() patie!ts ra!"o$ly assi!e" to either epoieti! al%a or








"ar0epoieti! al%a, Lo#atelli et al "e$o!strate" !o si!i%i#a!t "i%%ere!#e i! $ortality or sa%ety pro%ile

:8;

Newer E/As i!#l-"i! #o!ti!-o-s erythropoiesis re#eptor a#tivator 'CERA*, he$ati"e a!" hypo5ia1

i!"-#i0le %a#tor 'HI?* sta0iliers are !ot yet ?)A1approve" a!" their sa%ety a!" #li!i#al -tility are still

to 0e "eter$i!e"

The (1)OI -i"eli!es rear"i! the -se o% E/A i! C() patie!ts are as %ollows :;

• E/A $ay 0e a"$i!istere" s-0#-ta!eo-sly i! C() patie!ts, while IV a"$i!istratio! is pre%erre" i!

"ialysis patie!ts

• The less %re2-e!t a"$i!istratio! o% E/A is %avore", parti#-larly i! C() patie!ts

Iron Pre%arations

Iro! assess$e!t sho-l" always 0e "o!e 0e%ore the start o% E/A therapy, a!" iro! "e%i#ie!#y sho-l"

0e treate" /everal oral a!" IV iro! preparatio!s are availa0le i! the.NITE) /TATE/ 'Table

( a!" Table -* Oral iro! sho-l" 0e ive! 0etwee! $eals i% tolerate", as its a0sorptio! $ay 0e

lowere" 0y %oo" a!" a!ta#i"s The e%%i#a#y a!" sa%ety o% IV iro! vers-s oral iro! %or treat$e!t o% C()

patie!ts has 0ee! eval-ate" i! several st-"ies A $eta1a!alysis o% 3 trials i!#l-"i! a!e$i# patie!ts

with C() '!ot o! he$o"ialysis* showe" $i!i$al a"va!taes o% IV iro! 0-t hiher #ost a!" $ore si"e

e%%e#ts :8=; ?-rther$ore, re#-rre!t i!%-sio!s o% IV iro! i! C() patie!ts Feopar"ie the %-t-re -se o%

vei!s %or arteriove!o-s %ist-las /i"e e%%e#ts %ro$ IV iro! %or$-latio!s $ay i!#l-"e a!aphyla5is,

sepsis, re!al i!F-ry, a!" iro! to5i#ity ?er-$o5ytol is a! -ltras$all s-perpara$a!eti# iro! o5i"e

!a!oparti#le #oate" with a se$i1sy!theti# #ar0ohy"rate a!" "esi!e" to $i!i$ie i$$-!oloi#

se!sitivity :<4; It #a! 0e rapi"ly i!Fe#te" '794 $ over 96 se#o!"s* a!" has %ewer si"e e%%e#ts tha!





other iro! preparatio!s It $iht 0e a !ewer alter!ative to tra"itio!al preparatio!s However, the

#li!i#al e5perie!#e with %er-$o5ytol is still li$ite" I! a""itio!, %er-$o5ytol treat$e!ts are very #ostly

The (1)OI -i"eli!es rear"i! the -se o% iro! i! C() patie!ts are as %ollows :;

• The ro-te o% a"$i!istratio! o% iro! #a! 0e either oral or IV i! patie!ts with C() '!ot o!

"ialysis*, while the IV ro-te is pre%erre" %or patie!ts o! "ialysis

• Iro! stat-s tests sho-l" 0e per%or$e" every $o!th "-ri! i!itial E/A treat$e!t, a!" every <

$o!ths "-ri! sta0le E/A treat$e!t

Timin' of Treatment

The ti$i! o% treat$e!t is a "e0ata0le topi# /t-"ies have show! a #lear asso#iatio! 0etwee! a!e$ia

a!" LVH, 0-t the level o% H0 at whi#h #orre#tio! o% the a!e$ia #a! reverse LVH is still to 0e

"eter$i!e" This 2-estio! was a""resse" i! a $eta1a!alysis o% 97 st-"ies i!volvi! 96<9 C() a!"

