RENAL ANAEMIA - CKD 1-5

RENAL ANAEMIA - CKD 1-5

FP183 CONTINUOUS ERYTHROPOIETIN RECEPTOR ACTIVATOR (C.E.R.A.) ONCE MONTHLY MAINTAINS STABLE HEMOGLOBINVALUES IN HIGH-RISK PATIENTS WITH CHRONIC KIDNEYDISEASE ON DIALYSIS: AN ANALYSIS OF 10INTERNATIONAL TRIALS

Danilo Fliser1 and Valery Shilo21Department of Internal Medicine IV, Saarland University Hospital, 2Departmentof Nephrology for Postgraduates, Moscow University of Medicine and Dentistry

Introduction and Aims: Hemoglobin (Hb) stability with C.E.R.A. once-monthly(QM) was evaluated in high risk patients with chronic kidney disease (CKD) ondialysis switched from shorter-acting erythropoiesis-stimulating agents (ESAs).Methods: Adult CKD patients on dialysis were converted to C.E.R.A. QM to achievea target Hb of 10.0–12.0 g/dL (5 studies), 10.5–12.5 g/dL (3 studies), 11.0–12.5 g/dLand 11–13 g/dL (one study each). High risk (HR) and low risk (LR) subgroups weredefined on the basis of therapy parameters before switching: epoetin or darbepoetinalfa dose (=8000 IU or 40 μg, respectively), average Hb at screening (below the 40%percentile [<P40] for HR or above the 60% percentile [>P60] for LR). The ratio ofdose and achieved Hb at screening >P60 (HR), or Hb fluctuation >P60 (HR) weredefined by the same parameters. Cardiovascular (CV) risk groups were defined bypre-existing cardiac risk factors (diabetes or cardiac disorder), or through >P60

N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Treatment switchoverwas followed by a 16-week titration and an 8-week evaluation period. Hb parameters,dosing and safety in the evaluation period were compared.Results: Patients (N=1577); median age 63 (range: 19–93) years were classified intoHR/LR subgroups as shown in the table.Evaluation of therapy-related subgroups showed generally significantly higher meanHb values for the LR subgroups. The largest difference (0.4 g/dL) was seen forsubgroups by dose/Hb, while subgroups by Hb fluctuation showed no difference. Thedifference seen for the HR/LR screening Hb group represented a reduction from 1.2g/dL difference at screening to 0.3 g/dL after the switch to C.E.R.A. There was lessvariation in mean Hb levels for the HR/LR subgroups by CV risk factors. Hbstability (mean Hb within target range or change from baseline =1 g/dL) was similaracross all subgroups. Mean required C.E.R.A. dose QM was higher for all HR groupsthan the LR counterparts, with significant differences for four of the comparisons. Asexpected, significantly higher frequencies of cardiac and vascular SAEs were seen inHR versus LR patients for NT-proBNP (HR/LR, 5.7/1.9; p<0.004 for cardiac SAEs)and baseline risk factors (4.6/2.0; p<0.02 for cardiac SAEs; 4.9/1.3; p=0.0004 forvascular SAEs).Conclusions: The pooled analysis in dialysis patients shows that C.E.R.A. QMmaintains stable Hb levels in all HR patients as well as in patients with prevailingCV risk factors.

FP184 RELATIONSHIP BETWEEN CARDIOVASCULAR (CV) EVENTSAND HEMOGLOBIN (HB) LEVEL OR HB RATE OF CHANGE INHEMODIALYSIS (HD) PATIENTS ON PEGINESATIDE

Adrian Covic1, Anatole Besarab2, Robert Provenzano3, Anne-Marie Duliege4,Minjia Chen4, Sandra Tong4, Carol Francisco4, Hong-Ye Gao4, Krishna Polu4 andAngel Lm De Francisco51University of Medicine 'gr. T. Popa' Iasi, 2Henry Ford Hospital, Detroit, MI, USA,3Saint Claire Specialty Physicians, Pc, Detroit, MI, USA, 4Affymax, Inc., Palo Alto,Ca, USA, 5Hospital Universitário de Valdecilla, Santantder, Spain

Introduction and Aims: Persistently low Hb levels and rapid Hb change duringtreatment with erythropoiesis- stimulating agents (ESAs) have previously beenassociated with increased rate of CV events in HD patients (Unger et al. 2010 NEJM362:189). Peginesatide is a synthetic, PEGylated, investigational, peptide-based ESAdeveloped for the treatment of anemia due to chronic kidney disease in patients ondialysis. Peginesatide demonstrated noninferiority to epoetin in maintenance of Hblevels in HD patients in two Phase 3 randomized, active-controlled, open- label trials(EMERALD 1, 2). A pre-specified on-drug analysis of a pooled, adjudicated CVcomposite safety endpoint (CSE) showed a hazard ratio of 0.85 (95% CI, 0.68-1.07;Affymax, data on file). This retrospective, event-based analysis investigated thetemporal relationship between Hb levels and Hb rates of change and CSE events.Methods: The two trials compared peginesatide (1x monthly; N=1066) with epoetin(1-3x wkly; N=542) in HD patients previously on stable epoetin. The CSE includedstroke, myocardial infarction, death, and serious adverse events of congestive heartfailure, unstable angina, arrhythmia. Exposure-adjusted CSEs, defined as totalnumber of on-drug CSE events (i.e., when patient was on study treatment) dividedby time-at-risk (CSE events/patient-year), were evaluated for association with fourHb level categories (=10, >10 to =11, >11 to =12, and >12 g/dL) and five Hbrate-of-change categories (estimated by linear regression: =-1, >-1 to =-0.2, >-0.2 to=0.2, >0.2 to =1, and >1 g/dL per 2 wks). Association of comorbidity of diabetesmellitus was also evaluated.Results: While on study medication, 18% (195/1066) patients on peginesatideexperienced 343 total CSE events vs 22% (121/542) patients on epoetin with 242events. Event-based analysis of CSE event rates by Hb level categories showed highestevent rates in the lowest Hb level category (=10 g/dL) for either treatment arm: 0.64and 0.90 events/patient-year for peginesatide and epoetin, respectively; for higher Hblevel categories, CSE event rates were =0.29 and =0.38 events/patient-year forpeginesatide and epoetin, respectively. For rate-of- change categories, both arms hadhigher CSE rates associated with rapid Hb decline (=-1 g/dL per 2 wks), whereasonly the epoetin arm showed higher CSE rates with rapidly increasing Hb (>1 g/dLper 2 wks). These trends were magnified in diabetics (Figure).Conclusions: These results suggest an association between increased rate of CVevents with low Hb levels (=10g/dL) or with Hb decreases of 1 or more g/dL per 2wks in HD patients receiving either peginesatide or epoetin. Higher event rates werealso observed with Hb increases exceeding 1 g/dL per 2 wks in the epoetin arm, butnot in the peginesatide arm. These associations were more pronounced in diabetics.

FP183 Table 1

*abaseline NT-proBNP values not available for one trial*p<0.05, **p<0.01, ***p<0.001CV: cardiovascular; Hb, hemoglobin; HR: high risk; LR: low risk

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Nephrology Dialysis Transplantation 27 (Supplement 2): ii133–ii145, 2012doi:10.1093/ndt/gfs217

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FP185 HIGHER DOSING REQUIREMENTS OF PEGINESATIDE ANDEPOETIN FOR TREATMENT OF ANEMIA IN US VS NON-USHEMODIALYSIS (HD) PATIENTS

Iain Macdougall1, Iain Macdougall1, Brigitte Schiller2, Francesco Locatelli3,Andrzej Wiecek4, Carol Francisco5, Helen Tang5, Sandra Tong5, Minjia Chen5,Anne-Marie Duliege5, Krishna Polu5, Martha Mayo5 and Adrian Covic61King's College Hospital, London, United Kingdom, 2Satellite Healthcare, Inc.,San Jose, Ca, USA, 3Ospedale A. Manzoni, Lecco, Italy, 4Department ofNephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia,5Affymax, Inc., Palo Alto, Ca, USA, 6University of Medicine 'gr. T. Popa' Iasi

Introduction and Aims: Lower dose requirements have previously been reportedwith subcutaneous (SC) vs intravenous (IV) dosing of epoetin for treatment ofanemia in patients on dialysis (Kaufman et al. NEJM 1998). Peginesatide is asynthetic, PEGylated, investigational, peptide-based ESA developed for the treatmentof anemia due to chronic kidney disease (CKD) for patients on dialysis. Peginesatidedemonstrated noninferiority to epoetin in maintenance of hemoglobin (Hb) levels inHD patients in two global Phase 3 randomized, active-controlled, open-label trials(EMERALD 1, 2; Schiller et al. ASN 2010). This retrospective analysis compareddose requirements (IV or SC) and cardiovascular (CV) safety between US andnon-US HD patients in the two trials.Methods: Pooled data from the two trials assessed safety and efficacy of peginesatide(once monthly; N=1066) compared with epoetin (1-3 times weekly; N=542) in HDpatients previously on stable epoetin. Patients received study drug via the sameadministration route (IV or SC) used at time of screening. Crude rates of CVcomposite safety events (CSE; stroke, myocardial infarction, death, serious adverseevents of congestive heart failure [CHF], unstable angina, arrhythmia) weresummarized by region. US (n=853 peginesatide; n=436 epoetin) and non- USpatients (n=213 peginesatide; n=106 epoetin) were compared.Results: US and non-US patients differed significantly in several baselinecharacteristics, including higher rates of CHF and of diabetes as cause of CKD,higher BMI, inflammatory markers, ACE inhibitor and angiotensin receptor blockeruse, and lower iron stores in US patients. US patients had a mean BMI of 30 and 29kg/m2 (peginesatide and epoetin, respectively), compared with 26 kg/m2 (both arms)in non-US patients. While mean Hb levels were similar across regions, medianweight-adjusted ESA doses were higher in US than non-US patients, regardless ofroute of administration (Figure). Across regions, epoetin dose during the evaluation

period (EP; wks 29-36) was lower with SC vs IV route (US: 90 vs 121 U/kg/wk;non-US: 63 vs 72 U/kg/wk), but this trend was not observed with peginesatide (US:0.08 vs 0.07 mg/kg; non-US: 0.06 vs 0.05 mg/kg). CSE events were also higheramong US vs non-US patients, regardless of treatment arm (US: 25% peginesatide,27% epoetin; non-US: 14% peginesatide; 15% epoetin).Conclusions: In these randomized controlled trials, a lower dose requirement ofepoetin was observed for SC compared to IV administration during the EP; thispersisted even after adjustment for different BMIs in US vs non-US patients. Thisobservation was not evident for peginesatide. Overall, US patients had higherweight-adjusted ESA dose requirements and higher rates of CSE events than non-USpatients.

FP186 LONG-TERM RESULTS FROM A STUDY OF PEGINESATIDEIN PATIENTS WITH ANTIBODY-MEDIATED PURE RED CELLAPLASIA (AB+PRCA)

Iain Macdougall1, Iain Macdougall1, Nicole Casadevall2, Richard Stead3,Maarten Taal4, Bernadette Faller5, Alexandre Karras6, Minjia Chen7,Sandra Tong7, Anne-Marie Duliege7, Richard Rowell7, Krishna Polu7 andKai-Uwe Eckardt81King's College Hospital, London, United Kingdom, 2Hôpital Saint Antoine, Paris,France, 3Biopharma Consulting Services, Bellevue, Wa, USA, 4Royal DerbyHospital, Derby, United Kingdom, 5Hôpitaux Civils, Colmar Cedex, France,6Néphrologie, Hegp, Paris, France, 7Affymax, Inc., Palo Alto, Ca, USA,8University of Erlangen-Nuremberg, Erlangen, Germany

Introduction and Aims: Ab+PRCA is a rare but debilitating condition caused byanti-erythropoietin (EPO) antibodies that may develop after treatment of anemiawith human recombinant EPO. Peginesatide is a synthetic, PEGylated,investigational, peptide-based erythropoiesis-stimulating agent in development fortreatment of anemia in patients with chronic kidney disease (CKD) on dialysis. APhase 2 study of peginesatide treatment for Ab+PRCA in CKD patients previouslydemonstrated durable correction of anemia without regular RBC transfusions in 13of 14 patients treated up to 36 months (median 28 months of treatment)(Macdougall et al. NEJM 2009; 361:1848). Here we present updated results from thestudy, wherein patients were followed for up to 60 months.Methods: This open-label study evaluated peginesatide treatment for anemia in CKDpatients in Europe with documented Ab+PRCA. Both dialysis and non-dialysispatients were included. The primary objective was to evaluate the ability ofpeginesatide to increase and maintain hemoglobin (Hb) levels in these patients.Secondary objectives were to evaluate safety, and the ability of peginesatide to reducethe frequency of red blood cell transfusions over time. Hb, peginesatide dose, ironstorage (serum ferritin and TSAT), anti-EPO antibody titers, and transfusionrequirements were monitored. Only patients with at least 6 months of dosing wereevaluated.Results: As of March 2011, 18 patients (11 dialysis and 7 non-dialysis patients) withconfirmed Ab+PRCA were enrolled. Median Hb values increased from 8.2 g/dL to11.5 g/dL by 4 months, remaining at or near this level for up to 60 months (Figure).Peginesatide dosing remained constant for the duration of the study (Figure).Anti-EPO antibody levels were decreased (median ~10 U/mL at baseline to <1 U/mLby 56 weeks and thereafter). Median serum ferritin and TSAT gradually decreasedover time, reaching >50% reduction from baseline by 1 and 3 years, respectively, afterinitiation of peginesatide (ferritin: 2070 mg/L to 911 mg/L, n=16; TSAT: 90.0% to40.3%, n=11). Mean peginesatide doses were similar between dialysis andnon-dialysis PRCA patients. Peginesatide treatment within this population continuedto show no new safety concerns.Conclusions: Updated results from this study of peginesatide for Ab+PRCAdemonstrated sustained correction of anemia without requirement for regular RBCtransfusions. Reduction in serum ferritin and TSAT is indicative of reversal of ironoverload, albeit via slow mobilization of iron. For dialysis patients, the mean SC

FP185 Figure.: Mean Hb and Median Weight-Adjusted Dose, (A) US and (B)non-US FP186

FP184

Abstracts Nephrology Dialysis Transplantation

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peginesatide doses were similar between the PRCA patients in this study andnon-PRCA patients in previous Phase 3 peginesatide studies. For the non-dialysispatients, the mean SC peginesatide doses were much higher for the PRCA patientsthan for non-PRCA patients in previous Phase 3 peginesatide studies.

