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Anemia normalization in patients with type 2 diabetes and chronic kidney disease:results of the NEPHRODIAB2 randomized trial

Emmanuel Villar a,, Michel Livre b,c, Michle Kessler d, Vincent Lematre e, Eric Alamartine f,Michel Rodier g, Maud Franois h, Philippe Zaoui i, Olivier Moranne j, Gabriel Choukroun k,Abdallah Guerraoui l, Anne Jolivot m, Grard Janin n, Bernard Branger o, Anne-Elisabeth Heng p,Catherine Boudray q, Alvine Bissery r, Muriel Rabilloud c,r, Claire Pouteil-Noble a,c

a Hospices Civils de Lyon, Department of Nephrology, Lyon Sud Hospital, Pierre Benite, Franceb Hospices Civils de Lyon, Department of Clinical Pharmacology, Lyon, Francec Universit de Lyon 1, Villeurbanne, Franced

Centre Hospitalier et Universitaire de Nancy, Department of Nephrology, Vandoeuvre les Nancy, Francee Centre Hospitalier de Valenciennes, Department of Nephrology, Valenciennes, Francef Centre Hospitalier et Universitaire de St Etienne, Department of Nephrology, St Priest en Jarez, Franceg Centre Hospitalier et Universitaire de Nmes, Department of Endocrinology, Nmes, Franceh Centre Hospitalier et Universitaire de Tours, Department of Nephrology, Tours, Francei Centre Hospitalier et Universitaire de Grenoble, Department of Nephrology, La Tronche, Francej Centre Hospitalier et Universitaire de Lille, Department of Nephrology, Lille, Francek Centre Hospitalier et Universitaire d'Amiens, Department of Nephrology and Institut National de la Sant et de la Recherche Mdicale ERI-12, Universit Jules Verne, Amiens, Francel Centre Hospitalier de Vichy, Department of Nephrology, Vichy, Francem Hospices Civils de Lyon, Department of Nephrology, E. Herriot Hospital, Lyon, Francen Centre Hospitalier de Macon, Department of Nephrology, Macon, Franceo Centre Hospitalier et Universitaire de Nmes, Department of Nephrology, Nmes, Francep Centre Hospitalier et Universitaire de Clermont Ferrand, Department of Nephrology, Clermont Ferrand, Franceq Centre Hospitalier de Bourg en Bresse, Department of Nephrology, Fleuriat, Francer Hospices Civils de Lyon, Department of Biostatistic, Lyon, France

a b s t r a c ta r t i c l e i n f o

Article history:

Received 4 January 2011

received in revised form 22 February 2011

accepted 8 March 2011

Available online 20 May 2011

Keywords:

Anemia

Chronic kidney disease

Erythropoiesis-stimulating agent

Glomerularltration rate

Type 2 diabetes

Statements of the Problem: Correction of anemia in type 2 diabetes (T2DM) patients with chronic kidney

disease stages 34 may slow the decline of kidney function but may increase cardiovascular risk through

higher hematocrit. The NEPHRODIAB2 study was designed to assess efcacy and safety of completehemoglobin (Hb) normalization in these patients.Methods: We randomly assigned 89 T2DM patients with an estimated glomerular ltration rate (eGFR;

abbreviated 175 Modication of Diet in Renal Disease formula) of 25 to 60 ml/min per 1.73 m2 and moderateanemia (Hb, 100129 g/l) to a target Hb value in subnormal range (110129g/l, group 1,n=43) or normal

range (130149 g/l, group 2, n =46). The primary end point was eGFR decline after 2 years of follow-up.Secondary end points included iron and erythropoietin dosage, quality of life (Medical Outcomes Study 36-

item Short-Form Health Survey scores) and adverse events.Results:Six months after randomization, the mean Hb levels were b120 g/l in group 1 and N130 g/l in group 2

(Pb.05 at 6, 12, 18 and 24 months). Blood pressure, 24-h proteinuria and HbA1c did not differ during follow-

up (PN.05). Two-year declines in eGFR were 8.712.2 in group 1 and 5.17.8 ml/min per 1.73 m2 in

group 2 (P=.29). Mean weekly use of erythropoietin was 7.811.6g in group 1 and 30.133.6g in group 2(Pb.0001). There was no signicant difference regarding Medical Outcomes Study 36-item Short-Form Health

Survey score change or adverse event occurrence.Conclusions:In this trial, normalization of Hb level in T2DM patients with chronic kidney disease was safe butdid not signicantly slow renal function decline and increased treatment cost due to erythropoietin use.

