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In-Depth Topic Review

Am J Nephrol 2014;40:263–279

DOI: 10.1159/000366025

Erythropoiesis-Stimulating Agents (ESA) forPreventing the Progression of Chronic KidneyDisease: A Meta-Analysis of 19 Studies

Adrian Covica Ionut Nistora Mihaela-Dora Donciua Raluca Dumeaa

Davide Bolignanob David Goldsmithc

a Nephrology Department, Faculty of Medicine, University of Medicine and Pharmacy ‘Gr. T. Popa’, Iasi, Romania;b CNR-Institute of Clinical Physiology, Reggio Calabria, Italy; c Renal Unit, Guy’s and St. Thomas’ NHS Foundation

Hospital, King’s Health Partners, London, UK

drawal of treatment due to adverse events (RR, 1.18 [CI 0.77–

1.81], 10 trials, n = 1,958 participants) for patients at higher

hemoglobin (Hb) targets. Furthermore, no statistically sig-

nificant differences in mortality (Risk Ratio [RR] 1.10 [CI 0.90–

1.35], 16 trials, n = 8,082 participants) were observed. Key

Messages: There is no evidence that ESA treatment affects

renal function in patients with CKD. Use of these agents

should not therefore be influenced by considerations about

influencing CKD progression. © 2014 S. Karger AG, Basel

Introduction

Chronic kidney disease (CKD) is a worldwide healthburden, affecting about 10–15% of the Western adultpopulation [1]. It is associated with premature death, car-

diovascular disease, infection and cancer; it also con-sumes many valuable healthcare resources [2–5]. Preven-tion of CKD progression therefore is pivotal. Control ofblood pressure (BP) by blockade of the renin-angioten-sin-aldosterone system (RAAS) is the cornerstone of cur-rent CKD preventive treatment, delaying both cardiovas-cular and renal disease progression [6, 7]. Alternativenephroprotective therapies have yet uncertain values(statins, pentoxyphillin, bicarbonate) [8]. Despite the

Key Words

Chronic kidney disease · Anemia ·

Erythropoiesis-stimulating agents · ESA ·

CKD-progression · Meta-analysis · Systematic review

Abstract

Background: The effect of anemia correction on kidney

function in chronic kidney disease (CKD) patients remains

unclear. As 19–40% of patients with CKD receive an erythro-

poiesis-stimulating agent (ESA), this is a potentially impor-

tant consideration. Summary: We conducted a systematic

review and meta-analysis of randomized trials to January 1,

2014 in adult patients with CKD stages 1 to 4. Selection cri-

teria for studies: randomized controlled trials of at least

2 months duration. Patients were allocated to ESA versus

placebo, no treatment, or different ESA doses with the pur-

pose of achieving a higher versus a lower hemoglobin tar-get. The analyzed outcomes were the need for renal replace-

ment therapy, doubling of serum creatinine, change in GFR

(ml/min), mortality and withdrawal of treatment due to ad-

verse events. A total of 19 trials (n = 8,129 participants with

CKD stage 1–4) were reviewed. There was no difference in

the risk of end-stage kidney disease (RR, 0.97 [CI 0.83–1.20],

17 trials, 8,104 participants), change in GFR (Mean Difference

[MD] –0.45 [–2.21, 1.31], 9 trials, 1,848 participants) or with-

Published online: October 15, 2014NephrologyAmerican Journal of

Dr. Ionut NistorUniversity of Medicine and Pharmacy ‘Gr. T. Popa’Nephrology Department, Faculty of MedicineUniversity Street no 16, RO–700115 Iasi (Romania)E-Mail ionutni @ yahoo.com

© 2014 S. Karger AG, Basel0250–8095/14/0403–0263$39.50/0

www.karger.com/ajn

http://dx.doi.org/10.1159%2F000366025http://dx.doi.org/10.1159%2F000366025


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currently available therapy, CKD patients remain at ahighly increased risk for progression toward end-stagerenal disease and concomitant cardiovascular complica-tions [9].

The effect of anemia correction on kidney functionand progressive GFR loss is an under-researched topic. In

this regard, the available literature is contradictory, withsome researchers suggesting that correction of anemiawith ESAs is beneficial for preventing further renal func-tional decline, while others suggest potential detrimentaleffects [10, 11].

Recently, comprehensive meta-analysis focusing onthe impact of anemia treatment on mortality and cardio-

vascular impacts of anemia treatment was published [12].They did not, however, focus on or report conclusive in-formation on the impact of anemia treatment on renalfunction over time. Since some recent studies [13–15]have suggested that anemia treatment has a beneficial im-

pact on renal function, we decided to perform a system-atic analysis of the existing literature in order to establishif different degrees of anemia correction (low or high Hbtargets) by ESAs may have different impact on renal func-tion trajectories in CKD patients.

Methods

The systematic review and meta-analysis was performed ac-cording to a previously published protocol (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID = CRD42014007162).

We searched MEDLINE (January 1966 to 1st of January 2014)and the Cochrane Controlled Clinical Trials Register Database(through Issue 1 of 12, January 2014); we also hand searched refer-ence lists of textbooks, articles, and scientific proceedings for rel-evant articles (online suppl. table 1; for all online suppl. material,see www.karger.com/doi/10.1159/000366025).

We included all RCTs and quasi-RCTs with a study period ofat least 2 months duration and assessed the effects of different he-moglobin (Hb) targets in pre-dialysis patients with anemia of CKDon the prevention of the progression of CKD. The first period ofrandomized crossover studies was also considered for inclusion.There was no language restriction. The higher Hb target could beachieved by EPO (α or β) or darbepoetin; the lower target could beachieved by lower doses of the same drugs or by a placebo or notreatment or blood transfusion.