E/R) patie!ts treate" 0y EPO e5a$i!i! le%t ve!tri#-lar $ass i!"e5 'LVI* #ha!es with treat$e!t

:<9; I! patie!ts with severe a!e$ia 'H0 K 94 $@"L*, raisi! H0 to 98 @"L was asso#iate" with a

re"-#tio! o% LVI 0y a! esti$ate" e%%e#t sie o% <86< @$8 However, i! patie!ts with $o"erate

a!e$ia 'H0 Q 94 $@"L*, E/A treat$e!t was asso#iate" with !o!si!i%i#a!t #ha!es i! LVI E/A

treat$e!t is &!ow! to i$prove 2-ality o% li%e i! patie!ts with C() However, it $ay i!#rease the

thro$0oti# ris&s

The (1)OI -i"eli!es "i" !ot spe#i%y a parti#-lar H0 level at whi#h E/A therapy sho-l" 0e starte"

0-t rather le%t it to 0e "eter$i!e" 0y the #li!i#ia! 0ase" o! 0ala!#i! ris&s a!" 0e!e%its A 8446

-p"ate o% the (1)OI -i"eli!es state" that sele#tio! o% the H0 level at whi#h E/A therapy is i!itiate"

sho-l" i!#l-"e #o!si"eratio! o% pote!tial 0e!e%its 'i!#l-"i! i$prove$e!t i! 2-ality o% li%e a!"

avoi"a!#e o% tra!s%-sio!* a!" pote!tial har$s 'i!#l-"i! the ris& o% li%e1threate!i! a"verse eve!ts*



Hemo'lobin Tar'et

The H0 taret is "e%i!e" as the H0 val-e that is #li!i#ally opti$al %or ea#h patie!t 0ase" -po! the

parti#-lar #ir#-$sta!#es It is a s-0Fe#t o% "e0ate 0etwee! the ?)A a!" pra#ti#e -i"eli!e

re#o$$e!"atio!s The (1)OI -i"eli!es the$selves are #o!sta!tly #ha!i! ea#h year 0e#a-se o%

#o!%li#ti! res-lts o% !ew st-"ies The TREAT st-"y, p-0lishe" i! O#to0er 844=, will pro0a0ly

i!%l-e!#e pra#ti#e -i"eli!es a!" !ew re#o$$e!"atio!s

/everal st-"ies were "o!e to assess the H0 taret i! patie!ts with C() who are !ot o! "ialysis A

!-$0er o% s$all st-"ies #o!"-#te" i! the 9=4s o%te! la#&e" pla#e0o ro-ps a!" s-pporte" the

s-estio! that E/A therapy to hih H0 tarets provi"es s-rvival 0e!e%its However, !ew ra!"o$ie"

#o!trolle" trials have show! -!e5pe#te" res-lts

I! the Corre#tio! o% He$olo0li! a!" O-t#o$es i! Re!al I!s-%%i#ie!#y 'CHOIR* trial, 9<8 patie!ts

with C() a!" a!e$ia were ra!"o$ie" %or E/A treat$e!t to either a taret H0 o% 9<7 @"L or 99<

@"L :<8; The hih H0 ro-p ha" a hiher #o$posite e!"poi!t o% "eath, $yo#ar"ial i!%ar#tio!, stro&e,

a!" hospitaliatio! %or CH? #o$pare" with the low H0 ro-p, with a haar" ratio o% 9< The

"i%%ere!#e i! #o$posite e!"poi!t was 0la$e" o! os#illatio! a!" rapi" i!#rease i! H0 levels a%ter -si!

E/A as well as possi0le "a$ae to e!"otheli-$ a!" s$ooth $-s#le #ells "-e to hiher E/A "ose

The CHOIR trial, however, ha" so$e li$itatio!s i!#l-"i! $ore -!"erlyi! #o$or0i" #o!"itio!s i! the

hih H0 ro-p a!" hih with"rawal rate

The Car"iovas#-lar Ris& Re"-#tio! 0y Early A!e$ia Treat$e!t with Epoeti! Deta 'CREATE* trial

i!volve" 34< C() patie!ts assi!e" to a !or$al '9<+97 @"L* or s-0!or$al '947+997 @"L* H0

ra!e :<<; No "i%%ere!#e i! #ar"iovas#-lar eve!ts, s-rvival, LVH, or rate o% C() proressio! was

see! 0etwee! the 8 ro-ps however, the !or$al H0 ra!e patie!ts ha" a 0etter 2-ality o% li%e

The Trial to Re"-#e Car"iovas#-lar Eve!ts with Ara!esp Therapy 'TREAT* trial was the larest st-"y