FP187 CHARACTERISTICS OF PATIENTS WITH CHRONIC KIDNEYDISEASE ON DIALYSIS WITH A POOR RESPONSE TOCONTINUOUS ERYTHROPOIETIN RECEPTOR ACTIVATOR (C.E.R.A.) ONCE MONTHLY: AN ANALYSIS OF 10INTERNATIONAL TRIALS

Francesco Locatelli1 and Sylvie Dusilova Sulkova21Department of Nephrology, Dialysis and Renal Transplant, Alessandro ManzoniHospital, 2Department of Nephrology, Institute for Clinical and ExperimentalMedicine

Introduction and Aims: Some patients switched from shorter-actingerythropoiesis-stimulating agents to longer-acting agents have a poor response interms of hemoglobin (Hb) levels. This analysis of 10 international trials explores thecharacteristics of patients with chronic kidney disease (CKD) on dialysis whorespond poorly to C.E.R.A. once monthly (QM).Methods: Adult CKD patients on dialysis were switched to C.E.R.A. QM to achievetarget Hb levels of 10.0–12.0 g/dL (5 studies; n=710), 10.5–12.5 g/dL (3 studies;n=459), 11.0–12.5 g/dL and 11.0–13.0 g/dL (one study each; n=408). Followingtreatment switchover, there was a 16- week titration period followed by a 8-weekevaluation period, in which Hb parameters were obtained. Patients whoachieved maintenance Hb target (>10 g/dL) during the evaluation period (propermaintenance [PM] group) were compared with those with Hb <10 g/dL (not propermaintenance [NPM] group). Baseline characteristics before the switch to C.E.R.A.QM and therapy parameters during the screening period were compared.Results: From a total of 1577 patients (median age 63, range 19–93 years), 1296(82.2 %) patients were in the PM group and 281 (17.8 %), in the NPM group.Comparing baseline characteristics of the two groups, the PM group had asignificantly higher mean age (2.1 years, p<0.03) and a higher proportion ofCaucasian patients (odds ratio [OR]=1.85, p<0.02). A lower proportion of patients inthe PM group had CKD due to diabetes (OR=0.67, p=0.02), while more patients hadpolycystic kidney disease than in the NPM group (OR=2.6, p=0.05). N-terminalfragment brain natriuretic peptide levels and baseline cardiac risk factors did notdiffer between the two groups. The PM group had a significantly higher proportionof patients with iron supplementation (p<0.0001), significantly higher Hb levels(p<0.0002) and a significantly lower ESA dose/Hb ratio (p<0.0001) than the NPMgroup during the screening period.Conclusions: The pooled analysis shows that the presence of a number ofpre-existing factors associated with anemia can partially explain the poor response ofpatients with CKD on dialysis when switching to C.E.R.A. QM. Cardiovascular statusdoes not seem to affect successful Hb maintenance.

FP188 IMPACT OF ON-LINE HAEMODIAFILTRATION ON THEMANAGEMENT OF ANAEMIA BY CERA: HDFHD STUDY,INTERIM ANALYSIS

Stolz Arnaud1, Paris Bruno2, Guérard Arnaud2, Visanica Dorina2, Azoulay Eric2and Mangenot Gérard3

1Saint André Private Hospital Metz, France, 2Saint André Private Hospital Metz,France, 3Saint André Private Hospital Metz,France

Introduction and Aims: Haemodiafiltration (HDF) is used sporadically for renalreplacement therapy, in Europe (1,8 to 20,1% )1 and in France (8 %)2. On-line HDFis a technique with a good elimination capability of greater potentially toxic particles.Some studies suggest quality of life improvement, mortality rate reduction and allowsa better control of anaemia1,3. Indeed, several studies have shown a reduction of thedose of erythropoietin stimulating agent (ESA) needed to achieve the Hb target inHDF patients4-7 but no data were available for CERA (methoxy polyethyleneglycol-epoetin beta), a continuous erythropoietin receptor activator injected once amonth. Our aims were to evaluate the stabilization of Hb levels and ESA conumptionin Chronic Renal Failure (CRF) patients treated with CERA based on modes ofdialysis.Methods: HDFHD is a longitudinal, observational, mono centre study of twelvemonths. Patients with CRF, on conventional high permeability haemodialysis (HD)or High flux on-line haemodiafiltration (HDF) with an anaemia treated by ESA forat least six months and converting to CERA for at least three months wereconsidered for inclusion. The interval [-1; 1] g/dl defined the stabilization of Hblevel. The factors influencing the Hb rate was studied by using a univariate andmulti-variate model. The average quantity of CERA administered was comparedbetween the two groups using Student’s t-test with 5% significance level, andpresented with 95% confidence interval, adjusted for co-variances (sex, age, Hb level

before the studied treatment initiation). We conducted an interim analysis in patientswho completed 6 months of follow- up after converting to CERA.Results: 58 patients were included during the study period, 28 in HD and 30 in HDFgroup. Baseline characteristics for HD and HDF patients were similar except for thelength of dialysis and duration of treatment with ESA : age (72.7 ± 11.1 vs 72.8 ±10.8 ;p = 0.976); male (60.7 % vs 63.3 %; p =0.837); cardiovascular history (89.3 % vs86.7 %; p > 0.999); history of diabete (39.3 % vs 46.7 %; p = 0.606); length of dialysis(0.2 ± 0.8 years vs 2.5 ± 3 years; p < 0.001); duration of treatment with ESA (1.1 ±0.2 years vs 2.6 ± 1.8; p < 0.001). Furthermore, hemoglobin level was slightlydifferent between HD and HDF group at the time of initiation of CERA (11.6 ± 1 g/dl vs 11.2 ± 1g/dl; p = 0.026) and after 6 months of treatment (11.5 ± 0.9 g/dl vs11.1 ± 0.9 g/dl; p =0.027 ). Stabilization of Hb level in HD and HDF groups wasrespectively reached for 63% vs 52% of patients (p = 0.575). Otherwise, we observeda reduction in consumption of CERA between HDF and HD group during the first 3months (91 ± 49 μg vs 119.7 ± 64.3 μg ;p <0.001) of treatment. At the fourth to sixthmonths period, reduction dose consumption was confirmed by 35.1% (82.2 ± 51.1 μgvs 126.7 ± 75.2 μg ;p <0.001). Univariate analysis of factors influencing theeffectiveness of ESA, such as iron parameters (Ferritin, CST), PTH, CRP, Albumin,shown no differences between the two groups during this six month of follow-upexcept Kt/V (M1 –M3 : 1.4 HD vs 1.5 HDF; P < 0.001 and M4- M6 : 1.4 HD vs 1.6HDF ; p < 0.001).Conclusions: This interim analysis of the first study comparing CERA performancein HD and HDF showed no difference between the two groups for stabilization ofHb level. Moreover, as others ESA, we observed significantly reduction of CERAdoses needed to achieve the goal in term of hb rate in HDF patients with a reducedconsumption by 35 % at 4 to 6 months period.

FP189 PROSPECTIVE OBSERVATIONAL MULTICENTER STUDY TOEVALUATE THE EFFECTIVENESS AND SAFETY OFMETHOXY POLYETHYLENE GLYCOL-EPOETIN BETA(MIRCERA®) IN PATIENTS WITH ANAEMIA SECONDARY TOCHRONIC KIDNEY DISEASE. MINERVA STUDY

Aleix Cases1, J.M. Portolés2, J. Calls3, A. Martínez Castelao4,D. Sánchez-Guisande5 and A. Segarra61Nephrology and Transplantation Unit, Hospital Clínic, Barcelona, Spain,2Hospital Universitario Puerta de Hierro, Madrid, Spain, 3Hospital de Manacor,Palma de Mallorca, Spain, 4Hospital de Bellvitge, Barcelona, Spain, 5Hospital deBarbanza, A Coruña, Spain, 6Hospital Vall D'hebron, Barcelona, Spain

Introduction and Aims: MIRCERA® is a continuous erythropoietin receptoractivator approved for the treatment of symptomatic anaemia associated with chronickidney disease (CKD). This study was intended to evaluate the effectiveness andsafety of MIRCERA® when administered in patients with anaemia secondary to CKDin routine clinical practice.Methods: This was an observational, prospective, multicenter study. Information wascollected from CKD patients both on haemodialysis (HD) and not on dialysis and ontreatment with MIRCERA®. Patients were either correcting anaemia or had beenconverted from other erythropoiesis-stimulating agents (ESAs). Therefore patientswere classified as ESA-naïve, or on maintenance. Study data was recorded frombaseline visit, at month 6, and month 12. Final results are presented.Results: A total of 227 patients was evaluated (mean age, 71.2±14.7 years; male,55.5%). Diabetic nephropathy was the most common etiology of CKD (27.8%).Eighty-five (37.4%) patients were on HD and 142 (62.6%) were not on dialysis[eGFR (MDRD-4 equation): 24.7±9.6 ml/min]. The proportion of ESA-naïve patientsor those on maintenance were 14.5%, and 85.5%, respectively. Among HD patients,66.7% converted from epoetin beta and 33.3% from darbepoetin alfa with a meanweekly dose of 8,574.6±6,083.3IU and 29.7±33.1mcg, respectively; whereas patientsnot on dialysis, 81% had previously received epoetin beta (5,292.5±5,989.3 IU/week)and 19% darbepoetin alfa (52.2±29.7 mcg/week). Mean Hb levels in naïve patientsnot on dialysis between baseline, month 6, and month 12 were 10.7±1.2g/dl, 11.5±1g/dl, and 11.4±1.4g/dl, respectively; p<0.05. The percentage of patients onmaintenance and not on dialysis with Hb level within 11-12 g/dl did not changesignificantly between baseline (43.6%), month 6 (29.9%), and month 12 (43.1%);p>0.05. Similarly, the proportion of patients on maintenance and HD with Hb levelwithin 11-12 g/dl was 33.7%, 27%, and 32.7%, respectively (p>0.05). MeanMIRCERA® doses at month 12 were 106.3mcg (baseline, 86.3mcg) in naïve patients,104.1mcg (baseline, 100mcg) on maintenance and not on dialysis patients, and170.7mcg (baseline, 161.1mcg) on maintenance HD patients, with no significantdifferences. Maintenance HD patients required a mean number of 1.8±1.5 doseadjustment, whereas patients who converted from other ESAs needed 2.2±1.5 doseadjustments. No MIRCERA®-related adverse events were reported during the study.Conclusions: Results from this study indicate that monthly administration ofMIRCERA® in routine clinical practice is an effective and safe option for thetreatment of anaemia secondary to CKD in patients either on haemodialysis or noton dialysis. These data support the results obtained from previous phase III/IVclinical trials.