Studies enrolling any patient with CKD stages 1–4 (as definedby the Kidney-Disease Outcomes and Quality Initiative [K-DOQI]guidelines: stage 1 = GFR ≥ 90 ml/min/1.73 m2 ; stage 2 = GFR 60–89 ml/min/1.73 m2 ; stage 3 = GFR 30–59 ml/min/1.73 m2 ; stage 4 =GFR 15–29 ml/min/1.73 m2 ; stage 5 = GFR 50% indicatesstatistically large heterogeneity among the included studies. If sub-stantial statistical heterogeneity were noted (I2 >50%), we plannedto explore individual study characteristics and those of subgroupsof the main body of evidence. Plausible reasons for variations intreatment effect (heterogeneity) were explored using subgroupanalysis specifically for the length of follow-up, and type of ESAused and number of participants. All analyses were performed us-ing Revman 5.1 (© 2011, The Cochrane Collaboration, UK).



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Results

Search ResultsThe combined search of MEDLINE, CENTRAL data-

bases, and hand search by experts identified 5,257 cita-tions, of which 3,808 were excluded (non-RCTs or studiesevaluating other interventions not relevant to this review).Full-text assessment of 319 potentially relevant articles re-sulted in the identification of 19 eligible trials enrolling atotal of 8,129 patients [10, 11, 13–15, 22–35] (fig. 1).

Characteristics of the Included Studies

Baseline studies characteristics are presented in ta-ble 1. The population sample sizes varied between 88 and4,038 patients [10, 35]. Study duration ranged from twelveweeks [22–24], to 3.3 years [30]. The mean of the Glo-merular filtration rate at the trial outsets spanned from 16to 51 ml/min 1.73 m2 . Baseline albuminuria/proteinuriaranged from 0.5 to 3.1 g/day. Only two studies did notinclude patients with diabetes mellitus [10, 24]. One studyincluded only renal transplant recipients [15].

5,256 of records identifiedthrough database searching:

4,188 results: Medline1966 to January 2014

1,068 results:

Cochrane database of systematic reviews toissue 1 of 12, January 2014

1 of additional recordsidentified through othersources

4,127 of records after

duplicates removed

4,127 of recordsscreened

3,808 of records excluded:

Not RCTs

Other intervention

Other population

Surrogate outcomes

Follow-up less than 2 months

319 of full-text articlesassessed for eligibility

19 studies included inqualitative synthesis

19 studies included inquantitative synthesis

(meta-analysis)

300 of full-text articlesexcluded with reasons:

108 full-text articlesexcluded non-RCT;

40 full-text articles excludednon-relevant outcome;

94 full-text articles excludednot appropriate intervention;

58 full-text articles excludedfor being duplicates.

Fig. 1. Flowchart showing the number ofcitations retrieved by individual searchesand number of trials included in the sys-tematic review.



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T a b l e

1 . ( c o n t i n u e d )

N o

S t u d y

B a s e l i n e

k i d n e y

d i s e a s e

B a s e l i n e r e n a l

f u n c t i o n , m l /

m i n / 1 . 7 3 m 2

( m e a n ± S D )

B a s e l i n e H b

l e v e l , g / l

( m e a n ± S D )

U s e o f

A C E

i n h i b i t o r

o r A R B

N o . o f

p a t i e n t s

I n t e r v e n t i o n

C o - i n t e r v e n t i o n i n

t r e a t m e n t a r m ( n ) ,

t y p e o f E S A , n o t e s

S t u d y

d u r a t i o n ,

m o n t h s

S t u d y e n d p o i n t s

5

K u r i y a m a

1 9 9 7 [ 2 6 ]

D i a b e t e s

m e l l i t u s :

A r m 1

( n o E S

A ) :

5 8 % A r m 2

( E S A ) :

5 5 %

C r e a t i n i n e

c l e a r a n c e :

A r m 1 :

1 7 . 1 ± 7 . 2

A r m 2 :

1 9 . 1 ± 7 . 2

H C T ( % )

A r m 1 :

2 7 . 9 ± 1 . 8

A r m 2 :

2 7 ± 2 . 3

A r m 1 :

6 8 . 0 %

A r m 2 :

5 9 . 0 %

A r m 1 :

n = 3 1

A r m 2 :

n = 4 2

A r m 1 : A i m i n g H C T

l e v e l o f 3 8 % w i t h

p l a c e b o i n j e c t i o n

A r m 2 : A i m i n g H C T

l e v e l o f 3 8 % w i t h E P O

i n t r a v e n o u s l y i n j e c t i o n

o n c e a w e e k f o r 3 6

w e e k s , w h e n H C T

l e v e l r e a c h e d 3 8 %

d o s e s w e r e a d j u s t e d t o

m a i n t a i n i t a t a l e v e l o

f

3 3 – 3 5 %

I r o n t h e r a p y w a s

u n d e r t h e

r e s p o n s i b i l i t y o f e a c h

i n v e s t i g a t o r

9 m o n t h s

D o u b l i n g o f s e r u m

c r e a t i n i n e , m o r t a l i t y

r a t e s , a d v e r s e e v e n t s ,

n e e d f o r d i a l y s i s ,

p r o t e i n u r i a l e v e l ,

d i a b e t e s c o n t r o l

6

F u r u l a n d

2 0 0 3 [ 2 7 ]

D i a b e t i c

n e p h r o p a t h y

( t y p e 2

) :

2 4 – 1 5 %

2 4 - h u r i n e

c o l l e c t i o n ,

i o h e x o l

c l e a r a n c e o r

C r - E D T A

c l e a r a n c e :

A r m 1 : 1 6 ± 9

A r m 2 : 1 7 ± 6

A r m 1 :

1 0 6 ± 1 0

A r m 2 :

1 0 9 ± 7

N o t

r e p o r t e d

A r m 1 :

n = 3 6

A r m 2 :

n = 3 6

A r m 1 : A i m i n g H b

l e v e l 1 3 5 – 1 5 0 g / l i n

f e m a l e s a n d 1 4 5 – 1 6 0

g / l i n m a l e s


l e v e l 9 0 – 1 2 0 g / l

I V i r o n t o k e e p

t r a n s f e r r i n s a t u r a t i o n

> 2 0 % a n d s e r u m

f e r r i t i n b e t w e e n

4 0 0 – 8 0 0 m g / d l ;