"o!e o! a!e$i# patie!ts with C() :<; I! this st-"y i!volvi! 4< patie!ts with "ia0etes, C(), a!"

a!e$ia, P%e%%er et al ra!"o$ly assi!e" patie!ts to either "ar0epoieti! al%a with a taret H0 o% 9< @"L

or pla#e0o with res#-e "ar0epoeti! al%a whe! the he$olo0i! level %alls 0elow = @"L There was !o

si!i%i#a!t "i%%ere!#e 0etwee! the 8 ro-ps i! the overall rates o% the pri$ary e!"poi!ts 'o% "eath or a

#ar"iovas#-lar eve!t or o% "eath or e!"1stae re!al "isease* /-rprisi!ly, $ore stro&es o##-rre" i!

patie!ts assi!e" to "ar0epoieti! al%a, with a haar" ratio o% 9=8 The TREAT st-"y, however,

showe" "e#rease" !ee" %or tra!s%-sio! a!" $o"est i$prove$e!t i! patie!t1reporte" %ati-e i! the

"ar0epoeti! al%a ro-p as #o$pare" with the pla#e0o ro-p



I! #o!#l-sio!, the opti$al H0 taret is yet to 0e "eter$i!e" What is #lear %or !ow is that hiher H0

tarets are !ot 0e!e%i#ial a!" pote!tially har$%-l ore #o!servative H0 tarets 'H0 K 98 @"L* sho-l"

0e eval-ate" thro-h well1"esi!e" ra!"o$ie" #o!trolle" st-"ies The 8443 (1)OI -i"eli!es

were p-0lishe" 0e%ore the e!"i! o% the < st-"ies $e!tio!e" a0ove A 8446 -p"ate %ollowe" the

CREATE a!" CHOIR trial :;

• H0 taret i! C() patie!ts sho-l" e!erally 0e 0etwee! 99 a!" 98 @"L

• H0 taret sho-l" !ot e5#ee" 9< @"L

Tar'ets of &erritin.TSAT

.!%ort-!ately, there are !o ra!"o$ie" #o!trolle" trials o! patie!ts with C() '!ot o! "ialysis* The

#-rre!t (1)OI -i"eli!es are e5trapolate" %ro$ st-"ies #o!"-#te" o! "ialysis patie!ts a!"

re#o$$e!" tarets that re%le#t a #o!servative esti$atio! o% e%%i#a#y :;

• /-%%i#ie!t iro! sho-l" 0e a"$i!istere" to $ai!tai! %erriti! B 944 !@$L a!" T/AT B 84> i!

patie!ts with C()

• /-%%i#ie!t iro! sho-l" 0e a"$i!istere" to $ai!tai! %erriti! B 844 !@$L a!" T/AT B 84> 'or

CHr B 8= p@#ell* i! patie!ts who are o! "ialysis

/hat if TSAT 0 (2 and &erritin 3 4 n'.m!5

This is a 2-estio! o% "i%%ere!tiati! %-!#tio!al iro! "e%i#ie!#y 'where iro! therapy is e%%e#tive* a!" iro!

restri#tio! %ro$ i!%la$$atio! a!" i!#rease" hep#i"i! level 'where iro! therapy is !ot 0e!e%i#ial a!"

$ay 0e har$%-l* The s-0Fe#t o% -pper level o% %erriti! was raise" 0y the )ialysis Patie!ts Respo!se to

IV Iro! with Elevate" ?erriti! ')RIVE* trial :<7; It i!volve" patie!ts o! he$o"ialysis with H0 K 99 @"L,

%erriti! 744 to 9844 !@$L, T/AT K 87>, a!" EPO "osae B 88,744 i!ter!atio!al -!its@w& I! the

)RIVE trial, Coy!e et al ra!"o$ly assi!e" 9< parti#ipa!ts to either IV %erri# l-#o!ate 'S "oses* or

pla#e0o There was a reater H0 i!#rease i! the IV iro! ro-p tha! i! the #o!trol ro-p, as well as a

reater i!#rease i! %erriti! a!" T/AT oreover, there was !o si!i%i#a!t "i%%ere!#e i! the a"verse

eve!ts 0etwee! the 8 ro-ps

The la#& o% st-"ies relati! sa%ety to a spe#i%i# hih %erriti! level $a&es the a!swer to the a0ove