Nephrology Dialysis Transplantation Abstracts

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FP190 EFFICACY AND SAFETY OF PEGINESATIDE IN JAPANESECHRONIC KIDNEY DISEASE PATIENTS NOT ON DIALYSIS

Yoshiharu Tsubakihara1, Yoshiharu Tsubakihara1, Akira Saito2 and Af37702/Cct-001 Study Group3

1Department of Kidney Disease and Hypertension, Osaka General MedicalCenter, Osaka, Japan, 2Yokohama Dai-Ichi Hospital, Yokohama, Japan, 3Japan

Introduction and Aims: Peginesatide, previously referred to as Hematide™, is anovel synthetic peptide-based, PEGylated erythropoiesis stimulating agent (ESA).The aim of this study is to evaluate efficacy and safety of peginesatide for thetreatment of renal anemia, compared with rHuEPO (epoetin beta), in Japanesechronic kidney disease (CKD) patients not on dialysis and not on ESA treatment.Methods: This was a multicenter, randomized, active-controlled, open-label phase 3study in Japanese non-dialysis CKD patients. Those who had not received ESAtreatment for at least 12 weeks and had hemoglobin (Hb) values of less than 10.0 g/dL were randomly assigned (1:1 ratio) to receive subcutaneously once-monthlypeginesatide (1.0 - 2.5 mg/4week) or weekly rHuEPO (6000 IU/week). Forpeginesatide group, doses were subsequently adjusted to maintain Hb levels between10.0 and 12.0 g/dL during the study period of 24 weeks. For rHuEPO group,biweekly rHuEPO (6000 IU/2week) was administered after achieving the target Hbvalue (≥10.0 g/dL), and then, doses were adjusted to maintain Hb levels between10.0 and 12.0 g/dL during the study period of 24 weeks. The primary endpoint wasthe change from baseline in mean Hb values evaluated from Week 16 to Week 24,and the primary objective was to determine whether peginesatide was equivalent torHuEPO.Results: A total of 230 patients (mean age, 67.0 years; men 55.7%) were randomized,and 229 patients (peginesatide group, n=115, rHuEPO group, n=114) received studydrug. As for efficacy, the mean (S.D.) of the primary endpoint in the peginesatideand rHuEPO groups was 1.945 g/dL (0.8518 g/dL) and 2.026 g/dL (0.8348 g/dL),respectively. The difference in the primary endpoint between two groups was -0.0803g/dL (95% CI = -0.3087 to 0.1481 g/dL), and met the statistical criterion for theequivalence (?=0.75 g/dL). The mean Hb values in the peginesatide and rHuEPOgroups reached 10.0 g/dL at Week 6 and Week 3, respectively, and were stablymaintained between 10.0 and 12.0 g/dL thereafter in both treatment groups. As forsafety, adverse events (AEs) and Serious AEs (SAEs) were consistent betweentreatment groups.

Conclusions: This was the first study to demonstrate that once-monthly peginesatidetreatment was equivalent in efficacy to rHuEPO (weekly or biweekly) and had asimilar safety profile in a population of Japanese CKD patients not on dialysis andnot on ESA treatment.

FP191 EFFICACY AND SAFETY OF PEGINESATIDE IN JAPANESECHRONIC KIDNEY DISEASE PATIENTS ON HEMODIALYSIS

Akira Saito1, Akira Saito1, Yoshiharu Tsubakihara2 and Af37702/Cct-101 StudyGroup3

1Yokohama Dai-Ichi Hospital, Yokohama, Japan, 2Department of Kidney Diseaseand Hypertension, Osaka General Medical Center, Osaka, Japan, 3Japan

Introduction and Aims: Peginesatide, previously referred to as Hematide™, is anovel synthetic peptide-based, PEGylated erythropoiesis stimulating agent (ESA).The aim of the study is to evaluate efficacy and safety of peginesatide for thetreatment of renal anemia, compared with rHuEPO (epoetin beta), in Japanesechronic kidney disease (CKD) patients on hemodialysis (HD) and previously onrHuEPO treatment.Methods: This was a multicenter, randomized, active-controlled, double-blind, Phase3 study in Japanese HD patients. Those who were previously treated with rHuEPOand had hemoglobin (Hb) values of 10.0 - 12.0 g/dL were randomly assigned (1:1ratio) to receive once-monthly peginesatide (2.0 to 6.0 mg/4week) or twice/thriceweekly rHuEPO (3,000 to 9,000 IU/week). Doses were subsequently adjusted tomaintain Hb levels between 10.0 to 12.0 g/dL during the study period of 24 weeks.The primary endpoint was the change from baseline in mean Hb values evaluatedfrom Week 16 to Week 24, and the primary objective was to determine whetherpeginesatide were equivalent to rHuEPO.Results: A total of 156 patients (mean age, 61.2 years; men, 60.9%) were randomized,and 154 patients (peginesatide group, n=79, rHuEPO group, n=75) received studydrug. As for efficacy, the mean (S.D.) of the primary endpoint in the peginesatide

and rHuEPO groups was -0.157 g/dL (0.6475 g/dL) and 0.340 g/dL (0.6677 g/dL),respectively. The difference in the primary endpoint between two groups was -0.4971g/dL (95% CI = -0.7138 to -0.2804 g/dL), and met the statistical criterion for theequivalence (?=1.0 g/dL). The mean Hb values in the peginesatide and rHuEPOgroups were stably maintained between 10.0 and 12.0 g/dL throughout the studyperiod. As for safety, adverse events (AEs) and Serious AEs (SAEs) were consistentbetween treatment groups.

Conclusions: This was the first study to demonstrate that once-monthly peginesatidetreatment was equivalent in efficacy to rHuEPO (twice/thrice weekly) and hadsimilar safety profile in a population of Japanese CKD patients on HD andpreviously on rHuEPO treatment.

FP192 MANAGEMENT OF RENAL ANAEMIA IN PATIENTS WITHCHRONIC KIDNEY DISEASE STAGES 3, 4 AND 5 NOT ONDIALYSIS TREATED WITH C.E.R.A. IN CATALONIANNEPHROLOGY UNITS (THE MICENAS II STUDY)

A. Martínez-Castelao1, Alberto Martínez-Castelao1, A. Cases2, J. Fort3,J. Bonal4, X. Fulladosa1, J.M. Galcerán5, V. Torregrosa1 and E. Coll61Nephrology Unit, Hospital de Bellvitge, Barcelona, Spain, 2Nephrology andTransplantation Unit, Hospital Clínic, Barcelona, Spain, 3Nephrology Unit,Hospital Vall D'hebron, Barcelona, Spain, 4Nephrology Unit, Hospital GermansTrias I Pujol, Badalona, Spain, 5Nephrology Unit, Fundación Althaia, Manresa,Spain, 6Nephrology Unit, Fundación Puigvert, Barcelona, Spain

Introduction and Aims: C.E.R.A. (methoxy polyethylene glycol-epoetin beta)treatment corrects and maintains stable hemoglobin levels administered oncemonthly in patients with chronic kidney disease (CKD). The aim of the study was toknow the therapeutic management of renal anaemia in patients with CKD stages 3-5not on dialysis treated with C.E.R.A. in Catalonia.Methods: An observational retrospective study was conducted in CatalonianNephrology Units. The study was approved by an Ethical Committee. CKD patientsstages 3, 4 and 5 not on dialysis, or 5-T, aged =18 years, with anaemia and treatedwith C.E.R.A. at least during 6 months, who gave their informed consent wereconsecutively recruited. Patients without data for C.E.R.A. dose and haemoglobin(Hb) measurement at the beginning of C.E.R.A. treatment and at least two additionalevaluations were dismissed for analysis.Results: A total of 331 patients were recruited by 15 investigators, of which 272 werevalid for analysis. 52.2% of patients were women with a mean age of 66.6±17.3 years;mean time from CKD and from anaemia diagnosis was 8.4±8.9 and 4.3±4.1 years,respectively. 38.5% of the patients were kidney transplant recipients. More commoncauses of CKD were diabetic nephropathy (18%) and vascular disease (17.3%). 40.4%out of the 272 patients had CKD stage 3, 46.7% stage 4 and 12.9% stage 5. Of them,51.8% of patients had been previously treated with an erythropoiesis stimulatingagent (ESA) and 48.2% were naïve patients. Epoetin-beta (56.6%) was the mostcommon previous ESA. Mean Hb at the beginning of C.E.R.A. treatment for naïvepatient was 10.2±0.9 g/dL and 11.5±1.2 g/dL for patients converted to C.E.R.A.(U-Mann Whitney test; p<0.05). 40.7% of patients were receiving iron at theinitiation of C.E.R.A. treatment. The mean initial monthly C.E.R.A. dose in naïveand converted patients was 85.5±36.6 and 87.6±34.9 μg, respectively. At 6 months,mean C.E.R.A. dose was 82.9±40.2 and 90.8±45.6 μg, respectively. Median C.E.R.A.dose at baseline and 6 months was 75 μg per month in naïve and converted patients.Regarding previous ESA and the respective ranks of weekly dose administered: <8000UI; 8000-16000 UI; >16000 UI; mean C.E.R.A. dose administered per month inconverted patients was 87.7±48.0 μg; 79.5±23.1 μg; 100.9±43.7 μg, respectively. After6 months with C.E.R.A. treatment, mean Hb level showed a significant increase of1.4±1.5 g/dL for naïve patients (Student-t Test; p<0.05). Stable Hb levels frombaseline to month 6 were observed for patients converted to C.E.R.A. from aprevious ESA (mean change 0.2±1.5 g/dL; Student-t Test; p>0.05). When regardingESA doses and Hb levels at base-line and at the time of the observation, nodifferences were observed comparing CKD patients with or without a renaltransplant.Conclusions: C.E.R.A. once monthly corrects anemia in ESA naïve CKD patientsand maintains stable Hb levels in CKD patients converted from a previous ESA.Conversion from a previous ESA to C.E.R.A. requires lower doses than thoserecommended by the Summary of Product Characteristics.

FP190 Table 1 Primary Endpoint: Change from baseline in mean Hb valuesevaluated from Week 16 to Week 24

FP191 Table 1. Primary Endpoint: Change from baseline in mean Hb valuesevaluated from Week 16 to Week 24



FP193 SWITCH TO LOW DOSE C.E.R.A. MAINTAINS HEMOGLOBIN(HB) LEVELS IN NON DIALYSIS CHRONIC KIDNEY DISEASE(CKD): A MULTICENTRIC PROSPECTIVE STUDY IN ITALY

Roberto Minutolo1, Mario Cozzolino2, Biagio DI Iorio3, Pasquale Polito4,Domenico Santoro5, Flavia Manenti6, Felice Nappi7, Sandro Feriozzi8,Giuseppe Conte9 and Luca De Nicola91DIV Nephrology, Second University of Naples, Naples, Italy, 2Dmco, Universityof Milan, Renal Division, San Paolo Hospital, Milan, Italy, 3County HospitalSolofra, 4County Hospital Tivoli, 5University of Messina, 6San Salvatore Hospital,Pesaro, 7County Hospital Nola, 8Belcolle Hospital Viterbo, 9Second University ofNaples

Introduction and Aims: Recent trials have emphasized the need of finding thelowest effective dose of erythropoiesis stimulating agents (ESA). This holdsparticularly true in non-dialysis CKD where ESA are prescribed at doses remarkablylower than in dialysis patients and long-acting agents are preferred. This study wasaimed at evaluating efficacy of switching either darbepoetin (DA) or a/b epoetin(EPO) to the long-acting ESA (C.E.R.A.) at doses lower than those recommended bymanufacturer.Methods: We selected consecutive adult CKD stage III-IV patients receiving eitherDA =60 μg/wk or EPO =12,000 IU/wk unchanged in the previous 3 months. Weexcluded patients with kidney transplant, iron deficiency, recent blood transfusion,bleeding, neoplasia, myocardial infarction or stroke in the last 3 months. Patientstreated with DA =20 μg/wk or EPO =4,000 IU/wk were switched to C.E.R.A. 75 μg/month; those treated with DA 21-40 μg/wk or EPO 4,001-8,000 IU/wk were switchedto C.E.R.A. 100 μg/month and those receiving DA 41-60 μg/wk or EPO 8,001-12,000IU/wk were switched to C.E.R.A. 120 μg/month. Patients were evaluated monthly inthe 24 wks after switch. Primary endpoint was maintenance of Hb in the range 11-13g/dL.Results: We selected 162 patients (safety population); of these, 152 (efficacypopulation) completed the study (8 were lost to follow-up and 2 reached ESRD).Mean age was 73±12 yrs and body weight was 73±15 kg; prevalence of males,diabetes and prior CV disease was 49%, 34% and 18%, respectively. Doses of DA(n=120) and EPO (n=32) before switching were 25±16 μg/wk and 5,630±3,214 IU/wk, respectively.

C.E.R.A. dose was unchanged in 779 out of 912 visits (85%), increased in 55 (6%)and decreased in 78 (9%) visits. The mean number of dose adjustment per patientwas 0.9±1.0. In safety population, no patients required blood transfusions; eightpatients were hospitalized for CV (n=4), metabolic (n=2) and surgical causes (n=2).Blood pressure did not change; four patients had systolic level >180 mmHg in asingle occasion.Conclusions: This study suggests that in CKD stage III-IV patients, switching fromother ESAs to C.E.R.A. at doses lower than the recommended threshold is associatedwith maintenance of adequate anemia control in absence of safety concerns and withsmall percentage of dose changes during the follow-up.