E p o e t i n a l f a

a d m i n i s t e r e d

s u b c u t a n e o u s l y ; I n

t h e l o w H b g r o u p ,

t h e t a r g e t l e v e l w a s

o b t a i n e d w i t h o r

w i t h o u t E S A

t r e a t m e n t

1 2 m o n t h s

w e e k s t o

1 9 m o n t h s

Q u a l i t y o f l i f e , a l l - c a u s e

m o r t a l i t y ,

c a r d i o v a s c u l a r / n o n

c a r d i o v a s c u l a r

m o r t a l i t y , r e n a l

f u n c t i o n ,

h o s p i t a l i z a t i o n ,

s e r i o u s a d v e r s e

e v e n t s ,

t h r o m b o e m b o l i c

e v e n t s , b l o o d

p r e s s u r e c o n t r o l

7

G o u v a

2 0 0 4 [ 1 0 ]

D i a b e t e s

m e l l i t u s w a s

a n e x c l u s i o n

c r i t e r i o n

C o c k c r o f t –

G a u l t e q u a t i o n :

A r m 1 :

2 5 . 7 ± 9 . 1

A r m 2 :

2 2 . 3 ± 6 . 0

A r m 1

( m e a n s ± S D ) :

1 0 1 . 0 ± 5

A r m 2

( m e a n s ± S D ) :

1 0 1 . 0 ± 6

N o t

r e p o r t e d

A r m 1 :

n = 4 5

A r m 2 :

n = 4 3


l e v e l r a n g e o f ≥ 1 3 0 g / l

A r m 2 : s t a r t

e r y t h r o p o i e t i n o n l y

w h e n H b l e v e l r a n g e

< 9 0 g / l

S u b c u t a n e o u s E P O

a l p h a ( E p r e x ,

J a n s s e n - C i l a g )

P r o t o c o l :

u n t i l a l l

p a t i e n t s h a d

c o m p l e t e d

2 y e a r s o f

f o l l o w - u p .

B e c a u s e

o f E P O a l p h a

w i t h d r a w ,

p a t i e n t s

w e r e f o l l o w e d

f o r a m e d i a n

o f 2 2 . 5

m o n t h s

( i n t e r q u a r t i l e

r a n g e 1 6 t o

2 4 m o n t h s )

T h e p r i m a r y e n d p o i n t

w a s a c o m p o s i t e o f

d o u b l i n g o f c r e a t i n i n e ,

r e n a l

r e p l a c e m e n t , o r d e a t h ;

h o s p i t a l i z a t i o n s ,

h y p e r t e n s i o n , s e v e r e

a n e m i a , a l l e r g i c l o c a l o r

s y s t e m i c r e a c t i o n s



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T a b l e

1 . ( c o n t i n u e d )

N o

S t u d y

B a s e l i n e

k i d n e y

d i s e a s e



m i n / 1 . 7 3 m 2

( m e a n ± S D )

B a s e l i n e H b

l e v e l , g / l

( m e a n ± S D )

U s e o f

A C E

i n h i b i t o r

o r A R B

N o . o f

p a t i e n t s





S t u d y

d u r a t i o n ,

m o n t h s


1 2

C R E A T E

2 0 0 6 [ 1 1 ]

D i a b e t e s

m e l l i t u s :

A r m 1

: 2 7 %

A r m 2

: 2 5 %



A r m 1 :

2 4 . 9 ± 6 . 3

A r m 2 :

2 4 . 2 ± 6 . 0

A r m 1

( m e a n s ± S D ) :

1 1 6 . 0 ± 6 . 0

A r m 2

( m e a n s ± S D ) :

1 1 6 ± 6 . 0

A r m 1 :

7 0 . 0 %

A r m 2 :

6 9 . 0 %

A r m 1 :

n = 3 0 1

A r m 2 :

n = 3 0 2

A r m 1 : A i m i n g H b l e v e l

r a n g e o f 1 3 0 – 1 5 0 g / l


r a n g e 1 0 5 – 1 1 5 g / l

S u b c u t a n e o u s

e r y t h r o p o i e t i n -

e p o e t i n b e t a ; I r o n

s u p p l e m e n t a t i o n

( i n t r a v e n o u s o r o r a l )

w a s r e c o m m e n d e d a t

t h e d i s c r e t i o n o f t h e

i n v e s t i g a t o r s

M e a n

f o l l o w - u p

d u r a t i o n o f

3 6 m o n t h s

( 1 , 0 4 4 d a y s

f o r a r m 1 a n d

1 , 0 9 2 d a y s

f o r a r m 2 )

T i m e t o t h e f i r s t

c a r d i o v a s c u l a r e v e n t ,

d e a t h f r o m a n y c a u s e ;

c o n g e s t i v e h e a r t

f a i l u r e ; h o s p i t a l i z a t i o n

f o r a n y c a u s e ; c h a n g e s

i n l e f t v e n t r i c u l a r m a s s

i n d e x , l e f t v e n t r i c u l a r

v o l u m e , a n d l e f t

v e n t r i c u l a r f r a c t i o n a l

s h o r t e n i n g ; t i m e t o

i n i t i a t i o n o f r e n a l

r e p l a c e m e n t t h e r a p y ;

c h a n g e s i n n u t r i t i o n a l

s t a t u s , q u a l i t y o f l i f e ,

n e e d f o r d i a l y s i s ,

d e c r e a s e i n t h e

e s t i m a t e d G F R

1 3

M a c d o u g a l l

2 0 0 7 [ 3 2 ]

D i a b e t i c

n e p h r o p a t h y :

2 2 . 0 – 2

3 . 4 %



A r m 1 :

2 5 . 7 5 ± 1 2 . 2 3

A r m 2 :

2 3 . 2 6 ± 1 0 . 1 5

A r m 1 :

1 0 8 . 9 ± 6 . 0

A r m 2 :

1 0 7 . 6 ± 6 . 6

N o t

r e p o r t e d

A r m 1 :

n = 6 5

A r m 2 :

n = 1 3 2


1 1 . 0 ± 1 . 0 g / d l


1 1 . 0 ± 1 . 0 g / d l ;