2011 Elsevier Inc. All rights reserved.

1. Introduction

Type 2 diabetes (T2DM) is now the main cause of end-stage renaldisease in industrialized countries (Foley & Collins, 2007; Stengelet al., 2003; Villar, Chang, & McDonald, 2007). Despite survival

Journal of Diabetes and Its Complications 25 (2011) 237243

ClinicalTrials.gov number: NCT00279084.

Corresponding author. Centre Hospitalier Lyon-Sud, Service de Nphrologie,

Dialyse et Transplantation Rnale, 69495 Pierre Bnite Cedex, France. Tel.: + 33 4 72 67

87 00; fax: + 33 4 72 67 87 10.

E-mail address:[email protected](E. Villar).

1056-8727/$ see front matter 2011 Elsevier Inc. All rights reserved.

doi:10.1016/j.jdiacomp.2011.03.003

Contents lists available at ScienceDirect

Journal of Diabetes and Its Complications

j o u r n a l h o m e p a g e : W W W. J D C J O U R N A L . C O M
http://dx.doi.org/10.1016/j.jdiacomp.2011.03.003http://dx.doi.org/10.1016/j.jdiacomp.2011.03.003http://dx.doi.org/10.1016/j.jdiacomp.2011.03.003mailto:[email protected]://dx.doi.org/10.1016/j.jdiacomp.2011.03.003http://www.sciencedirect.com/science/journal/http://www.sciencedirect.com/science/journal/http://dx.doi.org/10.1016/j.jdiacomp.2011.03.003mailto:[email protected]://dx.doi.org/10.1016/j.jdiacomp.2011.03.003


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improvement among T2DM patients on dialysis over the last decades(Sorensen, Mathiesen, Heaf, & Feldt-Rasmussen, 2007; Villar et al.,2007), this condition remains associated with poor outcomes. Innondialysis-dependent T2DM patients with associated chronic kidneydisease (CKD), level of evidence A strategies that slow the decline ofkidney function and improve cardiovascular risk are blood pressurelowering using angiotensin-II receptor blockers (ARB) (Brenner et al.,2001; Lewis et al., 2001; Parving et al., 2001) and intensive glycemic

control (Skyler et al., 2009).Anemia is a common consequence of CKD due to erythropoietindeciency. In CKD patients, glomerular ltration rate (GFR) under45 ml/min per 1.73 m2 is the mean threshold for detection of anemiadened as hemoglobin (Hb) level b110 g/l (Moranne et al., 2009). InT2DM patients with associated CKD, anemiais more severeand occursearlier in the course of CKD (Ravanan, Spiro, Mathieson, & Smith,2007; Thomas et al., 2004).

Observational studies suggested that anemia correction with anerythropoietin-stimulating agent (ESA) in predialysis care mayslow the decline of kidney function (Jungers et al., 2001) andimprove CKD patient cardiovascular risk (Hayashi et al., 2000) andquality of life (Alexander, Kewalramani, Agodoa, & Globe, 2007).Since 1999, international guidelines on anemia have recommendedan Hb target of 110 g/l in predialysis CKD patients (Hrl et al.,2007; Levin & Rocco, 2007), based on evidence of a better qualityof life.

Nevertheless, higher Hb levels may increase in T2DM patients therisk for cardiovascular events through higher hematocrit and higherblood viscosity in the context of diabetic micro- and macrovasculardisease (Orasanu & Plutzky, 2009). Due to these medical specicities,we therefore designed the NEPHRODIAB2 randomized study to assessthe effect of complete Hb normalization on renal function decline andcardiovascular safety in patients with T2DM and associated CKDstages 34, when compared to recommended Hb level (Hrl et al.,2007; Levin & Rocco, 2007).