FP194 DOSE RELATIONSHIP BETWEEN PEGINESATIDEAND EPOETIN FOR PATIENTS ON DIALYSIS

Ashraf Mikhail1, Robert Provenzano2, Brigitte Schiller3, Anatole Besarab4,Carol Francisco5, Hong-Ye Gao5, Richard Daley5, Sandra Tong5, Martha Mayo5,Alex Yang5, Krishna Polu5 and Iain Macdougall61Renal Unit, Morriston Hospital, Swansea, United Kingdom, 2Saint ClaireSpecialty Physicians, Pc, Detroit, MI, USA, 3Satellite Healthcare, Inc., San Jose,Ca, USA, 4Henry Ford Hospital, Detroit, MI, USA, 5Affymax, Inc., Palo Alto, Ca,USA, 6King's College Hospital, London, United Kingdom

Introduction and Aims: It has been hypothesized that there may be a directrelationship between increased cardiovascular risk and epoetin dose in chronickidney disease (CKD) patients. Development of longer-actingerythropoiesis-stimulating agents (ESAs) with less frequent dosing requirementscould provide an alternative therapeutic option for anemia management in patients

with CKD. Peginesatide is a once monthly PEGylated, investigational, peptide-basedESA in development for treatment of anemia in CKD patients on dialysis. Two Phase3 randomized, open-label, active-controlled trials (EMERALD 1, 2) demonstratednoninferiority of peginesatide to epoetin in maintaining Hb levels in hemodialysis(HD) patients previously receiving 1-3 times weekly epoetin (Schiller et al. ASN2010). This retrospective analysis evaluated the relationship between baseline (BL)epoetin doses and peginesatide dose.Methods: Data from the two trials were pooled (peginesatide, once monthly,N=1066; epoetin 1-3 times weekly, N=542). BL epoetin dose for all patients duringthe week prior to randomization was divided into quartiles; patients in the lowestquartile (“low” BL epoetin) received =4800 U/week, while those in the highestquartile (“high” BL epoetin) received =16350 U/week. For patients receivingpeginesatide, the relationship between BL epoetin dose and mean peginesatide doseduring the evaluation period (EP; weeks 29-36) was evaluated, and the dose ratio (BLepoetin/EP peginesatide) was calculated for each patient. Subgroup analysis ofdiabetic vs non-diabetic patients was included.Results: The relationship between BL epoetin and peginesatide dose was nonlinear(Figure); for patients receiving “high“ BL epoetin, the relative peginesatide dose wasless than half that of patients receiving “low“ BL epoetin (median dose ratio: 2153:1for “high“ vs 1044:1 for “low“). The dose relationship was similar in diabetic andnon-diabetic subgroups (Figure). Of note, Hb levels were similar at BL and duringthe EP across the dose quartiles.Conclusions: For patients requiring high ESA doses, a strategy to reduce overallexposure to ESA therapy while maintaining Hb within target could be a bettertherapeutic option. The relationship between epoetin and peginesatide dose wasnonlinear, suggesting that HD patients requiring more epoetin at baseline (i.e., lessresponsive) tend to require relatively less peginesatide to achieve similar Hb levels. Asa result, ESA dose requirements may be reduced in those patients who are relativelyless responsive. Given current concerns about the association between ESA exposureand increased cardiovascular risk, these post hoc data are of interest and warrantfurther evaluation.

FP195 RELATIONSHIP BETWEEN CARDIOVASCULAR (CV) EVENTS,MORTALITY AND DOSES OF PEGINESATIDE VS EPOETIN INHEMODIALYSIS (HD) PATIENTS

Andrzej Wiecek1, Brigitte Schiller2, Bernard Canaud3, Francesco Locatelli4,Alex Yang5, Minjia Chen5, Krishna Polu5, Carol Francisco5, Hong-Ye Gao5,Sandra Tong5, Anne-Marie Duliege5 and Robert Provenzano61Department of Nephrology, Endocrinology and Metabolic Diseases, MedicalUniversity of Silesia, 2Satellite Healthcare, Inc., San Jose, Ca, USA, 3University ofMontpellier, Hôpital Lapeyronie, Dep. of Nephrology, Montpellier, France,4Ospedale A. Manzoni, Lecco, Italy, 5Affymax, Inc., Palo Alto, Ca, USA, 6SaintClaire Specialty Physicians, Pc, Detroit, MI, USA

Introduction and Aims: Previous studies have reported an association between highdoses of erythropoiesis- stimulating agents (ESAs) and increased risk for CV eventsand death (Szczech et al. 2008 KI 74:791). Peginesatide is a synthetic, PEGylated,investigational, peptide-based ESA developed for the treatment of anemia in chronickidney disease patients on dialysis. Peginesatide demonstrated noninferiority toepoetin for maintaining hemoglobin in HD patients in two Phase 3 randomized,active-controlled, open-label trials (Schiller et al. ASN 2010). This retrospectiveanalysis evaluated relationships between CV events, mortality and ESA dose.Methods: Pooled data from the two trials (EMERALD 1, 2) were used to comparepeginesatide (once monthly; N=1066) with epoetin (1-3 times weekly; N=542) in HDpatients. The mean exposure-adjusted ESA dose per patient was calculated ascumulative dose divided by on- drug exposure time (i.e., when patient was on studytreatment). Dose categories were defined by quartile dose ranges: Q1: =3.23 mg/Q4W(peginesatide) or =4500 U/wk (epoetin); Q2: >3.23 to =5.20 mg/Q4W or >4500 to=8400 U/wk; Q3: >5.20 to =8.79 mg/Q4W or >8400 to =15000 U/wk; Q4: >8.79 mg/Q4W or >15000 U/wk. An adjudicated CV composite safety endpoint (CSE)included stroke, myocardial infarction, death, serious adverse events of congestiveheart failure, unstable angina, and arrhythmia. Exposure-adjusted event rates (EAER)of on-drug CSE and mortality rates by mean dose quartile (Q1-Q4), risk ratio ofEAER (RR, peginesatide:epoetin), and 95% CI are summarized.Results: CSE event rates were lowest among the lowest dose quartile (=3.23 mg/Q4Wpeginesatide or =4500 U/Wk epoetin), reaching its peak at Q3 (5.20 to 8.79 mg/Q4W) for peginesatide and at the highest dose quartile (>15000 U/wk) for epoetin.The overall RR for CSE event rates was 0.84 (95%CI, 0.67-1.05). Mortality rates were

FP193 Table 1

*P=0.004 for trend

FP194



1.5- to 2-fold higher in the epoetin arm than the peginesatide arm for each of the dosequartiles. The overall RR for mortality was 0.58 (95%CI, 0.39-0.87), favoringpeginesatide. CSE and mortality rates by dose quartiles are presented in the figure below.

Conclusions: Peginesatide and epoetin showed similar associations of higher CSEevent rates at higher ESA doses. While there was no clear association of mortalitywith ESA dose, mortality rates appeared to be lower with peginesatide comparedwith epoetin.

FP196 IRON UTILIZATION IN US HEMODIALYSIS (HD) PATIENTSTREATED WITH PEGINESATIDE VS EPOETIN FOR ANEMIAOF CHRONIC KIDNEY DISEASE (CKD)

Francesco Locatelli1, Francesco Locatelli2, Robert Provenzano3,Anatole Besarab4, Thomas Rath5, Alex Yang6, Martha Mayo6, Carol Francisco6and Iain Macdougall71Ospedale A. Manzoni, Lecco, Italy, 2Department of Nephrology, Dialysis andRenal Transplant, Alessandro Manzoni Hospital, 3Saint Claire SpecialtyPhysicians, Pc, Detroit, MI, USA, 4Henry Ford Hospital, Detroit, MI, USA,5Westpfalz-Klinikum Kaiserslautern Medizinische Klinik III Abteilung FürNephrologie und Transplantation, Kaiserslautern, Germany, 6Affymax, Inc., PaloAlto, Ca, USA, 7King's College Hospital, London, United Kingdom

Introduction and Aims: Iron deficiency, defined as TSAT <20% or serum ferritin<100 ng/mL, which occurs in the absence of iron supplementation in HD patientstreated with erythropoiesis-stimulating agents (ESAs), due to high rates of RBCproduction and increased iron losses in this population. Peginesatide is a synthetic,PEGylated, investigational, peptide-based ESA developed for the treatment of anemiadue to CKD in patients on dialysis. Two Phase 3 randomized open-label,active-controlled trials (EMERALD 1,2) demonstrated noninferiority of peginesatideto epoetin for maintaining Hb levels in HD patients (Schiller et al. ASN 2010). Dueto differences in anemia management between US and non-US centers, ironutilization and storage were evaluated in US patients, with the rationale that: 1) USpatients receive up to 2.5x more ESA than patients in the EU (Pisoni et al. AJKD2004; 44:94), while achieving similar Hb levels, potentially amplifying differences iniron use; and 2) there were 4x more US (n=1289) than non-US patients (n=319) inthe two studies, thus providing a larger dataset for evaluation.Methods: Pooled data from the two trials compared peginesatide (1x monthly;N=1066) with epoetin (1- 3x weekly; N=542) in HD patients previously on stableepoetin. Mean IV iron dose and iron stores (serum ferritin, TSAT) from patients inthe US (peginesatide: n=853; epoetin: n=436) were determined in 12-week intervalsthrough Week 60.Results: Mean Hb levels were similar in both arms for the duration of the study.Mean iron use and mean iron status through Week 60 is presented (Figure).Patients in the peginesatide arm generally received less iron than those in the epoetinarm at each time point. Ferritin levels were similar through the 60 weeks of study,and TSAT levels were slightly higher in the peginesatide arm. Comorbidities andinflammatory markers were balanced between arms at BL.Conclusions: While maintaining similar levels of Hb over time, US patients in thepeginesatide arm received less IV iron with similar serum ferritin and achievedhigher TSAT levels, than patients in the epoetin arm. While it is possible that theseobservations may be attributed to random variations, hypotheses for an improvementin iron availability with peginesatide treatment include potential differences in (1)comorbidities or inflammation (although no differences were observed between thetwo arms at BL), (2) iron mobilization, (3) interaction with hepcidin, and (4)efficiency of iron incorporation into protoporphyrin IX complex duringerythropoiesis. A potential difference in iron utilization between peginesatide andepoetin warrants further exploration.

FP197 EFFECT OF METHOXY POLYETHYLENE GLYCOL – EPOETINBETA ON POLYMORPHONUCLEAR (PMN) CELLS APOPTOSISIN PREDIALYSIS PATIENTS WITH CHRONIC KIDNEYDISEASE (CKD)

Piotr Bartnicki1, Zbigniew Baj2, Ewa Majewska2 and Jacek Rysz31Department of Nephrology Hypertension and Family Medicine, 2MedicalUniversity, 3Wam University Hospital

Introduction and Aims: In patients with CKD was observed increased PMN cellsapoptosis quantified by flow cytometry using annexin V and propidium iodidestaining. Erythropoiesis – stimulating agents (ESAs) using in these patients, beyondanemia correction seem to have renoprotective effect and slow progression of CKD.One of possible renoprotective mechanism of ESAs is antiapoptotic effect. In thisstudy we aimed to determine the effect of methoxy polyethylene glycol – epoetinbeta (Mircera) on PMN cells apoptosis in predialysis patients with CKD.Methods: 28 patients with CKD and anemia, treated with Mircera, were enrolled.The healthy control group included 15 volunteers. Data about hemoglobin level (Hg)and estimated glomerular filtration rate (eGFR) are shown in the table below.Apoptosis of PMN cells was quantified by flow cytometry using annexin V andpropidium iodide staining and changes of FAS, FAS Ligand, CD16 and CD11bactivity were assessed by flow cytometry too using respective monoclonal antibody.Results: The results of our study are shown in the table belowConclusions: These data suggest that correction of anemia using methoxypolyethylene glycol – epoetin beta (Mircera) might have antiapoptotic effect.