P a t i e n t s i n g r o u p 1

s t a r t e d e p o e t i n a t a n

e a r l y s t a g e a n d t h o s e

i n g r o u p 2 w e r e

m o n i t o r e d e v e r y

2 m o n t h s u n t i l t h e i r H

b

c o n c e n t r a t i o n h a d f a l l e n

t o a t r i g g e r l e v e l o f

– 9 . 0 g / d l

2 4 . 1 ± 1 0 . 8

m o n t h s

f o r g r o u p 1

a n d 2 1 . 1 ± 1 0 . 8

m o n t h s

f o r g r o u p 2

l e f t v e n t r i c u l a r m a s s

( L V M ) , p r o g r e s s i o n o f

r e n a l f a i l u r e , e x e r c i s e

t o l e r a n c e , e p o e t i n - a

d o s e s , n u m b e r o f

p a t i e n t s w h o w i t h d r e w

b e c a u s e o f s t a r t i n g

d i a l y s i s o r d e a t h

1 4

A C O R D

2 0 0 7 [ 3 3 ]

D i a b e t e s

m e l l i t u s

t y p e 1

o r 2 :

1 0 0 %


G a u l t e q u a t i o n

( m e d i a n

( I Q R ) ) :

A r m 1 :

5 1 ( 3 9 – 6 7 )

A r m 2 :

4 6 ( 3 5 – 5 5 )

A r m 1

( m e d i a n

( I Q R ) ) : 1 1 . 9

( 1 1 . 3 – 1 2 . 2 )

A r m 2 ( m e d i a n

( I Q R ) ) : 1 1 . 7

( 1 1 . 3 – 1 2 . 0 )

N o t

r e p o r t e d

A r m 1 :

n = 8 8

A r m 2 :

n = 8 2


r a n g e o f 1 3 0 – 1 5 0 g / l


r a n g e 1 0 5 – 1 1 5 g / l

s u b c u t a n e o u s


e p o e t i n b e t a ;

1 5 m o n t h s o f

f o l l o w - u p

P r i m a r y e n d p o i n t w a s

c h a n g e i n l e f t

v e n t r i c u l a r m a s s

i n d e x ( L V M I ) .

S e c o n d a r y e n d p o i n t s

i n c l u d e d

e c h o c a r d i o g r a p h i c

v a r i a b l e s , r e n a l

f u n c t i o n , q u a l i t y o f

l i f e , a n d s a f e t y



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Four studies reported the decline in renal function orprogression of renal disease as the primary endpoint [10,14, 15, 26]. Only one study reported early terminationdue to safety issues [30].

Baseline Hb levels varied from 9.0 [10, 27] to 12.9 g/dl [14]. In trials performed earlier (between 1990 and

2005), there was a trend toward a higher Hb target level(in the intervention group the upper Hb level limit was15.0 g/dl [11, 27, 30, 33]). After 2006, the anemia guide-line committee of the KDOQI raised the suggested Hbcut-offs to 11.0 g/dl for the lower limit (evidence-basedrecommendation) and 13.0 g/dl for the upper limit(clinical practice recommendation) [36]. Followingthese guideline modifications, the more recent trials re-ferred to a lower limit for the high Hb target (13 g/dl[35], 13.5 g/dl [13]), with two notable exceptions: 14.9g/dl [14] and 15 g/dl [15].

The treatment comparisons in the identified trials

were: (a) ESA versus placebo or no treatment or, (b) dif-ferent doses of ESA therapy as needed to achieve two(higher vs. lower) hemoglobin target levels. Doses of ESAused in the trials were not available in one third of thestudy reports (table 2).

As for the type of ESA, Erythropoietin alpha was usedin eight trials [10, 27–32, 34], erythropoietin beta in three[11, 15, 33] and darbepoetin alpha in two studies [35, 37].In old studies, the type of ESA was not specified [14, 22–24, 26].

In the control arm, different treatment strategieswere used. Treatment comparisons included differenttypes of ESA versus placebo or no treatment unless Hblevels decreased below a specified value [10, 11, 22–24,26, 28–30, 32–35], or different doses of ESA [14, 15, 31,37].

Trial QualityTrial quality was sub-optimal on overall. Allocation

concealment was adequate in three of 19 trials (16%) [29,32, 34] and unclear in the remaining 10 out of 19 trials(85%). A consistent high risk of bias concerning the blind-ing of participants and personnel was found for the ma-

jority of included studies, with exception of one, in whichthe investigators stated the ‘double-blinded’ design of thetrial, but without providing any additional information[23] and two studies with low risk of bias [22, 35]. Onlythree of the 19 trials (16%) were analyzed on an intention-to-treat basis [11, 35, 37]. The dropout rate ranged from0 to 15% and did not differ between the treatment andcontrol groups (fig. 2).

T a b l e

1 . ( c o n t i n u e d )

N o

S t u d y

B a s e l i n e

k i d n e y

d i s e a s e



m i n / 1 . 7 3 m 2

( m e a n ± S D )

B a s e l i n e H b

l e v e l , g / l

( m e a n ± S D )

U s e o f

A C E

i n h i b i t o r

o r A R B

N o . o f

p a t i e n t s





S t u d y

d u r a t i o n ,

m o n t h s


1 9

C A P R I T 2 0 1 2

[ 1 5 ]

O n p a t i e n t s

w i t h p o s t -

t r a n s p

l a n t

a n e m i a o n l y ;

n o d a t

a a b o u t

t h e i n c i d e n c e

o f d i a b

e t e s

m e l l i t u s



A r m 1 :

3 8 . 9 ± 1 0 . 6

A r m 2 :

3 7 . 8 ± 1 1 . 0

M D R D A r m 1 :

3 4 . 4 ± 1 0 . 0

M D R D A r m 2 :

3 3 . 7 ± 1 0 . 8

A r m 1

( m e a n s ± S D ) :

1 0 4 . 0 ± 9

A r m 2

( m e a n s ± S D ) :

1 0 6 . 0 ± 7

A r m 1 :

6 9 . 8 %

A r m 2 :