2. Materials and methods

2.1. Study design

NEPHRODIAB2 was a multicenter, randomized, open-label,parallel group study involving 15 nephrology centers in France.The study was performed in accordance with the Declaration ofHelsinki and Good Clinical Practices. The study protocol wasapproved by a local ethical review board (Comit de Protectiondes Personnes Lyon A). The trial was registered at ClinicalTrials.gov(NCT00279084). Patients were randomized centrally into twotreatment groups by using a block-size randomization procedurestratied by center and estimated GFR [eGFR; b45 and 45 ml/minper 1.73 m2, abbreviated 175 Modication of Diet in Renal Disease(MDRD) formula]. Group 1 patients were assigned to a subnormal

Hb level range (110129 g/l) and group 2 to a normal Hb level range(130149 g/l).

All patients gave written consent before inclusion. The trial beganin February 2004 and ended in May 2008, 2 years after inclusion of thelast patient.

The NEPHRODIAB2 study enrolled adult patients (1880 years old)with T2DM, moderate anemia (Hb level: 100129 g/L) and CKDstage 24 (eGFR of 2560 ml/min per 1.73 m2, abbreviated 175-MDRD formula).

Major exclusion criteria were neoplasia, history of solid organtransplantation, acute medical or surgical condition in the 2 monthsbefore inclusion, myocardial infarction or unstable angina or stroke inthe 6 months before inclusion, contraindication to iron or ESA therapyor inability to complete the Medical Outcomes Study 36-item Short-

Form Health Survey (SF36) quality of life questionnaire.

Patients who fullled the inclusion and exclusion criteria wererandomly assigned to receive iron and/or ESA therapy for targetingHbvalue in subnormal range (110129 g/l, group 1) or normal range(130149 g/l, group 2). Iron and ESA therapy modality was under theresponsibility of each investigator (type of iron and ESAwas free).ESAtherapy should not be started unless serum ferritin was N200g/l.

All patients had clinical and biological assessment at 1, 2, 3, 6, 12,18 and 24 months after inclusion. The study was scheduled to end

after each patient had completed 24 months of follow-up.

2.2. Study end points

The primary end point was the change from baseline in eGFR at 24months using abbreviated 175-MDRD formula. Secondary end pointswereas follows:(i) mean daily iron use and mean weekly ESA use, (ii)quality of life assessed by the SF36 (score foreach subscale range from0 to 100, with higher scores indicating better quality of life) and (iii)critical events. Critical events included death from all causes,myocardial infarction, stroke, peripheral arterial disease, heart failureleading to hospitalization, new diagnosis of cancer (except non-melanoma skin cancer), bacterial infection, chronic renal replacementtherapy andsymptomaticdeep vein thrombosis. Alltheseevents wereadjudicated by an event committee blinded to the assigned Hb range.

2.3. Statistical analyses

Sample size calculation for NEPHRODIAB2 was based on theprimary outcome variable, eGFR change. The expected mean changein eGFR from baseline to 24-month follow-up was 10 ml/min per1.73 m2 per 24 months in group 1 and 8 ml/min per 1.73 m2 per24 months in group 2. With a sample size of at least 102 patientsper treatment arm, NEPHRODIAB2 would have had 90% power toshow this difference by study group.

All quantitative values are reported as meanS.D. or medianvalue. All qualitative values are reported as number and percentage.

All primary and secondary end point analyses were based on theintent-to-treat principle. The primary end point (change in eGFR)

was analyzed by the Student's t test. An eGFR of 10 ml/min per1.73 m2 was attributed to patients who required renal replacementtherapy at each visit after rst dialysis. Analyses were reprocessedwith eGFR value of 5 and 0 ml/min per 1.73 m2 to testreproducibility of the results. Lastly, a linear mixed-effects modelwas used to compare the eGFR variation slopes between random-ization groups.