2-estio! aai! i!"ivi"-alie" a!" 0ase" o! patie!t #hara#teristi#s The

(1)OI -i"eli!es rear"i! this iss-e are as %ollows :;

• There is i!s-%%i#ie!t evi"e!#e to re#o$$e!" ro-ti!e a"$i!istratio! o% IV iro! i% %erriti! B 744

!@$L



• Whe! %erriti! B 744 !@$L, "e#isio!s rear"i! IV iro! a"$i!istratio! sho-l" weih E/A

respo!sive!ess, H0 a!" T/AT level, a!" the patie!ts #li!i#al stat-s

I! other ter$s, #he#& patie!ts %or i!%e#tio! or other i!%la$$atory #o!"itio!s 'where IV iro! is har$%-l*,

#he#& C1rea#tive protei!, CHr 'i% availa0le*, H0@EPO "ose ratio, a!" #o!si"er IV iro! i! i!"ivi"-alie"

patie!ts

Indications for Blood Transfusion

The pa#&e" re" 0loo" #ells tra!s%-sio! i! C() patie!ts sho-l" 0e avoi"e" as $-#h as possi0le It is

well &!ow! that tra!s%-sio!s $ay i!"-#e the %or$atio! o% a!ti0o"ies to h-$a! le-&o#ytes a!tie!

'HLA* that #a! re"-#e the s-##ess o% &i"!ey tra!spla!tatio! i! the %-t-re :<3; I! a""itio!, tra!s%-sio!s

$ay #a-se hypervole$ia a!" sy$pto$s o% #o!estive heart %ail-re, parti#-larly i! el"erly patie!ts

The (1)OI -i"eli!es state that !o si!le H0 level sho-l" F-sti%y or re2-ire tra!s%-sio! :; Ris&s a!"

0e!e%its o% tra!s%-sio! therapy sho-l" 0e #o!si"ere" i! i!"ivi"-alie" patie!ts

S)**AR A#D R$CO**$#DATIO#S

A!e$ia has 0ee! i$pli#ate" i! the sy$pto$s, $or0i"ity, a!" pro!osis asso#iate" with re"-#e"

&i"!ey %-!#tio! The etioloy o% C()1relate" a!e$ia is $-lti%a#torial I! all C() patie!ts, #o$plete

0loo" #o-!t, $ea! #orp-s#-lar vol-$e, reti#-lo#yte #o-!t, vita$i! D98, %oli# a#i", %erriti!, T/AT, a!"

possi0ly CHr 'i% availa0le* sho-l" 0e $eas-re" as part o% a!e$ia wor&-p Iro! "e%i#ie!#y, i% prese!t,

sho-l" 0e treate" a!" its #a-ses esta0lishe" I% H0 is less tha! 99 @"L, E/A therapy i!itiatio! sho-l"

0e "is#-sse" with the patie!t with %o#-s o! pote!tial ris&s a!" 0e!e%its It appears %ro$ availa0le "ata

that hiher H0 tarets are !ot 0e!e%i#ial a!" pote!tially har$%-l The #-rre!t (1)OI -i"eli!es

a"vise %or a H0 taret o% 99 to 98 @"L witho-t e5#ee"i! 9< @"L La0oratory testi! sho-l" 0e

repeate" $o!thly -!til E/A "ose is sta0le H0 level a!" iro! $ar&ers sho-l" 0e %ollowe" every <

$o!ths "-ri! sta0le E/A treat$e!t

$orrespondin% a#thor! Wissam Saliba, MD, &&'( )#ann )n., Apt. &*+, Madison, W -+'+,

saliba/issam0hotmail.com.

Financial disclos#res! 1one.

A#thor contrib#tions! conception and desi%n, WS2 analysis and interpretation of data, WS, SA, JA2

draftin% of article, WS, SA, JA2 administrative or technical s#pport, WS, SA, JA.