FP198 FUNCTIONAL IRON DEFICIENCY IS A FACTOR LIMITINGTHE USE OF HIGH DOSES OF INTRAVENOUS IRONIN PREDIALYSIS

Patrick Fievet1, Maryam Assem1, François Brazier1, Xiaoli Xu1, OumeriaNadia Soltani1 and Renato Demontis11Service de Néphrologie Hémodialyse, Ch Laennec, Creil

Introduction and Aims: Iron deficiency anemia is a common complication ofchronic kidney disease (CKD) in pre- dialysis stage. New forms of injectable ironallow the use of high doses. This is of interest to preserve venous capital and reduceinterventions. The effectiveness to correct iron deficiency anemia in predialysis isdemonstrated with the iron carboxymaltose in high doses, but the risk of ironoverload has not been evaluated. However, patients are more likely thanhaemodialysis patients because of lower blood loss.Methods: We have studied the efficacy of iron dextran, low molecular weight(LMWD) in high doses to correct and treat iron deficiency anemia in pre-diaysisCKD. The doses administered (total dose) were consistent with iron deficiencycalculated by the Ganzoni formula, depending on the number of hemoglobin (Hb)and weight of the patient. 40 doses from 500 to 1600 mg (mean = 760 ± 291 mg)were administered in 28 patients followed for CKD (mean GFR = 23.7 ±12.6 ml/min/1.73 m2) with iron deficiency defined by a coefficient of transferrin saturation(TSAT) below 20% and/or a serum ferritin below 100 mg/L and receivingerythropoiesis stimulating agent (ESA) in 22 cases on 40. ESA doses were notchanged. A balance control was performed at 1 month later. The results of ironstatus were compared with targets set by the KDOQI and ERBP.Results: Hb has significantly increased (11,4 ± 1.4 vs 10.3 ± 1.3 g/dL, p < 0,001 ) inparallel with a significant increase of TSAT (22.6 ±8.5 vs 14.0 ±3.9%, p < 0,001) andserum ferritin (320 ±265 vs 97 ± 61 μg/L, p < 0,001). Serum ferritin reached highervalue than 500 mg/L (upper limit KDOQI and ERBP) after treatment, exposing torisk of iron overload, in 9 cases. These patients were characterized by serum ferritinvalues before treatment higher than others patients (169 ± 65 vs 76 ±42 μg/L, p =0,03) whereas TSAT were identical (13,8 ± 3,7% vs 14.1 ±4%, NS). In patients with

FP195

FP196 Figure 1:

FP197 Table 1

□p < 0.05 Kendall’s tau coefficient value



serum ferritin higher than 500 μg/L after treatment, Hb has not significantlyincreased whereas it has in the others.In the 9 patients with excessive response of ferritin, initial iron status values were infavour of functional deficiency (low TSAT associated with normal or high ferritin).In these cases, the increase of ferritin after intravenous iron suggests incorporation ofiron in iron stores. Nevertheless the lack of hematopoïetic response is in accordancewith unavailability of so stored iron which could be due to increase of hepcidinlevels.Conclusions: Administration of high doses of LMWD is efficient to correct irondeficiency and anemia in pre-dialysis CKD. High doses of intravenous iron expose torisk of iron overload in patients with a profile of functional iron deficiency (TSAT <20% and ferritin > 150 μg/L). They are likely to be reserved for patients whose serumferritin is less than or equal to 150 μg/L.

FP199 IS HEPCIDIN-25 A CLINICALLY RELEVANT PARAMETERFOR THE IRON STATUS IN NON-DIALYSIS CHRONIC KIDNEYDISEASE PATIENTS?

Liliana Barsan1, Simona Stancu2, Simona Stancu3, Ana Stanciu1,Cristina Capusa3, Ligia Petrescu2, Adrian Zugravu2 and Gabriel Mircescu41"Dr Carol Davila" Teaching Hospital of Nephrology, Bucharest, Romania,2Nephrology, "Carol Davila" University of Medicine and Pharmacy, Bucharest,Romania, 3Nephrology Dept., "Carol Davila" University of Medicine andPharmacy, Bucharest, Romania, 4Nephrology Dept., “carol Davila” University ofMedicine and Pharmacy, Bucharest, Romania

Introduction and Aims: Depletion of bone marrow iron and iron restrictederythropoiesis are frequently reported in anemic non-dialysis patients with chronickidney disease (CKD), but peripheral iron indices have only a limited diagnosticutility. It was suggested that hepcidin, one of the primary regulators of systemic ironhomeostasis, could be a clinically relevant parameter of the iron status inhemodialysis patients and probably also in non-dialysis CKD patients.Objective: To investigate the relationship between hepcidin levels, peripheral ironindices and bone marrow iron stores in anemic non-dialysis CKD patients, iron andepoetin naïve.Methods: Hepcidin was assessed by a commercial ELISA kit using hepcidin-25antibody (Bachem UK) in 118 non-dialysis CKD patients. Smears were preparedfrom marrow fragments obtained by aspiration from sternum and coloured withPerls' Prussian blue stain. Bone marrow iron stores were evaluated using asemi-quantitative scale.Results: 118 patients [51% males; median age 66.5 (iqr 57-75) years; 42.4% vascularnephropathies; 21% diabetic nephropathy; 57.6% stage 5; 20.3% stage 4; 16% stage 3and 6% stage 2 CKD].Mean hemoglobin level was 9.4±1.5g/dl. Serum parameters were: median transferrinsaturation 15% (iqr 10-21); median ferritin 167.5ng/ml (iqr 90-331); median CRP6mg/l (iqr 4-17) and median hepcidin-25 level 75.25 ng/ml (iqr 40.3-100). Bonemarrow iron stores were depleted in 53.5%, normal in 5% and overloaded in 41.5%.In receiver operator curve (ROC) analysis, ferritin performed better than hepcidin inidentifying bone marrow iron depletion. Areas under ROC were 0.73 (95%CI0.6-0.83) and 0.63 (95%CI 0.5-0.75) (p=0.03), and cut-off values were 184ng/mL(sensitivity 0.75 95%CI 0.63-0.85; specificity 0.74 95%CI 0.59-0.85) and 77ng/mL(sensitivity 0.64 95%CI 0.50-0.75; specificity 0.61 95%CI 0.46-0.75) for ferritin andhepcidin, respectively.Hepcidin-25 was weakly correlated with bone marrow iron stores (r2=0.11; p=0.003),ferritin (r2=0.12; p<0.001) and GFR (r2=0.11, p<0.001) but not with transferrinsaturation index, hemoglobin or CRP.In logistic regression analysis, in a model which explained 38% of variation in bonemarrow iron status, older age, higher hemoglobin, ferritin and hepcidin, but not GFRwere predictors of replete iron stores.Conclusions: Hepcidin is not better than ferritin as a predictor of bone marrow ironrepletion in anemic non-dialysis CKD patients.

FP200 IRON METABOLISM IN HEMODIALYSIS PATIENTS- STILL AMYSTERY?

Jolanta Malyszko Malyszko1, Nomy Levin-Iaina2, Jacek Malyszko1,Irena Głowinska1, Ewa Koc-Zorawska1, Itzachk Slotki3 and Michal Mysliwiec11Department of Nephrology and Transplantology, Medical University, BialystokPoland, 2Nephrology and Hypertension, Sheba Medical Center, Tel Hashomer,Israel, 3Shaare Zedek Medical Center, Jerusalem, Israel

Introduction and Aims: All living organisms have evolved sophisticated mechanismsto maintain appropriate iron levels in their cells and within their body. Recently ourunderstanding of iron metabolism has dramatically increased. Overt Labile PlasmaIron (LPI) represents a component of non- transferrin bound iron (NTBI) that isboth redox active and chelatable, capable of permeating into organs and inducingtissue iron overload. LPI measures the iron-specific capacity of a given sample toproduce reactive oxygen species. The aim of the present study was to evaluate for thefirst time NTBI correlations with markers of iron status and inflammation inprevalent hemodyalsis patients.

Methods: Complete blood count, urea, creatinine, serum lipids, fasting glucose,ferritin, serum iron and TIBC were studied by standard laboratory method in thehospital central laboratory. NTBI was assessed by FeROS™ eLPI kit(florescence-based assay intended for the in vitro semi- quantitative detection of bothover and cryptic redox active forms of NTBI) by Aferrix Ltd in Tel Aviv, Israel. Atest result of 0.6 units of LPI or more indicates a potential for iron- mediatedproduction of reactive oxygen species in the sample.Results: In hemodialysis patients, NTBI was correlated with hsCRP (r=0.37, p<0.01),ferritin (r=0.41, p<0.001) and IL-6 (r=0.43, p<0.001). Patients with LPI units = 0.6had higher serum iron (p<0.01), they were treated with higher ESA dose (p<0.01),higher ferritin (p<0.001) and higher CRP (p<0.05). Very high ferritin together withhigh NTBI were found in patients that received multiple transfusions. In a subset of10 patients treated with intra venous ferric sucrose, NTBI showed a tendency tohigher values, although insignificant after 1 g of IV iron.Conclusions: Elevated NTBI as well as ferritin levels in hemodialysis patients may bedue to disturbed iron metabolism, since human body have no possibility to removeiron excess. NTBI could be responsible for excessive synthesis of reactive oxygenspecies, and therefore it may be linked to complications due this phenomenon, suchas atherosclerosis, frequently encountered in this population.

FP201 ACUTE RENAL AND VASCULAR EFFECTS OF INTRAVENOUSIRON

Gabriel Mircescu1, Gabriel Mircescu1, Cristina Capusa2, Simona Stancu1,Liliana Barsan3, Doina Grabowski3, Violeta Blaga3 and Daniela Dumitru31Nephrology Dept., “carol Davila” University of Medicine and Pharmacy,Bucharest, Romania, 2Nephrology Dept., "Carol Davila" University of Medicineand Pharmacy, Bucharest, Romania, 3“dr Carol Davila” Teaching Hospital ofNephrology, Bucharest, Romania

Introduction and Aims: Although intravenous (IV) iron is widely used in anemia ofchronic kidney disease (CKD), concerns about its potential deleterious effects onvarious tissues, including vascular endothelium and nephrons exist. We conducted aprospective, crossover study to investigate changes in the endothelial and kidneyfunctions in the first 24 hours after a single IV iron infusion in non-dialysis CKDpatients.Methods: Twenty stable subjects with CKD stages 3 to 5 not on renal replacementtherapy (30% male, 61 [50-71] years, eGFR 17.5 [11.8-30.3]mL/min) treated with IViron as part of their routine medical care were enrolled. Exclusion criteria were:previous iron therapy, signs of iron overload, nephrotic syndrome, acute infections,recent exposure to nephrotoxic drugs or iodine contrast agents, and severe systemicatherosclerosis.The effects of an infusion containing 200mg iron sucrose in 250mL 0.9% salinesolution were compared to those of an infusion containing 250mL 10% glucose. Theinfusions were administered over 30 minutes, 72 hours apart, the comparator (10%glucose), first. The glucose solution was chosen because of the similar osmolalitywith the iron solution.Markers of kidney damage - beta-2 microglobulin (bMG), protein (P), albumin (A)urinary excretions (as ratios to urinary creatinine - Cr), and serum creatinine (foreGFR calculation) - were measured before, 30 minutes and 24 hours after eachinfusion.Endothelial function was assessed by the ultrasound measurement of the brachialartery flow mediated dilatation (FMD), performed 15 minutes before and after eachinfusion.The post-/pre-infusion differences (?) were compared for each parameter.Results: Urinary excretion of bMG increased at 30min after IV iron (32.5 [15.3-47.3]vs. 18.2 [8.6- 25.4]mg/g, p=0.03) and returned toward baseline values at 24 hours (24[9.1-40.3]mg/g, p=0.26). Significantly higher ? bMG/Cr was found at both momentsafter iron infusion (9.7 [3.7-17.1] at 30min and 3.6 [0.1-8.1] at 24 hours vs. 0.4[0-4.8], p=0.01, and -0.2 [-6.6- +3.9]mg/g, p=0.02, respectively), pointing to tubulartoxicity. Urinary excretion of total proteins and albumin had minor variations.Higher percentage of patients had decreased FMD after iron (75% vs. 33%, p=0.01).Moreover, the median change in FMD was significantly different (-3 [-5.3 to -0.4]after iron vs. 1 [-1-+1.3] after glucose, p=0.02), suggesting iron-related decrease inarterial reactivity, which is further supported by the reduction in eGFR only afteriron (? eGFR: 0 [-3.3-+1.0] vs. 1 [-0.4-+1.3]mL/min after glucose, p=0.03).Conclusions: A common dose of IV iron sucrose seems to induce transient renaltubular toxicity and acute endothelial dysfunction in non-dialysis CKD patients.Until further prospective studies will settle the long-term effects of iron therapy, IViron remains a useful adjuvant in renal anemia management, but it should becautiously prescribed.

FP202 SYSTEMIC INFLAMMATION AS A FACTOR OF ANEMIADEVELOPMENT IN PATIENTS WITH EARLY STAGES OFDIABETIC NEPHROPATHY

Ivan Pchelin1 and Alexander Shishkin21St.Petersburg University, St. Petersburg, Russia, 2St.Petersburg University, St.Petersburg, Russia

Introduction and Aims: Anemia is an early complication of diabetic nephropathy(DN) that has a negative impact on survival and quality of life. It may result



from various factors including erythropoietin (EPO) deficiency, iron and vitamindeficiencies, systemic inflammation, hemolysis and adverse effects of some drugs.However, the relative contribution of each factor on different stages of DN is notfully known. In this study we assessed the role of systemic inflammation inpatients with early stages of DN who do not have EPO or iron deficiency.Methods: We investigated 71 anemic patients with DN (CKD stages 1-3). GFRwas calculated by Cockcroft-Gault formula. Anemia was defined according toWHO criteria (2008). We measured serum levels of EPO, ferritin, interleukin-1β(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) usingimmunoassay (Labsystems MR 600 analyser). To assess the correlation betweenlevels of hemoglobin (Hb) and each of cytokines we used Pearson correlationcoefficient. Coefficients were calculated for the entire group and for patientswithout EPO and iron deficiency.Results: 45,7 % of patients were EPO-deficient, 11,3 % were iron-deficient.Elevated levels of IL-1β, IL-6 and TNF-a were observed in 73,2 %, 53,5 % and19,7 % of patients, respectively. We found the following correlation coefficientsbetween Hb and cytokines levels: for the entire group – +0,27 (Hb/IL-1β), +0,20(Hb/IL-6), +0,04 (Hb/TNF-a); for patients without EPO and iron deficiency –-0.54(Hb/IL-1β), -0,79 (Hb/IL-6), +0,18 (Hb/TNF-a).Conclusions: The results of the study suggest that about a half of patients withearly stages of DN don’t have absolute EPO or iron deficiency. These patients arecharacterized by strong negative correlations between Hb and proinflammatorycytokines (IL-1β, IL-6) levels. Therefore, systemic inflammation is a substantialfactor of anemia development in patients with early stages of DN.