For analyses of secondary end points, we used the Student's ttestfor quantitative variables, and the 2 test for qualitative variables. Wecompared SF36 scores within each randomized group at inclusion,6 month and 24 months by using analysis of variance. We comparedSF36 scores between randomized groups at inclusion, 6 months and24 months by using Student'sttest.

Iron therapy was expressed in milligrams. ESA use was expressed

as darbepoetin equivalent dose (1 g of darbepoetin equals 200 UI ofepoetin).

All statistical analyses were performed with STATA 10.0 statisticalsoftware.Pvalue less than .05 was considered statistically signicant.

2.4. Role of the funding source and study committees

NEPHRODIAB2 was mainly funded by an institutional grant(Programme Hospitalier de Recherche Clinique) in 2002 and by agrant from the Socit de Nphrologie. The trial was designed,implemented and overseen by a Study Steering Committee that wasindependent from these funding sources and from two otherindustrial sponsors, Amgen France and Roche France. Sponsors havenot been involved in study design, recruitment of participating

centers, monitoring centers, data collection, data cleaning and

238 E. Villar et al. / Journal of Diabetes and Its Complications 25 (2011) 237243


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analysis plan. The Steering Committee was granted access to all studydata. Interpretation of all study data was done independentlyof sponsors.

An Event Validation Committee was constituted and validated allclinical and adverse events during the study.

The clinical research organizer was the Hospices Civils de Lyon.

89 patients enrolled

43 assigned

to subnormal Hb level range.

Group1: 110 129 g/L

46 assigned

to normal Hb level range.

Group 2: 130 149 g/L

32 completed 24-month follow-up.

5 died

5 required dialysis

1 withdrew before termination

38 completed 24-month follow-up.

4 died

2 required dialysis

2 withdrew before termination

Fig. 1.Enrolment and outcomes.

Table 1

Patient characteristics at randomization

Group 1, 110129 g/l (n=43) Group 2, 130149 g/l (n=46) P

Hb (g/l), meanS.D. 114.78.10 114.210.6 .80

Serum ferritin (g/l), meanS.D. 191235 141129 .22

Age (years), meanS.D. 65.29.1 68.57.6 .07

Male sex, no. (%) 28 (65.1) 28 (60.9) .68

Original nephropathy, no. (%) .10Diabetic 27 (62.8) 23 (50.0)

Vascular 11 (25.6) 21 (45.6)

Other 5 (11.6) 2 (4.3)

Renal biopsy, no. (%) 9 (21.0) 7 (15.2) .48

Body mass index (kg/m2), meanS.D. 31.55.3 31.55.6 1

Cardiovascular history, no. (%)

Hypertension 43 (100) 45 (97.8) .97

Myocardial infarction 3 (7.0) 6 (13.0) .34

Angina pectoris 4 (9.3) 4 (8.7) .92

Stroke 4 (9.3) 3 (6.5) .63

Peripheral vascular disease 10 (23.3) 11 (23.9) .94

Diabetic retinopathy, no. (%) 17 (39.5) 15 (32.6) .50

Neoplasm history, no. (%) 2 (4.6) 5 (10.9) .28

Chronic bacterial infectious history, no. (%) 1 (2.3) 0 (0) .48

Blood pressure (mmHg), meanS.D.

Systolic 146.818.9 145.719.0 .78

Diastolic 75.911.9 74.711.1 .62No. of antihypertensive agent, meanS.D. 3.10.9 3.31.0 .32

Antihypertensive agent, no. (%)

ACEI 24 (55.8) 27 (58.7) .78

ARB 21 (48.8) 22 (47.8) .92

ACEI and/or ARB 42 (97.7) 41 (89.1) .11

Renal function, meanS.D.