7 1 . 0 %

A r m 1 :

n = 6 3

A r m 2 :

n = 6 2


r a n g e o f 1 3 0 – 1 5 0 g / l


r a n g e 1 0 5 – 1 1 5 g / l

S u b c u t a n e o u s


e p o e t i n b e t a

2 4 m o n t h s

e G F R a t t h e e n d

o f s t u d y , t h e

v a r i a t i o n i n e C r c l ,

d o u b l i n g o f

s e r u m c r e a t i n i n e ,

p r o t e i n u r i a ,

n u m b e r o f

p a t i e n t s w h o

p r o g r e s s e d t o

E S R D , t i m e t o

r e t u r n t o d i a l y s i s ,

g r a f t s u r v i v a l ,

o c c u r r e n c e

o f a c u t e g r a f t

r e j e c t i o n , p a t i e n t

s u r v i v a l , Q o L



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Table 2. Baseline, target and achieved hemoglobin concentrations for the included studies

Study Baseline Hgbconcentration, g/dl

Target Hgb concentration, g/dl Achieved Hgb concentration, g/dl

high/active group low/no treatment high/active group low/no treatment

Kleinman et al., 1989 [22] HCT of 28.2% HCT of 38–40% HCT of 38–40% HCT of 35.8% HCT of 28.3%

Watson et al., 1990 [23] HCT of 28±2% HCT of 38% No target HCT of 35±2% HCT of 26±2%

Clyne et al., 1992 [24] 8.6±0.8 HCT of >30% No target 11.7±1.1 9. 4±1.0

Revicki et al., 1995 [25] HCT of 26.8±3.6% HCT of 35% No target Not reported 8.9±1.2

Kuriyama et al., 1997 [26] HCT of 27.9±1.8% HCT of 33–35% HCT


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Quantitative AnalysisNumber of Patients Starting RRT during the StudyPeriodWith regard to the number of patients that required

the initiation of RRT during the study, there were no datathat would favor either of the two groups (low versus high

Hb target) (17 trials, 8,104 participants, RR 0.97; 95% CI0.83–1.15). The heterogeneity for this outcome was mod-erate: (χ2 = 28.59, I2 = 44%) (fig. 3, table 3).

For the composite outcome all-cause mortality orRRT, there was no statistically significant difference be-tween the high Hb and the low Hb arm (17 trials, 8,104participants, RR = 0.95; 95% CI 0.81–1.12); heterogeneitywas again moderate (χ2 = 38.23, I2 = 58%) (fig. 3).

Reduction in GFR at the End of the Study. Doublingof Serum CreatinineNine studies reported changes in GFR, and did not re-

veal a significant difference between the two groups (9trials, 1,828 participants, Mean Difference (MD) –0.45;95% CI –2.21–1.31 ml/min), although for this outcomemeasure, the heterogeneity was important (χ2 = 302.4;I2 = 97%) (fig. 4, table 3).

Doubling of serum creatinine was reported only bythree small studies (n = 286 participants) [10, 15, 26].There was a statistically significant difference indicatinga 47% reduction in the risk of doubling of the serumcreatinine when aiming at higher Hb values (fig. 3, ta-ble 3).

Serum Creatinine or GFR Value at the End of theStudyThere was no difference between the high and the low

Hb target in serum creatinine values or GFR (ml/min)at the end of the study. This analysis included four studiesfor the creatinine outcome and 8 studies for the GFR out-come (fig. 4); an important heterogeneity was found forboth outcomes (χ2 = 15.29; I2 = 80% and χ2 = 29.90; I2 =77%).

Proteinuria at the End of the Study and Changes in

Proteinuria from BaselineProteinuria was reported only by three studies [14, 30,33]. One study [33] reported that there was no change inurine protein, a more recent study [14] reported no sta-tistically significant difference between baseline protein-uria and end-of-treatment proteinuria and the oldest one[30] reported the worsening of proteinuria in a dichoto-mous format with more events in the low Hb group (10events vs. 4 events, n = 195 participants per arm).

Blood Pressure at the End of the Study. Changes inBPTargeting for a higher Hb level was not associated

with higher systolic or diastolic BP levels (5 studies; 934participants; MD = 1.83; 95% CI –0.79–4.45 mm Hg).Heterogeneity across these 5 studies was moderate (χ2 =

9.33; I2

= 57%). However, the CREATE study [11] most-ly contributes (32%) to the overall weight of this analysis(fig. 4).

Adverse EffectsThe number of participants who discontinued the

treatment due to adverse events was reported by ten stud-ies as 1,958 participants, and these studies did not revealany statistically significant difference between the twocomparison groups (fig. 3, table 3). Also, there was no dif-ference for the number of patients experiencing at leastone adverse event, including one serious event during the

intervention period (RR = 1.01, 95% CI 1.00–1.03, 8 stud-ies, 7,108 participants). Heterogeneity was low for boththe analyses (I2 = 0%).

However, there was an 18% higher risk of having atleast one serious adverse event during the interventionperiod for higher as compared to lower Hb targets (6studies, 6,268 participants, RR 1.18, 95% CI 1.01–1.07).

Finally, the risk of having at least one hospitalizationduring the intervention period was 11% higher in thehigher-Hb target (3 studies, 1,910 participants, RR = 1.11,95% CI 1.00–1.23; I2 = 0%) (fig. 3).

Investigation for Sources of HeterogeneityHeterogeneity in the effects of lower or higher Hb tar-

gets on renal function at the end of treatment (end ofstudy GFR and change in GFR from baseline) was ex-plored through sub-group analyses based on the type ofESA used (erythropoietin alpha, erythropoietin beta, dar-bopoetin alpha or undefined ESA), number of partici-pants (less or more than 100) and study duration (less ormore than 12 weeks) (online suppl. fig. 1). Causes of het-erogeneity were not explored for the serum creatinineoutcome since few studies looked at this endpoint. The

analysis showed that the type of treatment, number ofparticipants and length of follow-up did not change theeffects of anemia corrections at different Hb targets onrenal function. In addition, a subgroup sensitivity analy-sis, with or without data available from the TREAT 2009trial [35] (fig. 3) and with or without data available fromthe CAPRIT trial [15] (transplanted patients), was per-formed for all dichotomous and continuous outcomesthat included this study in the analysis (online suppl. fig. 2



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Fig. 3. Effect of high Hb target versus low Hb target on dichotomous outcomes: 1.2.1 number of patients starting RRT during study pe-riod. 1.2.2 number of patients starting RRT during study period_TREAT trial excluded. 1.2.3 number of patients starting RRT and all-cause mortality: composite outcome. 1.2.4 doubling of serum creatinine. 1.2.5 number discontinued due to adverse events.