R$&$R$#C$S

9 Gil0ertso! )T, Li- , U-e L, et al ProFe#ti! the !-$0er o% patie!ts with e!"1stae re!al "isease

i! the.NITE) /TATE/ to the year 8497 A$ /o# Nephrol 844793<6<3+9

8 Coresh , Astor DC, Gree!e T, et al Prevale!#e o% #hro!i# &i"!ey "isease a!" "e#rease" &i"!ey

%-!#tio! i! the a"-lt ./ pop-latio! Thir" Natio!al Health a!" N-tritio! E5a$i!atio! /-rvey A$

(i"!ey )is 844<99+98

< Poio E), R-le A) A #riti#al eval-atio! o% #hro!i# &i"!ey "isease1sho-l" isolate" re"-#e"

esti$ate" lo$er-lar %iltratio! rate 0e #o!si"ere" a "isease Nephrol )ial Tra!spla!t 844=83=+

644

()OI #li!i#al pra#ti#e -i"eli!es a!" #li!i#al pra#ti#e re#o$$e!"atio!s %or a!e$ia i! #hro!i#

&i"!ey "isease A$ (i"1!ey )is 84436'7 /-ppl <*/99+97

7 Ce!ters %or )isease Co!trol a!" Preve!tio! Natio!al Ce!ter %or Health /tatisti#s Natio!al Health

a!" N-tritio! E5a$i!atio! /-rvey )ata Hyattsville, ) ./ )epart$e!t o% Health a!" H-$a!

/ervi#es Availa0le at www#"#ov@!#hs@!ha!esht$

3 Tho$as C, a#Isaa# R, Tsala$a!"ris C, et al .!re#o!ie" a!e$ia i! patie!ts with "ia0etes a

#ross1se#tio!al s-rvey )ia0etes Care 844<83993+=

6 Dro#& H, Halli"ay W, Pippar" , Powell LW, e"itors Iro! $eta0olis$ i! health a!" "isease

Phila"elphia /a-!"ers 9==

Ga! T Iro! ho$eostasis %itti! the p-le pie#es toether Cell eta0 84468+=4

= A!"rews NC )isor"ers o% iro! $eta0olis$ N E!l e" 9===<99=3+=7

94 Ga! T ole#-lar #o!trol o% iro! tra!sport A$ /o# Nephrol 84469<=+44

99 )o!ova! A, Li$a CA, Pi!&-s L, et al The iro! e5porter %erroporti!@/l#4a9 is esse!tial %or iro!

ho$eostasis Cell eta0 844799=9+844

98 Rivera /, Li- L, Ne$eth E, et al Hep#i"i! e5#ess i!"-#es the se2-estratio! o% iro! a!"

e5a#er0ates t-$or1asso#iate" a!e$ia Dloo" 844794796=6+48






9< Ga! T, Ne$eth E Iro! i$ports IV Hep#i"i! a!" re-latio! o% 0o"y iro! $eta0olis$ A$

Physiol Gastroi!test Liver Physiol 84438=4G9==+84<

9 )o!!elley /, /hah DE Erythropoieti! "e%i#ie!#y i! hypore!i!e$ia A$ (i"!ey )is 9===<<=6+

7<

97 O0er DP, #e!a$i! E, L-#as ?L, et al I!#rease" prevale!#e o% o5i"a!t stress a!"

i!%la$$atio! i! patie!ts with $o"1erate to severe #hro!i# &i"!ey "isease (i"!ey I!t 84437944=+

93

93 ?ish0a!e / Iro! $a!ae$e!t i! !o!"ialysis1"epe!"e!t C() A$ (i"!ey )is 8446=6<3+<

96 etivier ?, ar#hais /, G-eri! AP, et al Pathophysioloy o% a!ae$ia %o#-s o! the heart a!"

0loo" vessels Nephrol )ial Tra!spla!t 844497 /-ppl <9+

9 oha!ra$ A, Xha! X, /hahi!%ar /, et al A!e$ia a!" e!"1stae re!al "isease i! patie!ts with

type 8 "ia0etes a!" !ephropathy (i"!ey I!t 8443399<9+

9= Pii LT, D-! T, Coy!e )W, et al ?erri# l-#o!ate treat$e!t provi"es #ost savi!s i! patie!ts

with hih %erriti! a!" low tra!s%erri! sat-ratio! (i"!ey I!t 844697+=7

84 (ala!tar1Xa"eh (, H%%&e! D, WZ!s#h H, et al )ia!osis o% iro! "e%i#ie!#y a!e$ia i! re!al %ail-re

patie!ts "-ri! the post1erythropoieti! era A$ (i"!ey )is 9==7838=8+=

89 ?ish0a!e /, (owals&i EA, I$0ria!o L, aesa&a ( The eval-atio! o% iro! stat-s i! he$o"ialysis

patie!ts A$ /o# Nephrol 9==36837+6

88 ?ish0a!e /, /hapiro W, )-t&a P, et al A ra!"o$ie" trial o% iro! "e%i#ie!#y testi! strateies i!