Serum creatinine (mol/l) 190.452.8 183.459.1 .56

Cockcroft and Gault (ml/min per 1.73 m2) 37.09.1 36.69.4 .83

MDRD (175 formula; ml/min per 1.73 m2) 29.612.8 31.814.3 .49

Proteinuria (g/24 h) 2.52.8 1.72.4 .16

Proteinuria/creatininuria ratio (g/mmol) 3.13.6 2.04.9 .23

HbA1c (%), meanS.D. 7.51.3 7.61.4 .73

Treatment by insulin, no. (%) 25 (58.1) 32 (69.6) .26

LDL-cholesterol in (mmol/l), meanS.D. 2.91.1 2.91.2 1

HMG CoA reductase inhibitor use, no. (%) 24 (55.8) 28 (60.9) .63

Creactive protein in (mg/l), meanS.D. 7.08.8 8.816.0 .51

HMG CoA reductase, hydroxy-mthyl-glutaryl-coenzyme A rductase (i.e., statin).

239E. Villar et al. / Journal of Diabetes and Its Complications 25 (2011) 237243


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3. Results

3.1. Patient disposition and baseline characteristics

Patient disposition is shown inFig. 1.Due to lower rates of renalfunction decline than expected, the study had to be stopped beforerecruiting the planned number of patients. Eighty-nine patients wererandomly assigned to the Hb target groups (group 1, 43 patients;

group 2, 46 patients). Patient characteristics did not differ at inclusion(Table 1).In average, patients were 65 years old, had serum creatinine

around 180190 mol/l corresponding to an eGFR of 3032 ml/minper 1.73 m2 using 175-MDRD formula, had overt proteinuria higherthan 2 g/24 h and had moderate anemia (Hb values around 114 g/l).

All patients but one had history of hypertension. The vast majoritywere treated by an angiotensin receptor inhibitor (ARB) and/or anangiotensin-converting enzyme inhibitor (ACEI). In average, 3.2antihypertensive agents were used to achieve a mean blood pressurearound 146/76 mmHg in both groups. One quarter of the patients hadhistory of peripheral vascular disease.

The mean glycosylated Hb was 7.5%7.6%, and two thirds of thepatients received insulin.

Three patients withdrew their written consent after inclusion anddid not nish the study.

3.2. Anemia correction

Mean Hb levels were higher than 130 g/l in group 2 at 6 to24 months, while they remained lower than 120 g/l in group 1 overthe study period (Fig. 2). Hb differed signicantly between the groupsat 6 (+12.6 g/l in mean in group 2), 12 (+16.3 g/l), 18 (15.6 g/l) and24 months (+10.6 g/l) (allPb.05).

Over the study period, the mean daily iron dosage was69.791.4 mg in group 1 and 91.6100.3 mg in group 2 ( P=.28).Usual iron route administration was per os in all treated patients.Height patients have had occasionally intravenous iron administra-tion during the study period.

Mean weekly ESA dosage was 7.811.6 g (=15581314 UI) ingroup 1 and 30.133.6g (=60286729 UI) in group 2 (Pb.0001).

3.3. Renal function

The eGFR decline is shown in Fig. 3. Two-year declines in eGFRwere 8.712.2 in group 1 and 5.17.8 ml/min per 1.73 m2 ingroup 2 (P=.22). Changing eGFR values assigned to patients whostarted dialysis (10, 5 or 0 ml/min per 1.73 m2) did not modify themain result.

When adjusted on baseline eGFR, 24-h proteinuria and systolicblood pressure, eGFR change remained not statistically differentbetween randomization groups (P=.41). When eGFR changes werecompared by using linear mixed-effects model, the difference was notstatistically signicant either (P=.31).

3.4. Blood pressure, proteinuria and glycosylated Hb

Blood pressure (Fig. 4), 24-h proteinuria (Table 2), antihyperten-sive agent use (Table 2) and HbA1c (Table 2) did not vary signicantlybetween groups during follow-up (all PN.05).

3.5. Quality of life

SF36 scores are shown in Fig. 5. There was no signicant differenceat baseline and at 6 and 24 months between randomization groups(allPN.05). In each randomization group, SF36 score changes over thestudy period were not signicantly different (allPN.05).

3.6. Safety

There was no signicant difference between the groups for theincidence of critical events (Table 3). In group 1, causes of death werecardiovascular disease in 1, infectious disease in 1, neoplasia in 1 andunknown in 2 patients. In group 2, causes of death were neoplasia in 2and unknown in 2 patients.