C o l o r v e r s i o n a

v a i l a b l e

o n l i n e

0.5 0.7 1 1.5 2.0

Favours high-Hb group

Study or Subgroup

1.2.1 Number of patients starting RRT during study period

Events EventsTotal Total M–H, Random, 95% CI M–H, Random, 95% CIYearWeight

Low-hemoglobin group Risk ratio Risk ratio

Clyne 1992Revicki 1995Kuriyama 1997Furuland 2003Roger 2004Gouva 2004Levin 2005CHOIR 2006

ACORD 2007CREATE 2006ECAP 2006Macdougall 2007Cianciaruso 2008TREAT 2009NEPHRODIAB2 2011Akizawa 2011CAPRIT 2012Subtotal (95% CI)

Total eventsHeterogeneity: Tau2 = 0.03; Chi2 = 28.59; df = 16 (p = 0.03); I2 = 44%Test for overall effect: Z = 0.32 (p = 0.75)

116142

241011

155

2127

3304

3382

213

763

12434236754578

715

883011956446

2,01246

16163

4,022

213200

15188

134

3111

1634

3305

2613

766

10403136804374

717

8230219513249

2,02643

16062

4,082

0.5%5.5%7.0%0.3%5.9%4.8%3.1%

15.6%

0.8%15.9%0.5%

11.6%1.4%

18.1%1.0%6.4%1.7%

100.0% 0.97 [0.83, 1.15]

0.42 [0.04, 3.95]1.14 [0.63, 2.07]0.52 [0.31, 0.85]

5.00 [0.25, 100.63]1.71 [0.97, 3.00]0.53 [0.28, 1.02]1.30 [0.56, 3.06]1.16 [0.94, 1.43]

0.62 [0.11, 3.62]1.15 [0.94, 1.40]

3.00 [0.31, 28.59]0.98 [0.72, 1.35]1.07 [0.28, 4.01]1.03 [0.90, 1.18]0.37 [0.08, 1.83]0.80 [0.47, 1.37]0.23 [0.07, 0.76]

19921994199720032004200420052006

200620062007200720082009201120112012

1.2.2 Number of patients starting RRT during study period_Treat trial excludedClyne 1992Revicki 1995Kuriyama 1997Furuland 2003Roger 2004Gouva 2004Levin 2005CHOIR 2006CREATE 2006ACORD 2007ECAP 2006

Macdougall 2007Cianciaruso 2008NEPHRODIAB2 2011Akizawa 2011CAPRIT 2012Subtotal (95% CI)


116142

241011

155127

23

3042

213

425 436

12434236754578

71530188

195

644646

16163

2,010

213200

15188

134111

31

6345

2613

10403136804374

71730282

195

1324943

16062

2,056

0.8%7.5%9.1%0.5%8.0%6.7%4.5%

16.3%16.5%1.3%0.8%

13.4%2.2%1.6%8.5%2.6%

100.0%

0.42 [0.04, 3.95]1.14 [0.63, 2.07]0.52 [0.31, 0.85]

5.00 [0.25, 100.63]1.71 [0.97, 3.00]0.53 [0.28, 1.02]1.30 [0.56, 3.06]1.16 [0.94, 1.43]1.15 [0.94, 1.40]0.62 [0.11, 3.62]

3.00 [0.31, 28.59]

0.98 [0.72, 1.35]1.07 [0.28, 4.01]0.37 [0.08, 1.83]0.80 [0.47, 1.37]0.23 [0.07, 0.76]0.94 [0.77, 1.16]

19921994199720032004200420052006200620062007

20072008201120112012

1.2.3 Starting RRT and all cause mortality: composite outcomeClyne 1992Revicki 1995Kuriyama 1997Furuland 2003Gouva 2004Roger 2004Levin 2005CHOIR 2006CREATE 2006ACORD 2007ECAP 2006Macdougall 2007Cianciaruso 2008TREAT 2009NEPHRODIAB2 2011

Akizawa 2011CAPRIT 2012Subtotal (95% CI)


116156

132412

207158

24

315

7506

224

1,276 1,248

12434236457578

71530188

1956446

2,01246

16163

4,022

214221

221511

170132

37

684

72510

2616

10403136438074

71730282

19513249

2,02643

16062

4,082

0.5%5.4%7.1%0.6%5.8%5.5%3.6%

14.6%14.8%0.8%1.6%

10.8%1.5%

16.9%2.3%

6.1%2.1%

100.0%

0.42 [0.04, 3.95]1.06 [0.60, 1.89]0.50 [0.32, 0.80]

6.00 [0.76, 47.36]0.56 [0.33, 0.97]1.71 [0.97, 3.00]1.30 [0.49, 2.20]1.22 [1.03, 1.45]1.20 [1.02, 1.42]0.62 [0.11, 3.62]0.57 [0.17, 1.92]0.94 [0.70, 1.27]1.33 [0.38, 4.66]1.04 [0.96, 1.13]0.56 [0.22, 1.41]

0.84 [0.50, 1.42]0.25 [0.09, 0.69]0.95 [0.81, 1.12]

199219941997200320042004200520062006200620072007200820092011

20112012

1.2.5 Number discontinued due to adverse eventsKleinman 1989Watson 1990Revicki 1995Furuland 2003Levin 2005CREATE 2006Macdougall 2007ECAP 2006Cianciaruso 2008

Akizawa 2011Subtotal (95% CI)


12151

17265

7

47 43

75

433685

30165

19546

161944

00313

10865

7

76

403687

30213219549

1601,014

2.0%2.3%3.7%4.1%3.6%

31.2%7.9%

14.7%13.3%

17.4%100.0%

3.00 [0.14, 63.15]5.83 [0.34, 99.23]0.31 [0.03, 2.86]