FP203 EVALUATION OF RELATIONSHIP BETWEEN HEMOGLOBINVARIABILITY AND OXIDATIVE STRESS AND INFLAMMATIONIN CHRONIC RENAL FAILURE

Tulay Kus1, Celalettin Usalan2 and Ozlem Tiryaki31Gaziantep University School of Medicine, Department of Internal Medicine,2Gaziantep University School of Medicine, Department of Nephrology,3Gaziantep University School of Medicine, Department of Nephrology, Turkey

Introduction and Aims: Anemia frequently seen in chronic renal failure patients isone of the most important cause of mortality and morbidity. Besides anemia,hemoglobin (Hg) variability also causes increase in morbidity, hospitalization andmortality. However, this mechanism cannot be explained yet. Relation betweencardiovascular disease and oxidative stress and inflammation is described in uremicpatients. Moreover, increase in oxidative stress and inflammation is known as one ofthe most important cause of hemoglobin variability. While these abnormalitiescausing hemoglobin variability, it’s likely to be related with increase in mortality andmorbidity in these patients.Methods: We designed this study to levels of pro-oxidant (myeloperoxidase (MPO)),nitrotirosine (NTY), anti-oxidant (total anti-oxidant capacity (TAK)), inflammation(interleukin (IL-6, Hs- CRP, hepcidin), procoagulant (Plasminogen activatorinhibitor type 1 (PAI-1) activity) is planned in patients with variable hemoglobinlevels.In light of the studies done on this subject, hemodialysis patients (n=188) brokedown into different six groups according to Hg levels in last 6 months. Furthermore,a suitable control group (n=30) is composed according to acceptable demographicand clinical properties. Groups are described as group 1 (n=24, Low Hb<11g/dL);patients with Hg levels always less than 11 gr/dl; group 2 (n=32, LAL, low-amplitudefluctuation with low Hb); patients with Hg levels sometimes between 11-12 gr/dl andsometimes less than 11 gr/dl (group shows variability close to inferior limit), group 3(n=29, target, Hb 11 to 12 g/dL); patients with Hg levels between 11-12 gr/dl, group4 (n=25, LAH, low-amplitude fluctuation with high Hb); patients with Hg levelssometimes between 11-12 gr/dl sometimes more than 12 gr/dl (group showsvariability close to superior limit), group 5 (n=26, HA, high amplitude fluctuation);patients with Hg levels are wide-variable and group 6 (n=22,); patients with Hg levelsalways more than 12 gr/dl.Results: Avarage levels of pro-oxidant (MPO, NTY) (p<0.005), inflammation(IL-6, Hs-CRP, hepcidin) (p<0.01) and procoagulant (PAI-1 activity) (p<0.005)are higher than control group however, levels of anti-oxidant (TAK) (p<0.01) arelower than control group. Pro-oxidant, inflammation and procoagulant activitylevels are highest in group 1 and least in group 6 (p<0.005). TAK is least inanemic group and highest in Hg normal group. target group (group 3) that Hglevels between 11-12 gr/dl is the most a like the group 6, that is known as havingleast mortality and morbidity in terms of these parameters. Group 5 is the mostalike group 1 that is known as having highest mortality and morbidity in terms ofthese parameters. In all groups, there is no corelation between these parametersand erythropoetin and iron dosage (p>0.05).Conclusions: Oxidative stres, increased inflammation and procoagulant activity isrelated with cardiovascular mortality and morbidity in uremic patients, in recentstudies, these parameters are shown as increased mortality and morbidity inpatients with great variable Hg levels and so this shows a possible pathogeneticrelationship. To clear this subject, prospective studies with longer follow-up areneeded.

FP204 NUMBER OF RED BLOOD CELLS AS A RESPONSE OFINNATE ERYTHROPOIETIN IS AN IMPORTANT RISK FACTOR

Ho Jun Chin1, Dong-Wan Chae2 and Suhnggwon Kim3

1Seoul National University Bundang Hospital Seongnam Korea, 2Snubh, 3Snuh

Introduction and Aims: Patients with renal dysfunction suffer a shortage oferythropoietin (EPO) necessary to maintain adequate tissue oxygenation. There arefew data on the changes of red blood cell (RBC) number according to glomerularfiltration rate (GFR) and the cardio-renal risk factor and its influence on the clinicaloutcome.Methods: Based on the data from routine health checkups, 114,496 adult subjectswere enrolled. The final outcome was the all-cause mortality rate.Results: The RBC number increased with decreasing GFR and/or the presence of ametabolic syndrome (MS) component. The estimated mean RBC number of subjectswith GFR from 89 to 50 ml/min/1.73 m2 was higher compared to those with GFR>100 ml/min/1.73 m2. In men, the mortality rate was 1.22% in the lowest quartile ofRBC number (1Q RBC group), 0.42% in 2Q, 0.39% in 3Q, and 0.29% in 4Q RBCgroup (p <0.001). With Cox’s proportional hazard model, the hazard ratios of deathwere 0.446, 0.580, and 0.440 in 2Q, 3Q and 4Q RBC group, respectively, comparedto 1Q RBC group. The significance of RBC group on mortality was evident insubjects with GFR > 60 ml/min/1.73 m2 and with the presence of MS component. Inwomen, the RBC group showed an interaction with age to estimate the mortality andits significance disappeared in the analysis including the interaction parameter inCox’s model.Conclusions: The RBC number was well correlated with GFR and the presence of anMS component and was an important risk factor for mortality, especially in men.

FP205 A PHARMACODYNAMIC VIEW ON THE TREAT TRIAL –

THE DARBEPOETIN THRESHOLD AND CEILINGCONCENTRATIONS

Hartmann Bertram1 and Frieder Keller21Nephrology, Center for Internal Medicine, University Hospital. Albert EinsteinAllee 23, D-89070 Ulm, Germany, 2Nephrology, Center for Internal Medicine,University Hospital, Albert Einstein Allee 23, D-89070 Ulm, Germany

Introduction and Aims:In the TREAT trial, high darbepoetin dosage was associatedwith an increased risk of adverse events. This could be explained through a narrowtherapeutic index of darbepoetin.Methods: The literature analysis of the pharmacokinetics and pharmacodynamics oferythropoiesis stimulating agents in general and darbepoetin in particular wasconducted. The data were fitted to a unifying pharmacokinetic/ pharmacodynamicmodel. For the pharmacodynamic part of this model a sigmoidal Emax function wasused as described by the Hill equation.Results: According to our interpretation of published data the darbepoetin effect onerythropoiesis requires multiple dose trough concentrations at least as high as thethreshold concentration of CE05 = 0.18 ng/ml. Peak levels, however, above theceiling concentration of CE95 = 0.91 ng/ml will not produce a better response butwill be associated with an increased risk of adverse events (Figure 1). Thus, a 5-foldtherapeutic target range can be derived from these concentration limits (CE95 /CE05 = 5.05). This narrow index might indicate that darbeopoetinpharmacodynamics is characterized by a high Hill coefficient. The value for the Hill

FP205 Figure 1:



coefficient can be estimated as H = 3.67. This high Hill coefficient is compatible withtime-dependent pharmacodynamics.Conclusions: If such time-dependent pharmacodynamics is true, the darbepoetindose should not be increased but the administration interval should be shortenedand the dose be given more frequently in patients non-responsive to normal dosage.

FP206 MINIMISATION OF ESA THERAPY POST-TREAT STUDY:ONE-YEAR EXPERIENCE

Adam Rumjon1, Cheryl Wood1, Paul Wilson1, Shammim Khakoo1, MeeOnn Chai1 and Iain C. Macdougall21King's College Hospital NHS Foundation Trust, London, UK, 2Renal Unit, King'sCollege Hospital

Introduction and Aims: ESA therapy has successfully been used to treat theanaemia of chronic kidney disease (CKD) for over 20 years, but recent data from theTREAT study have shown an increased risk of thrombotic events and cancer-relatedmortality with this class of drugs. These safety concerns have prompted calls for thelowest possible doses of ESA therapy to be used. In January 2011, we initiated anESA minimisation programme to reduce exposure to ESAs in our pre-dialysis CKDpatient population, and prospectively monitored their progress over the next 12months.Methods: All 320 patients in our unit with CKD (stages 2-5) receiving ESA therapywere assessed regarding their feasibility of reducing their ESA dose. Patients wereexcluded from the analysis if they reached end-stage renal failure, died, or had lessthan four months of follow- up. A costing model was also developed in order tocalculate the potential cost savings with this programme, factoring in the reduceddrug costs offset by the need for increased follow-up clinic visits, and additionalnursing time required to supervise the changes.Results: After the exclusion criteria were applied, data from 190 patients wereanalysed (mean age 72.6 ± 14.3 (SD) years, 51% were male). The mean epoetin alfadose fell from 4171 ± 2875 units/week at the start, to 2102 ± 2444 units/week, themean initial reduction in epoetin alfa dose being 50.3 ± 39.8%. The meanhaemoglobin decreased from 11.6 ± 1.2 g/dL at the beginning of the study to 10.5 ±1.2 g/dL at the end. Prior to initiation of this programme, 2.6% of patients had anHb level below 9.0 g/dL, 46.8% were between 9.0 and 11.5 g/dL and 50.5% weregreater than 11.5 g/dL. Following implementation of the programme, more patients(74.7%) had a desirable Hb of 9.0-11.5 g/dL, and fewer (15.8%) had an Hb greaterthan 11.5 g/dL. More patients (9.5%), however, had an Hb lower than 9.0 g/dL. Intotal, 76.3% of patients had some reduction in their ESA dose, with 35.3 % havingtheir ESA completely withdrawn. 21.6% of patients had no eventual change in dose,and only 2.1% had a dose increase.Total projected ESA use was based on the patients’ ESA dose at the beginning of thestudy (24,990,500 IU), and this was compared to the actual use based on the numberof units used by each patient throughout the study period (12,681,700 IU) followingthe advent of the ESA minimisation protocol. It was calculated that 12,308,800 IUwere spared, which is equivalent to 49.3% of the projected ESA use, and thisgarnered a cost-saving of £24,864.18. A total of 260 dose changes were performedthroughout the study period at a cost of £2,253.33 for nursing costs, resulting in anet cost saving of £22,610.85.Conclusions: Following implementation of the programme, ESA use in our unit wasnearly halved over a 12-month period, with just over one-third of patients havingtheir ESA completely withdrawn. Mean haemoglobin levels fell by 1.1 g/dL, but werestill within the current desirable target range. The costs of increased monitoring ofthe patients was more than offset by the reduction in ESA usage.

FP207 USE OF PENTOXIFYLLINE IN HEMODIALYSIS PATIENTSWITH ERYTHROPOIESIS-STIMULATING AGENT (ESA)RESISTANCE: A CASE-CONTROL STUDY

Garcia-Fernandez Nuria1, Ferrer Maria Asuncion1, Mora-Gutierrez Jose Maria1,Calderon Carmen1, Martin-Moreno Paloma Leticia1 and Lavilla Francisco Javier11Clinica Universidad Navarra, Pamplona. Spain

Introduction and Aims: Anemia treatment in hemodialysis (HD) dependentpatients involves adequate supply of iron and an erythropoiesis-stimulating agent(ESA). However resistance to this therapy, associated with immune system activationand inflammation, has been described. Pentoxifylline, a phosphodiesterase inhibitorused to treat peripheral vascular disease, could be effective in ESA resistance. AIM:To study the effect of pentoxifylline treatment in ESA resistance in HD dependentpatients.Methods: A case-control study was performed. Forty patients undergoing regularHD were included in this study. Twenty of them (10 males), aged 59.3+14.1, receivedoral pentoxifylline (800- 1200 mg/day). Twenty HD dependent patients (withoutpentoxifylline treatment), matched for age and gender, formed the control group. In6 patients pentoxifylline treatment had been started due to vascular periphericaldisease, and in 14 patients the reason for the treatment was ESA resistance. ESAresistance was defined as persistent (= 3 months) hemoglobin deficit (< 11 g/dl)despite high doses of ESA. MIRCERA®, a continuous erythropoietin receptoractivator was given monthly to every patient (cases and controls). Hemoglobin,

MIRCERA® dose and C-reactive protein (CRP) were measured at baseline (beforepentoxifylline treatment), after 3 months of treatment and at present. A p-value<0.05 was considered significant.Results: Results are shown in Table 1. After 3 months of pentoxifylline treatment, asignificant increase in hemoglobin levels and a significant decrease in MIRCERA®dose were observed in the case group (p<0.05). Although at baseline hemoglobin

levels were significantly higher in the control than in the case group, these differenceswere not observed after 3 months. The improvement observed in pentoxifyllinegroup was maintained over time. The mean follow- up was greater than or equal to 6months in 16 patients (80%) and higher than one year in 11 patients (55%).Conclusions: Pentoxifylline treatment in hemodialysis patients witherythropoiesis-stimulating agent (ESA) resistance improves the hemoglobin level andreduces the ESA dose in 3 months. This effect remains for a long time.