100

110

120

130

140

150

0 3 6 9 12 15 18 21 24

Months after randomization

Hemoglobing/L

Group 1 Group 2

Fig. 2.Hb level (difference between groups: Pb.05 at 6, 12, 18 and 24 months).

5

10

15

20

25

30

35

40

45

M

DRDmL/min/1.73m

2

50

0 3 6 9 12 15 18 21 24


Group 1 Group 2

Fig. 3.Renal function decline (P=.29).

50

60

70

80

90

100

110

120

130

140150

160

170

180

0 3 6 9 12 15 18 21 24


BloodpressuremmHg

Group 1 Group 2 Group 1 Group 2

Fig. 4.Blood pressure evolution (all PN.05).



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4. Discussion

This randomized trial did not provide argument to fully normalizeHb level in T2DM patients with associated CKD stages 34. Despite anondeleterious impact on blood pressure level or adverse events, thisstudy did not demonstrate that increasing Hb level over 130 g/l inthose patients changed signicantlyCKD progression rate or quality oflife when compared to 110130 g/l Hb level target. The mean dose ofESA was fourfold higher in the group with high Hb level than in thegroup with low Hb level.

These results were in line with the results of previously publishedrandomized trials (Drueke et al., 2006; Gouva, Nikolopoulos,Ioannidis, & Siamopoulos, 2004; Macdougall, Temple, & Kwan, 2007;Pfeffer et al., 2009; Ritz et al., 2007; Rossert et al., 2006; Singh et al.,2006). NEPHRODIAB2 was designed to include only T2DM patients.Thehypothesis wasthat thepotential benet of anemia normalizationon renal function decline through decrease of peripheral ischemia

could have been counterbalanced by an increased risk of cardiovas-cular events through higher hematocrit and blood viscosity in thesepatients with diabetic microvascular and macrovascular complica-tions (Beckman, Creager, & Libby, 2002). The specic vascular

characteristics of T2DM justied a specic trial of anemia treatmentin CKD patients.

Previous studies that compared outcomes by Hb levelsand ESAuseare summarized inTable 4(Drueke et al., 2006; Gouva et al., 2004;Macdougall et al., 2007; Pfeffer et al., 2009; Ritz et al., 2007; Rossertet al., 2006; Singh et al., 2006). Two studies using subcutaneousepoetin alpha (Macdougall et al., 2007; Rossert et al., 2006) werediscontinued early in 2002 due to an emerging risk of epoetin-induced pure redcell aplasia that contraindicated this route of epoetinadministration (Casadevall et al., 2002). Only the recently publishedThe Trial to Reduce Cardiovascular Events with Aranesp Therapy(TREAT) Study reported byPfeffer et al. (2009) focused specically onT2DM patients with CKD. There was no signicant difference betweenthe groups regarding the primary end points: composite cardiovas-cular end point or renal composite end point (death or end-stagerenal disease). Rate of strokes was signicantly higher in thedarbepoetin group compared to the placebo group (5.0% vs. 2.6%).Authors concluded that the risk of darbepoetin in T2DM patients withCKD outweighed the potential benets. In NEPHRODIAB2, we did notnd difference in adverse event rates between the groups, but ourstudy was underpowered to detect such a difference.

With the exception of the study reported byGouva et al. (2004)in

88 patients in 1999, none of these studies showed a benet of higherHb level target in reducing the rate of renal function decrease or therate of cardiovascular event. With the exception of the TREAT Study(Pfeffer et al., 2009), all studies included patients with a mean GFR

Table 2

24-h proteinuria, antihypertensive agent use and HbA1c evolutions over the

study period

Inclusion 12 months 24 months

24-h proteinuria (g/24 h)

Group 1 (110129 g/l) 2.52.8 3.13.6 2.23.5

Group 2 (130149 g/l) 1.72.4 2.04.9 1.41.8

P .16 .23 .19

Antihypertensive agent, meanS.D.