5.00 [0.61, 40.70]0.34 [0.04, 3.22]1.71 [0.79, 3.66]0.51 [0.11, 2.32]1.00 [0.33, 3.05]1.07 [0.33, 3.44]

0.99 [0.36, 2.77]1.18 [0.77, 1.81]

198919891994200320052006200720072008

2011

1.2.4 Doubling of serum creatinineKuriyama 1997Gouva 2004CAPRIT 2012Subtotal (95% CI)


2226

426345

150

261011

30 47

316243

136

65.1%10.8%24.1%

100.0%

0.62 [0.45, 0.87]0.20 [0.04, 0.86]0.52 [0.21, 1.29]0.53 [0.31, 0.89]

199720042012

Favours high-Hb group Favours low-Hb group



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and 3) showing roughly the same effect. For the TREAT[35] subgroup sensitivity analysis, the analysis performedwithout the inclusion of this trial did not reveal signifi-

cant effects estimates differences (with TREAT, effect es-timates: 0.97 (0.83, 1.15) and without TREAT: 0.94 (0.77,1.16)) (fig. 3). As new data regarding a higher prevalenceof resistance to ESA treatment in US-CKD patients com-pared to non-US patients has been recently hypothesized[38], a geographical-subgroup sensitivity analysis wasconducted for the adverse events outcome including acomparison of relative effect and heterogeneity with stud-ies comprising US participants versus studies with only

non-US participants. There were no significant effect es-timates or heterogeneity differences found (online suppl.fig. 4).

Discussion

Key FindingsOur analysis included 19 studies, enrolling 8,129 par-

ticipants with CKD stages 1–4. There was no differencein risks for end-stage kidney disease, reduction in GFR,serum creatinine or GFR (ml/min) values, or in protein-

Table 3. Summary of findings

Outcome Trials reportingmore than oneevent/total numberof trials included inthe outcome

Number ofpatientsincluded inthe outcome

Relativeeffect

95% CI Mediantreatmentduration,months

Quality ofevidence*

Number of patients starting RRT during study period 17/17 8,104 0.97 (0.83, 1.15) 18.41 ModerateDoubling of serum creatinine 3/3 286 0.53 (0.31, 0.89) 18.5 Very low Number discontinued due to adverse events 9/10 1,958 1.18 (0.77, 1.81) 15.25 Low

Reduction in GFR at the end of the study, ml/min 9/9 1,828 –0.45 (–2.21, 1.31) 21.67 Very low

* Definition of quality of evidence: High quality = additional research is very unlikely to change our confidence in the estimates ofeffect; Moderate quality = additional research is likely to have an important impact on our confidence in the estimate of effect; Low qual-ity = additional research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change theestimate; Very low quality = any estimate of the effect is very uncertain.

Fig. 3. Effect of high Hb target versus low Hb target on dichotomous outcomes: 1.2.6 number of patients with at least one adverse eventduring the intervention period. 1.2.7 number of patients with at least one hospitalization during the intervention period.


v a i l a b l e

o n l i n e

0.5 0.7 1 1.5 2.0

Favours high-Hb group

Study or Subgroup Events EventsTotal Total M–H, Random, 95% CI M–H, Random, 95% CIYearWeight

Low-hemoglobin group Risk ratio Risk ratio

1.2.6 Number of patients with at least one adverse event during the intervention periodCHOIR 2006CREATE 2006ECAP 2006Macdougall 2007TREAT 2009Akizawa 2011NEPHRODIAB2 2011CAPRIT 2012Subtotal (95% CI)Total eventsHeterogeneity: Tau2 = 0.00; Chi2 = 4.38; df = 7 (p = 0.74); I2 = 0%Test for overall effect: Z = 1.67 (p= 1.10)

60727914462

1,88015422

413,2193,189

68630019565

2,00416146

633,520

589273140126

1,87815327

33

688302195132

2,01916043

493,588

10.8%7.8%1.2%4.3%

67.2%8.3%0.1%

0.3%100.0%

1.03 [0.99, 1.08]1.03 [0.98, 1.08]1.03 [0.91, 1.16]1.00 [0.94, 1.07]1.01 [0.99, 1.03]1.00 [0.95, 1.05]0.76 [0.52, 1.11]

0.97 [0.74, 1.26]1.01 [1.00, 1.03]

2006200620072007200920112011

2012

1.2.7 Number of patients with at least one hospitalisation during the intervention periodGouva 2004CHOIR 2006ECAP 2006Subtotal (95% CI)


Favours high-Hb group Favours low-Hb group

3694

32

71545

195955

3346

26

405 366

71743

195955

94.6%0.7%4.6%

100.0%

1.11 [1.00, 1.23]0.64 [0.19, 2.10]1.23 [0.76, 1.98]1.11 [1.00, 1.23]

200420062007



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uria, at the end of the study periods when aiming at high-er hemoglobin (Hb) targets. Furthermore, no statisticallysignificant differences in a composite outcome need forRRT plus mortality (Risk Ratio [RR] 0.95 [CI 0.81–1.12],17 trials, n = 8,104 patients) were observed. Withdrawal

of treatment due to adverse events was similar, as well asthe general control of BP, between high and low Hb tar-gets cohorts of patients.

Some important shortcomings in the manner of re-porting outcomes deserve mentioning. Only four studiesout of 19 had renal endpoints as primary outcomes; theremaining studies only described these events as second-ary outcomes. The studies did not generally feature orrecruit from ‘rapidly-progressing’ CKD cohorts. The

overall quality of the investigational and trial design ap-proaches used to address this key end-point was subopti-mal. Finally, data on proteinuria were reported only bythree studies.

Two rather different studies included in our meta-

analysis seemed to show protective outcomes for the de-ployment of ESAs in CKD. These were the studies byGouva et al. (2004) [10] and the more recent CAPRITstudy from 2012 [15].