he$o"ialysis patie!ts (i"!ey I!t 844934843

8< Yo-! D, Xarits&y Hep#i"i! %or #li!i#ia!s Cli! A$ /o# Nephrol 844=9<+6

8 U-e L, /t Peter WL, E00e! P, et al A!e$ia treat$e!t i! the pre1E/R) perio" a!" asso#iate"

$ortality i! el"erly patie!ts A$ (i"!ey )is 84484997<

87 He!&e , Lasi R, R-0e C, et al Erythropoieti! to treat hea" a!" !e#& #a!#er patie!ts with

a!ae$ia -!"eroi! ra"iotherapy ra!"o$ise", "o-0le10li!", pla#e0o1#o!trolle" trial La!#et

844<<389877+34



83 Leyla!"1o!es D, /e$ilaov V, Pawli#&i , et al ai!tai!i! !or$al he$olo0i! levels with

epoeti! al%a i! $ai!ly !o!a!e$i# patie!ts with $etastati# 0reast #a!#er re#eivi! %irst1li!e

#he$otherapy a s-rvival st-"y Cli! O!#ol 84478<7=34+68

86 Tho$as G, Ali /, Hoe0ers ?, et al Phase III trial to eval-ate the e%%i#a#y o% $ai!tai!i!

he$olo0i! levels a0ove 984 @"L with erythropoieti! vs a0ove 944 @"L witho-t erythropoieti! i!

a!e$i# patie!ts re#eivi! #o!#-rre!t ra"iatio! a!" #isplati! %or #ervi#al #a!#er Gy!e#ol O!#ol

84494<96+87

8 Lo#atelli ?, Olivares , Wal&er R, et al Novel erythropoiesis sti$-lati! protei! %or treat$e!t o%

a!e$ia i! #hro!i# re!al i!s-%%i#ie!#y (i"!ey I!t 84493469+6

8= Roe!1Xvi D, Ga%ter1Gvili A, Pa-l , et al I!trave!o-s vers-s oral iro! s-pple$e!tatio! %or the

treat$e!t o% a!e$ia i! C() syste$ati# review a!" $eta1a!alysis A$ (i"!ey )is 84478=6+

=43

<4 Prove!a!o R, /#hiller D, Rao , et al ?er-$o5ytol as a! i!trave!o-s iro! repla#e$e!t therapy

i! he$o"ialysis patie!ts Cli! A$ /o# Nephrol 844=<3+=<

<9 Par%rey P/, La-ve , Latre$o-ille1Via- ), Le%e0vre P Erythropoieti! therapy a!" le%t ve!tri#-lar

$ass i!"e5 i! C() a!" E/R) patie!ts a $eta1a!alysis Cli! A$ /o# Nephrol 844=677+38

<8 /i!h A(, /#e#h L, Ta! (L, et al Corre#tio! o% a!e$ia with epoeti! al%a i! #hro!i# &i"!ey

"isease N E!l e" 8443<77847+=

<< )rZe&e TD, Lo#atelli ?, Cly!e N, et al Nor$aliatio! o% he$olo0i! level i! patie!ts with #hro!i#

&i"!ey "isease a!" a!e$ia N E!l e" 8443<778469+

< P%e%%er A, D-r"$a!! EA, Che! CY, et al A trial o% "ar0epoeti! al%a i! type 8 "ia0etes a!"

#hro!i# &i"!ey "isease N E!l e" 844=<39849=+<8

<7 Coy!e )W, (apoia! T, /-&i W, et al ?erri# l-#o!ate is hihly e%%i#a#io-s i! a!e$i# he$o"ialysis

patie!ts with hih ser-$ %erriti! a!" low tra!s%erri! sat-ratio! res-lts o% the )ialysis Patie!ts

Respo!se to IV Iro! with Elevate" ?erriti! ')RIVE* /t-"y A$ /o# Nephrol 84469=67+

<3 Es#h0a#h W The a!e$ia o% #hro!i# re!al %ail-re pathophysioloy a!" the e%%e#ts o%

re#o$0i!a!t erythropoieti! (i"!ey I!t 9==<79<+

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