Group 1 (110129 g/l) 3.10.9 3.21.0 3.11.0Group 2 (130149 g/l) 3.31.0 3.31.0 3.20.9

P .32 .57 .65

ACEI and/or ARB (%)

Group 1 (110129 g/l) 97.7% 94.8% 92.3%

Group 2 (130149 g/l) 89.1% 93.0% 89.2%

P .11 .72 .63

HbA1c (%)

Group 1 (110129 g/l) 7.51.3 7.41.5 7.41.6

Group 2 (130149 g/l) 7.6 %1.4 7.6%1.3 7.5%1.5

P .73 .50 .76

0

20

40

60

80

BP GH MH PF ER PR SF VT BP GH MH PF ER RP SF VT

Group 1 (110 129 g/L) Group 2 (130 149 g/L)

Inclusion 6th

month 24th

month

Fig. 5.SF36 scores evolutions by randomization group. BP, body pain; GH, general health; MH, mental health; PF, physical function; ER, emotional role; PR, physical role; SF, social

function; VT, vitality. All PN.05 within each group at inclusion, at 6 and 24 months, and between groups at inclusion, 6 and 24 months.

Table 3

Adverse events by randomization group (all PN.05)

Group 1 (110129 g/l) Group 2 (130149 g/l)

Death 4 5

Myocardial infarction 1 1

Stroke 1 0

Peripheral vascular disease 4 2

Heart failure 3 4

Cancer 3 3

Bacterial infection 6 4Chronic RRT (dialysis) 5 2

Deep vein thrombosis 0 1

Total 27 22

RRT, renal replacement therapy.



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below 30 ml/min per 1.73 m2, and one can ask if Hb normalization hasa potential benecial effect at this CKD stage both on cardiovascularrisk and on renal function. NEPHRODIAB2 study was thereforedesigned to include CKD patients with associated T2DM and meaneGFR N30 ml/min per 1.73 m2. Randomized patients were represen-tative of CKD patients with associated T2DM: they were predomi-nantly male and obese, all but one patient had a history ofhypertension, the vast majority was treated with ACEI and/or ARB,23% had history of peripheral vascular disease, their renal involve-ment included macroproteinuria and one third had associateddiabetic retinopathy.

Regarding renal function, previous studies underlined that inT2DM patients with CKD stages 34, its decline was expected to be4.5 to5 ml/minper 1.73m2 per year (Estacio et al., 2000), (Leeheyet al., 2005) whereas in general population older than 40 years,

natural renal function decline is 1 ml/min per 1.73 m2 per year. Inthe NEPHRODIAB2 cohort, despite an average proteinuria above therecommended 1 g/24 h in both groups over the study period andtreatment with ACEI and/or ARB, renal function decline was lowerthan expected: 3.33.2 ml/min per 1.73 m2 per year in average.This may indicate that beyond reninangiotensin system blockers,aggressive treatment and close monitoring are useful in controllingrenal involvement in T2DM with CKD.

Interestingly, in the present study, there was only a slightly andnonsignicant increase in daily iron dosages in the group with highHb level, whereas weekly ESA dosage was fourfold higher in thisgroup than in the group with low Hb level over the study period.Those results indicated that a 10-g/l increase in Hb level in T2DMpatients with CKD, from 120 to 130 g/l in mean, requireda huge gap in

ESA treatment and consequently in related costs.Our study has limitations. GFR was not measured but estimated by

using abbreviated MDRD equation. Even if we cannot exclude bias inGFR decline evaluation, especially underestimation of GFR (Chudle-igh, Dunseath, & Evans, 2007; Chudleigh, Dunseath, & Peter, 2008;Chudleigh, Ollerton, & Dunseath, 2008) and underestimation of GFRdecline (Beauvieux et al., 2007;Rigalleau et al., 2008), randomizationdistributed equally factors that biased GFR evaluation between thecompared groups. The comparison of the groups was thereforeunbiased, and we did not nd difference between groups regardingCKD progression rate whatever the estimator and the statisticalmethod we used. Inclusions in the study were discontinued earlybecause renal function decline was overall lower than that wasexpected. The study was therefore underpowered to statistically

demonstrate signicant the difference we observed. Based on the

observed decline in eGFR in the NEPHRODIAB2 control group, with a0.9 power and a .05 risk, such a trial should include 672 patients todisplay a signicant difference. Strength of the present study was thatit included only patients with T2DM and that the control group wastreated as recommended by international guidelines (Hb levelbetween 110 and 120 g/l;Hrl et al., 2007; Levin & Rocco, 2007).