The Gouva study was one of the smallest ones (n = 88)of the 19 included in the meta-analysis, and was focusedon non-diabetic patients with a wide range of serum cre-atinine concentrations (2–6 mg/dl) and mild-to-moder-ate anemia (Hb 9–11 g/dl), from 14 clinical centers in

Fig. 4. Effect of high Hb target versus low Hb target on continuous outcomes: 1.3.1 reduction in GFR at the end of the study (ml/min).1.3.2 GFR at end of study (ml/min). 1.3.3 diastolic blood pressure at end of the study (mm Hg).


v a i l a b l e

o n l i n e

–20 –10 0 10 20

High-hemoglobin group

Study or Subgroup

1.3.1 Reduction in GFR at the end of the study (ml/min)

Mean Mean SDTotalSD Total Weight IV, Random, 95% CI

Low-hemoglobin group Mean difference Mean differenceIV, Random, 95% CI

ACORD 2007

Akizawa 2011

CAPRIT 2012

Cianciaruso 2008

CREATE 2006Levin 2005

Macdougall 2007

NEPHRODIAB2 2011

Roger 2004

Subtotal (95% CI)

5.5

2.3

2.4

2

3.67.4

6.96

5.1

8

8.29

3.18

1.1

0.9

6.711.1

8.28

7.8

9

85

160

63

37

28778

65

46

66

887

3.4

2.4

6

1.3

3.19.1

7.82

8.7

6

9.92

3.06

1.1

0.5

5.310

7.5

12.2

8

75

160

62

41

29374

132

43

61

941

10.0%

13.2%

13.4%

13.4%

12.9%9.1%

10.8%

7.5%

9.8%

100.0%

Heterogeneity: Tau2 = 5.99; Chi2 = 302.41; df = 8 (p < 0.00001); I2 = 97%

Test for overall effect: Z = 0.50 (p = 0.62)

2.10 [–0.75, 4.95]

–0.10 [–0.78, 0.58]

–3.60 [–3.99, –3.21]

0.70 [0.37, 1.03]

0.50 [–0.48, 1.48]–1.70 [–5.06, 1.66]

–0.86 [–3.27, 1.55]

–3.60 [–7.89, 0.69]

2.00 [–0.96, 4.96]

–0.45 [–2.21, 1.31]

Favours high-hemoglobin Favours low-hemoglobin

1.3.2 GFR at end of study (ml/min)

CAPRIT 2012

Clyne 1992

CREATE 2006

Furuland 2003

Gouva 2004

NEPHRODIAB2 2011

Roger 2004

Watson 1990

Subtotal (95% CI)

–36.5

–10

–18.1

–13

–21.9

–26.7

–19.9

–12.9

13.2

6

11.5

10

9.4

7.8

9

8.94

63

11

289

19

45

46

66

5

544

–28

–8

–19.2

–16

–16.1

–20.9

–22

–10.3

13.8

3

19

7

6.3

12.2

10

7.1

62

8

293

21

43

43

61

6

537

12.2%

13.2%

15.5%

11.2%

14.4%

12.9%

14.4%

6.2%

100.0%

Heterogeneity: Tau2 = 13.38; Chi2 = 29.90; df = 7 (p < 0.0001); I2 = 77%


–8.50 [–13.24, –3.76]

–2.00 [–6.11, 2.11]

1.10 [–1.45, 3.65]

3.00 [–2.40, 8.40]

–5.80 [–9.13, –2.47]

–5.80 [–10.09, –1.51]

2.10 [–1.22, 5.42]

–2.60 [–12.28, 7.08]

–2.24 [–5.23, 0.76]

1.3.3 Diastolic blood pressure at end of study (mm Hg)

CAPRIT 2012

Clyne 1992

CREATE 2006

Furuland 2003

Roger 2004

Subtotal (95% CI)

79

85

79

90

79

10

7

11

6

12

63

12

300

29

66

470

79

90

77

83

77

12

9

12

11

11

62

8

302

31

61

464

20.6%

9.4%

31.8%

18.1%

20.1%

100.0%

Heterogeneity: Tau2 = 4.72; Chi2 = 9.33; df = 4 (p = 0.05); I2 = 57%


0.00 [–3.88, 3.88]

–5.00 [–12.39, 2.39]

2.00 [0.16, 3.84]

7.00 [2.55, 11.45]

2.00 [–2.00, 6.00]

1.83 [–0.79, 4.45]



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Greece. It was non-blinded, the intervention being early versus later use of ESA. To be eligible for inclusion, pa-tients also had to have stopped all ACEI and/or ARBs for2 months, and to have controlled BP on non-ACE/ARBtherapy. These stringent, unusual, selection criteria makeit very challenging to extrapolate the findings of this

study, since a large proportion of current CKD patientsare on ACE/ARB-based drug therapy for BP control andproteinuria reduction. During follow-up, 13 (3 deaths)

versus 23 (4 deaths) patients reached the end point ofdoubling of creatinine, renal replacement, or death, in theearly versus deferred treatment arms, respectively. Thus,the difference between the two arms was largely causedby the initiation of renal replacement (a notoriously sub-

jective, symptom-led, judgment). The CAPRIT study [15] was a two-year, open-label tri-

al involving 125 post-renal transplant patients. Beside thewell-known multifactorial pathogenesis of post-renal

transplant anemia (including the presence of immuno-suppressive therapy and the altered inflammatory envi-ronment), the most notable anemia risk factor still re-mains and that is the loss of renal allograft function [39].This is consistent with the loss of endogenous EPO pro-duction in CKD patients. The findings of the CAPRITtrial suggested improved allograft survival among pa-tients treated to a higher Hb level.

Indeed, in the CAPRIT, the patient admixture and co-morbidity were highly different from those seen in otheranemia studies:


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with active therapy. However, in the quest for ‘nephro-protection’ to prevent progressive loss of renal functionand the eventual need for dialysis, adjusting the pa-tient’s Hb concentration using ESAs does not seem,from our evidence, to have a compelling logic to sup-port it.

Acknowledgements

None to declare.

Disclosure Statements

Adrian Covic received speaker honoraria from Amgen, Roche,Fresenius Medical Care and Abbott, and is a member of theEuropean Renal Best Practices Board.

David Goldsmith received speaker honoraria from Roche,Amgen, Vifor, Takeda, Sandoz.

Role of Funding Source

No funding source was available for this study.

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