FP208 HEMOGLOBIN AND QUALITY OF LIFE IN PATIENTSON PRE-DIALYSIS CARE

De Goeij Moniek1, Moniek De Goeij2, Meuleman Yvette3, Grootendorst Diana4,Dekker Friedo1 and Halbesma Nynke11Leiden University Medical Center, Dept of Clinical Epidemiology, Leiden, theNetherlands, 2Leiden University Medical Center, Leiden, the Netherlands,3Leiden University Medical Center, Dept of Medical Psychology, Leiden, theNetherlands, 4Kennemer Gasthuis, Linnaeus Institute, Haarlem, the Netherlands

Introduction and Aims: Anemia is a common complication in patients with chronickidney disease (CKD) and treatment with erythropoiesis-stimulating agents and/oriron supplements (ESA/iron) is recommended. However, a discussion is ongoingabout the optimal hemoglobin (hb) treatment target level for patients with anemiaon pre-dialysis care. Many trials showed that targeting high hb levels (=12 g/dl) hadno beneficial effect or even increased the risk of mortality, morbidity, and theprogression to end-stage renal disease. However, higher hb levels could potentiallyhave a positive effect on QOL, although there is not much evidence so far. Therefore,we wanted to investigate the association of different hb levels during follow- up,stratified for ESA/iron treatment and age, with QOL in patients on pre-dialysis care(CKD stages IV-V).Methods: In the prospective PREPARE-2 cohort, 504 incident pre-dialysis patientswere included when referred to one of 25 Dutch nephrology outpatient clinicsbetween 2004 and 2011. Patients were followed until the start of dialysis,transplantation, death, or end of follow-up. At the start of pre-dialysis care and ineach subsequent 6 month interval demographic, biometric, clinical, and QOL datawere routinely collected. QOL was assessed with the validated SF-36 questionnaire,summarized in two scores: Physical Component Summary (PCS) and MentalComponent Summary (MCS). The range of the PCS and MCS is 0-100 with a higherscore indicating a better QOL. A linear mixed model was used to investigate theassociation between hb levels (<11, 11-12 (reference), 12-13, =13 g/dl) and PCS andMCS on each time point during pre-dialysis care. An interaction term between timeand hb level was included in the model to investigate whether the associationchanges during pre-dialysis care. All analyses were stratified for ESA/iron treatmentand/or age (<65 and =65 years) at the start of pre- dialysis care.Results: Of the 504 patients included, 388 had at least one available hb level and oneavailable PCS and MCS during follow-up and were therefore available for statisticalanalyses. Median age was 68 (IQR, 55-76) years, mean eGFR was 17.1 (SD, 6.5) ml/min/1.73 m2, 55% were treated with ESA/iron, and mean PCS and MCS were 54.3(22.5) and 67.8 (20.4) respectively. Patients with a higher hb level were younger, hada higher eGFR and lower urea level, were more often male, and had less oftendiabetes mellitus (DM) but more often cardiovascular disease (CVD). In elderly

FP207 Table 1 Hemoglobin levels, MIRCERA® dose and C-reactive protein levels inhemodialysis patients treated with and without pentoxifylline

Data expresed as means and standard deviation. Follow-up time: 15 months (range:2-32 months)



patients, we found that a naturally high hb level (=13 g/dl compared to 11-12 g/dl)was associated with a higher PCS (12.1 (95% CI, 1.9 to 22.2)) and MCS (8.0 (- 0.7 to16.7)) on each time point during pre-dialysis care. In contrast, an ESA/iron inducedhigher hb level (=12 g/dl compared to 11-12 g/dl) did not result in a higher PCS orMCS in elderly patients. However, in young patients, an ESA/iron induced high hblevel (=12 compared to 11-12 g/dl) was associated with a higher PCS (11.4 (95% CI,5.2 to 17.6)) and MCS (9.9 (3.8 to 16.0)) and a natural high hb level was notassociated. Furthermore, the association of hb levels with QOL was not different overtime and did not change after adjustment for age, sex, primary kidney disease, eGFR,albumin, systolic blood pressure, CVD, and DM.Conclusions: These results may indicate that targeting high hb levels (=12 g/dl) withESA/iron therapy may increase both physical and mental QOL in young but not inelderly pre-dialysis patients.

FP209 PHARMACOKINETICS OF ERYTHROPOIETIN IN BALKANENDEMIC NEPHROPATHY PATIENTS

Visnja Lezaic1, Branislava Miljkovic2, Nenad Petkovic3, Ivko Maric4,Katarina Vucicevic2, Sanja Simic Ogrizovic5 and Ljubica Djukanovic61Medical Faculty, Belgrade, Serbia, 2Faculty of Pharmacy, University of Belgrade,Serbia, 3Fmc Center Šamac, Bh, 4Special Hospital for Endemic Nephropathy,Lazarevac, Serbia, 5Medical Faculty, University of Belgrade, Serbia, 6MedicalFaculty, Belgrade University, Serbia

Introduction and Aims: Balkan endemic nephropathy (BEN) patients onhemodialysis (HD) have more severe anemia than patients with other kidneydiseases. Treatment with recombinant human erythropoietin (rHuEpo) enabledsuccessful anemia correction of BEN patients but our recent study showed that theyrequired higher rHuEpo dose for maintaining target hemoglobin (Hb) level thannon- BEN patients. The aim of the present study was to examine whetherpharmacokinetics of erythropoietin participate in the pathogenesis of the differencein rHuEpo response.Methods: The study involved 25 HD patients, 10 with BEN – group 1 (6 males, aged70.9 ± 6.8 years, dialyzed for 59.4±32.3 months) and 15 with other kidney diseases –group 2 (8 males, aged 49.6±14.0 years, dialyzed for 106.6 ± 57.4 months). Allpatients were treated with rHuEpo for more than one year. To evaluate thedose-response effect of rHuEpo therapy erythropoietin resistance index (ERI) wascalculated as the ratio of the mean weekly weight-adjusted dose of rHuEpo in theobserved six-month period and the mean Hb level for the same period. Thepharmacokinetics of rHuEpo was examined after subcutaneous administration of75U/kg of rHuEpo. Pre-dose blood sample and 6-7 post-dose samples were taken.For pharmacokinetic analysis the pre-dose plasma level of endogenous erythropoietinwas subtracted from all post- dose levels of erythropoietin for each patient.Noncompartmental pharmacokinetic analysis using Kinetica software was performedin order to calculate relevant pharmacokinetic parameters.Results: In the six month period mean Hb level was 112±5.5 g/L in group 1 and 109±4.4g/L in group 2, mean rHuEpo dose 87±16.5 and 66.5±28.3 U/kg/week(p=0.459), mean ERI 0.77±0.11 U/kg/week/g Hb and 0.62±0.20 U/kg/week/g Hb(p=0.0481), respectively. Pharmacokinetics analysis showed that group 1 and 2differed, although not always significantly, in the maximal concentration (61±13vs.77±36 U/L), elimination rate constant (0.016±0.006 vs. 0.024±0.012/h; p=0.016),elimination half-life (50±19 vs. 42±35h), volume of distribution (79±15vs.61±29 L/kg) and mean residence time (74±26 vs.64±51h) of erythropoietin. In addition,higher interindividual differences in majority of pharmacokinetics parameters werefound in group 2 than in group 1. Significant positive correlation was found betweenERI and elimination rate constant, area under the concentration-time curve, butnegative with clearance.Conclusions: Differences in pharmacokinetics of erythropoietin between two smallexamined groups indicated that some pharmacokinetics features found in BENpatients could contribute to their weaker rHuEPo response.

FP210 PREVALENCE OF ANAEMIA AND ITS MANAGEMENT INPATIENTS WITH CHRONIC KIDNEY DISEASE STAGES 3, 4AND 5 NOT ON DIALYSIS AT NEPHROLOGY UNITS INCATALONIA (THE MICENAS I STUDY)

Aleix Cases1, A. Martínez-Castelao2, A. Fort3, J. Bonal4, X. Fulladosa2, J.M. Galcerán5, V. Torregrosa1 and E. Coll61Nephrology and Transplantation Unit, Hospital Clínic, Barcelona, Spain,2Nephrology Unit, Hospital de Bellvitge, Barcelona, Spain, 3Nephrology Unit,Hospital Vall D'hebron, Barcelona, Spain, 4Nephrology Unit, Hospital GermansTrias I Pujol, Badalona, Spain, 5Nephrology Unit, Fundación Althaia, Manresa,Spain, 6Nephrology Unit, Fundación Puigvert, Barcelona, Spain

Introduction and Aims: Anaemia is common among chronic kidney disease (CKD)patients, but its prevalence and management are unknown in nephrology units ofCatalonia. The aim of this study was to determine the prevalence and its therapeuticapproach in patients with stage 3-5 not on dialysis in Catalonia in usual clinicalpractice conditions.

Methods: A cross-sectional study was conducted in nephrology units in Catalonia.The study was approved by an Ethical Committee. Patients aged =18 years,diagnosed with CKD stages 3, 4 and 5 not on dialysis, who had an hemoglobin (Hb)measurement in the previous 2 months and give their informed consent wereconsecutively recruited. Anaemia was defined as an Hb<13.5 g/dL in men, Hb<12.0g/dL in women or patients receiving erythropoiesis stimulating agent (ESA) therapy.Statistical analysis was performed using the SAS 9.1.3 software package.Results: A total of 22 investigators recruited 531 patients for the study, of which 504were valid for analysis. More than half (56.4%) of patients were men with a meanage of 67.8±15.5 years and mean time from CKD diagnosis of 6.6±7.7 years. Themain causes of CKD were: vascular 25%, diabetic nephropathy 16.3%,glomerulonephritis 10.7% and unknown 25.4%. Regarding CKD Stage, 61.5% ofpatients were in stage 3 (3a: 23.0%, 3b: 38.5%), 30.2% in stage 4 and 8.3% in stage5. Mean Hb was 12.6±1.6 g/dL, statistically significant differences being observeddepending on the CKD stage (mean Hb decreased from 13.6±1.6 g/dL in stage 3a to11.4±1.2 g/dL in stage 5, p<0.01). The prevalence of anaemia was 58.5% (stage3a:35.3% and 3b:52.1%; stage 4:73.7%; stage 5:97.6%) showing a higher percentage inmore advanced stages of CKD. At the time of the visit, 40.5% of the patients receivedtreatment for anaemia. The percentage of treated patients was 16.7%, 31.3%, 58.2%and 85.7% in Stage 3a, 3b, 4 and 5, respectively (p<0.05). Sixty-six percent out of200 treated patients received iron (mostly orally), 14.5% folic acid, 10.0% vitaminB12 and 68.0% were treated with ESA. ESA therapy was more frequent among CKDstage 5 patients (Stage 3a: 31.6%, stage 3b: 51.7%, stage 4: 77.6%, stage 5: 91.7%;p<0.001). Darbepoetin alfa was the most frequently ESA prescribed (66.2%), mainlyevery two weeks; followed by methoxy polyethylene glycol- epoetin beta (25.0%)administered on a monthly basis, with a median monthly dose of 80 and 75 μg,respectively, both subcutaneously. Attending CKD stage, no statistically significantdifferences were observed for the use of analyzed ESAs. Thirteen percent of thepatients with Hb < 11 g/dL received no iron nor ESA; while among patients withHb> 13 g/dL, 37.5% received ESA (with or without iron).Conclusions: More than half of CKD patients in stages 3, 4 and 5 not on dialysisattended in Catalonian nephrology units had anaemia, being the patients on stage 5the more anemic ones and receiving more frequently therapy for anaemia treatment.