In conclusion, when compared to recommended Hb level target(110120 g/l), our study did not show a signicant reductionin rate ofrenal function decline with normalization of Hb level over 130 g/l inCKD patients with associated T2DM and mild anemia but underlinedthe increase of treatment cost due to ESA use.

Acknowledgments

We gratefully acknowledge all study participants, especially thenephrologists and professionals who included patients and collecteddata. We gratefully acknowledge Ms. J. Gillet for data monitoring.

Members of the Steering Committee: Prof. Eric Alamartine (StEtienne), Prof. Michle Kessler (Nancy), Dr. Vincent Lematre(Valenciennes), Dr. Michel Livre (Lyon), Prof. Claire Pouteil-Noble(Lyon), Dr. Emmanuel Villar (Lyon).

Members of the Event Validation Committee: Dr. Alexandre Belot(Pediatric Nephrology, Lyon), Dr. Sabrina Franois (Internal Medicine,Lyon), Dr. Patrice Nony (Cardiology, Lyon).

Clinical research organizer:Hospices Civils de Lyon.Conict of interest statement: None declared. Roles of funding

sources are described in the body of the article, in the Materials andmethodssection.

The results presented in this paper have not been publishedpreviously in whole or part, except in abstract form at the WorldCongress of Nephrology 2009 in Milano, Italia (abstract M561), and atthe 11th Joint Congress of the Socit de Nphrologie and the SocitFrancophone de Dialyse 2009 in Toulouse, France (abstract CO006).

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Beckman, J. A., Creager, M. A., & Libby, P. (2002). Diabetes and atherosclerosis:

epidemiology, pathophysiology, and management.JAMA,287, 25702581.

Table 4

Previous ESA-randomized trials in CKD patients

Study Population

eGFR at

inclusion Hb target Primary e nd point

Main result: primary

end point

Renal function

decline Adverse ev ents

TREAT

(Pfeffer et al., 2009)

T2DM,

n=4038 patients

34 ml/min

per 1.73 m2Hb N90 g/l or

Hb N130 g/l

Death or

cardiovascular

event or dialysis

No difference No difference Higher stroke rate

in the group with

higher Hb level

ACORD

(Ritz et al., 2007)

T1DM and T2DM,

n=172 patients

45 ml/min

per 1.73 m2Hb 105115 g/l or

Hb 130150 g/l

Left ventricular

mass reduction

No dif ference No diff erence No dif ference

Gouva et al. (2004) No diabetes patient,n=88 patients

24 ml/minper 1.73 m2

Hb N90 g/l orHb N130 g/l

Doubling ofcreatinine, or

dialysis, or death

Higher Hb level wasassociated with lower

rate of primary end point

Idem No difference

Rossert et al. (2006) 100 (25.6%) patients

with diabetic nephropathy

among 390 patients

19 ml/min

per 1.73 m2Hb 110120 g/l or

Hb 130150 g/l

eGFR decline No dif ference No diff erence No dif ference

Macdougall et al. (2007) 44 (22.3%) diabetic patients

among 197 patients

20 ml/min

per 1.73 m2Hb N90 g/l or

Hb N110 g/l

Left ventricular

mass reduction


CREATE

(Drueke et al., 2006)

157 (26%) diabetic patients

among 603 patients

25 ml/min

per 1.73 m2Hb 105115 g/l or

Hb 130150 g/l

Cardiovascular

event


CHOIR (Singh et al., 2006) 699 (49.4%) patients with

diabetic nephropathy

among 1416 patients

27 ml/min

per 1.73 m2Hb 105110 g/l or

Hb 130135 g/l

Cardiovascular

event




7/7

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