FP211 THE ASSOCIATION OF KIDNEY TRANSPLANT STATUS WITHESA DOSE REQUIREMENT: INTERIM ANALYSIS OF THEEXTEND STUDY

S DI Giulio1, S DI Giulio1, J Galle2, I Kiss3, H Herlitz4, G Wirnsberger5, K Claes6,M Suranyi7, A Guerin8, C Winearls9, J Addison10, M D’souza11 and M Froissart121Ospedale San Camillo Forlanini, Rome, Italy, 2Klinikum Luedenscheid,Luedenscheid, Germany, 3Fov. Onk. Szent Imre Korhaz, Budapest, Hungary,4Department of Molecular and Clinical Medicine/Nephrology, Institute ofMedicine, The Sahlgrenska Academy at the University of Gothenburg, Göteborg,Sweden, 5Department of Internal Medicine, Medical University of Graz, Graz,Austria, 6Uz Gasthuisberg, Leuven, Belgium, 7Renal Unit, Liverpool Hospital,Sydney, Australia, 8Clinique Mont Louis, Paris, France, 9Oxford Kidney Unit,Churchill Hospital, Oxford, UK, 10Amgen Limited, Cambridge, UK, 11ContractStatistician on Behalf of Amgen Limited, Cambridge, UK, 12Amgen (Europe)Gmbh, Zug

Introduction and Aims: EXTEND is an ongoing observational study of not ondialysis CKD patients at commencement of extended-dosing (ED) frequency ofdarbepoetin alfa (DA) once every 2 weeks or once monthly. This interim analysis(IA) examines whether kidney transplant status impacts on ESA dose requirementand on the ability to maintain Hb concentrations during follow-up, controlling forother anaemia determinants at baseline.Methods: This IA comprises data to Mar 2011 (maximum 36-months follow-up perpatient). Kidney transplant recipients (KTR) and non-transplanted patients(non-KTR) were enrolled. Observed achieved Hb and dosing data (Jan 2007-Mar2011) were summarized at quarterly intervals (excluding the first 6 months post-startof ED). Following initial comparisons of KTR and non-KTR groups for ESA doseand Hb, a 1:1 propensity score matching (PSM) of patients (for age, gender, CKDstage, baseline Hb, prior receipt of ESA, diabetes and CV disease history) createdbalanced groups at baseline. To determine whether inflammation/nutritional statusinfluenced ESA resistance in KTR, trend analyses compared changes overtime inserum ferritin (SF), transferrin saturation (TSAT), C reactive protein (CRP) andserum albumin (SA) concentrations in KTR and non-KTR.Results: Of the 5450 patients enrolled, 619 were KTR and 4831 were non-KTR. InKTR vs. non-KTR higher mean[95%CI] ESA doses, (18.9[18.5-19.2] vs 13.5[13.4-13.6] μg/week, respectively, P<0.0001) were used to maintain similar mean Hbconcentrations (11.59[11.54-11.63] vs. 11.61[11.59-11.62] g/dL, NS). To determine ifthis observation was due to factors other than transplant status, the PSM procedureallowed 521 KTR to be matched to non-KTR at baseline. KTR still receivedsignificantly more ESA (18.6[18.2-19.0] vs. 13.3[13.0-13.6] μg/week, P<0.0001) tomaintain Hb (11.57[11.52-11.62] vs. 11.60[11.54-11.65] g/dL, NS) than non-KTR.Analysis of associated factors after PSM showed that CRP significantly decreasedover time in non-KTR (P<0.01) whereas values remaining stable and elevated inKTR (P=0.32). In parallel, SA concentrations rose significantly in non-KTR(P<0.0001) but not in KTR (P=0.20). SF and TSAT remained stable and normal over



time with no significant trend for TSAT; a decrease in SF concentration was onlyobserved in KTR (P<0.001).Conclusions: KTR received larger ESA doses than non-KTR to maintain Hb, arequirement apparently related to transplant status rather than other PSM-matchedbaseline characteristics such as age, kidney function, and co-morbidities. Trendanalyses showed differences in CRP and SA between the groups suggestinginflammation/nutritional status may contribute to the higher ESA requirement inKTR.

FP212 EARLY RECOMBINANT HUMAN ERYTHROPOIETINTREATMENT PROMOTES CARDIORENAL CYTOPROTECTIONIN A RAT MODEL OF CHRONIC RENAL FAILURE

Patrícia Garrido1, Patrícia Garrido2, Margarida Teixeira3, Elísio Costa4,Paulo Rodrigues-Santos5, Belmiro Parada3, Luís Belo6, Rui Alves7,Frederico Teixeira3, Alice Santos-Silva6 and Flávio Reis31Pharmacology & Experimental Therapeutics, Ibili, Medicine Faculty, CoimbraUniversity,Coimbra., 2Pharmacology & Experimental Therapeutics, Ibili, MedicineFaculty, Coimbra University, 3Pharmacology & Experimental Therapeutics, Ibili,Medicine Faculty, Coimbra University, Coimbra., 4Institute of Health Sciences ofUniversity Catholic, Porto, 5Group of Immunology and Oncology, Cnc, Coimbra,6Institute for Molecular and Cellular Biology, Porto University,Porto., 7Service ofNephrology, Huc, Coimbra.

Introduction and Aims: Chronic kidney disease (CKD) patients develop anemia,mainly due to low kidney erythropoietin (EPO) production, which further promotesadverse cardiorenal complications. The degree of renal failure seems to determine themoment to start recombinant human erythropoietin (rhEPO) therapy; however, themolecular basis for these options deserves better elucidation. We intended to clarifythe cardiorenal effects of earlier rhEPO treatment in rats with moderate renal failure(MRF) induced by partial nephrectomy, focusing on apoptosis, inflammation, redoxstatus and proliferation.Methods: Four groups (n=7) of male Wistar rats (~280g) were evaluated during 15week follow-up period: Control - without surgery and treatment; rhEPO - treatedwith 50 IU/kg/week of beta- EPO (Recormon®); MRF - submitted to (3/4)nephrectomy; MRF+rhEPO - MRF and rhEPO treatment after the 3rd week ofsurgery. Blood samples were collected at the beginning and 3, 9 and 12 weeks afternephrectomy, in order to evaluate: renal function, haematological parameters, serumproliferative (TGF-b1), inflammatory (TNF-a, CRP, IL-2 and IL-1b) and redox status(MDA, TAS and 3-NT) markers. In the final time, kidney and heart were collectedfor analysis of tropism and/or gene expression (RT-qPCR) for apoptotic (Bax, Bcl2,Fas, FasL, Caspase 3 and 9), inflammatory (TNF-a, NF-kB and IL-2) andproliferation/ angiogenesis (TGF-β1, VEGF and PCNA) markers by RT-qPCR(arbitrary units). Blood pressure, heart rate, tissues trophy indexes and kidneyhistomorphology were also estimated. Results are means ± s.e.m. (ANOVA andPost-hoc tests; p<0.05 was considered as significant).Results: Our model has developed a MRF, but maintained over time, withdevelopment of transient and compensated anemia, as well as hypertension andincreased levels of serum TGF-β1 and 3-NT, suggesting proliferation and oxidativestress. The remnant kidney showed a proliferative profile, with increased mass(hypertrophism) and increased gene expression of apoptotic (Bax/Bcl2: 1.98±0.65;P<0.05), inflammatory (IL-2: 4,604.01±907.59 P<0.05) and pro-proliferative (PCNA:287.21±154.15) markers, when compared with the control group (Bax/Bcl2: 0.63±0.06; IL-2: 1662.35±403.94 and PCNA: 25.91±10.18). In addition, MRF rats havedemonstrated overexpression of EPO-R in the heart without changes on EPOexpression, together with overexpression of Bax/Bcl2 ratio, PCNA, and IL-2. rhEPOtreatment in MRF rats promoted attenuation of kidney deterioration, of dyslipidemiaand of heart rate; rise of serum TGF-b1; correction of anaemia and prevention of3-nitrotyrosine increment, together with kidney anti-apoptotic (Bax/Bcl2: 0.82±0.15;P<0.05), anti-inflammatory (IL-2: 592.23±224.39; P<0.01) and pro-proliferativeproperties. Concerning the impact on heart, rhEPO treatment in the MRF ratspromoted nonhematopoietic protection, including Bax/Bcl2 reduction (p<0.05),promotion of proliferation, due to PCNA increment, suggesting a cardioprotectiveaction.Conclusions: This study suggests that rhEPO treatment might present cardiorenalcytoprotective properties in earlier stages of MRF, mainly due to antiapoptotic,antioxidant and pro-proliferative actions.

FP213 TRENDS IN CKD ANAEMIA MANAGEMENT: THE IMPACT OFA CHANGING ENVIRONMENT (AN INTERIM ANALYSIS OFTHE EXTEND STUDY)

C Winearls1, C Winearls1, S DI Giulio2, J Galle3, I Kiss4, H Herlitz5,G Wirnsberger6, K Claes7, M Suranyi8, A Guerin9, J Addison10, M D’souza11 andB Fouqueray121Oxford Kidney Unit, Churchill Hospital, Oxford, UK, 2Ospedale San CamilloForlanini, Rome, Italy, 3Klinikum Luedenscheid, Luedenscheid, Germany, 4Fov.Onk. Szent Imre Korhaz, Budapest, Hungary, 5Department of Molecular andClinical Medicine/Nephrology, Institute of Medicine, The Sahlgrenska Academy atthe University of Gothenburg, Göteborg, Sweden, 6Department of Internal

Medicine, Medical University of Graz, Graz, Austria, 7Uz Gasthuisberg, Leuven,Belgium, 8Renal Unit, Liverpool Hospital, Sydney, Australia, 9Clinique Mont Louis,Paris, France, 10Amgen Limited, Cambridge, UK, 11Contract Statistician onBehalf of Amgen Limited, Cambridge, UK, 12Amgen (Europe) Gmbh, Zug,Switzerland

Introduction and Aims: EXTEND is an ongoing observational study of not ondialysis (ND) CKD patients at commencement of extended-dosing (ED) frequency ofdarbepoetin alfa (DA) either once every 2 weeks or once monthly. Eligible patientshad commenced ED on or after June 2006. Enrolment spanned the period ofpublication of the CREATE, CHOIR (Nov 2006) and TREAT (Nov 2009) outcometrials. In this period, new KDOQI treatment guidelines were issued and ESA labelswere updated with revised haemoglobin (Hb) treatment targets. This interim analysis(IA) examines whether anaemia practice patterns have been influenced by theseevents.Methods: Eligible patients were enrolled regardless of diabetic (DM) status andwhether they were ESA-naïve or had received an ESA prior to enrolment(ESA-prior). Patients were followed until time of kidney transplant, death or lost tofollow-up. This IA comprises data collected up to Mar 2011, to a maximum of36-months follow-up per patient.Hb concentrations collected at initiation of ED (Jul 2006-Sep 2009), and all observedHb data (Jan 2007-Mar 2011) were summarized at quarterly intervals (excluding datafrom the first 6 months post-start of ED). Data were censored at time of transition todialysis. Outcomes were explored in DM and non-DM subgroups at initiation of ED.Results: The IA comprises 5827 CKD stage 3-5 subjects; 3163 (54%) were ESA naïve;2219 (38%) had DM. Comparing Jul 2006 to Sep 2009 the mean Hb [95%CI] atinitiation of ED was lower in ESA naive subjects, 10.4 [10.2-10.6] vs 10.0 [9.8-10.1]g/dL and the mean Hb achieved from Jan2007 to March 2011 was also lower, 12.0[11.8-12.2] vs 11.5 [11.4-11.6] g/dL. Lower Hb concentrations were also observed inESA -prior patients (mean Hb [95%CI] at initiation: 12.2 [12.0-12.4] vs 11.4[11.1-11.8] g/dL, mean achieved Hb: 12.2 [12.0-12.3] to 11.5 [11.4-11.7] g/dL) duringthe same time frames. Although ED was commenced at higher Hb concentrations inESA prior compared to ESA naïve patients, by Mar 2011 the achieved mean Hbswere the same (11.5 g/dL).In a subgroup analysis of DM and non-DM subjects, Hb at initiation of ED waslower. Before the TREAT publication, a statistically significant decline was observedin achieved Hb, irrespective of the DM status. After the TREAT publication, therewas no further decrease in Hb and the trends in Hb observed were significantlydifferent from those noted in the pre- TREAT observational period.Conclusions: Since 2006, both the Hb at initiation of DA ED and the Hb achievedhave reduced. This was independent of status; ESA naive/prior or DM. Overall, thesetrends suggest that practice patterns are consistent with anaemia guidelines.Publication of the TREAT study was not followed by an additional decrease inachieved Hb in EXTEND patients, irrespective of the DM status.

FP214 CARDIORENAL SYNDROME TYPE 4 (CRS 4) ASSOCIATEDWITH ANAEMIA LONG TERM SURVIVAL ANALYSIS

Matteo Floris1, Maura Conti1, Riccardo Cao1, Gianfranco Pili1, Patrizia Melis1,Valeria Matta1, Efisio Murgia1, Alice Atzeni1, Valentina Binda1, Andrea Angioi1,Marcella Peri2 and Antonello Pani31Nephrology, Brotzu Hospital, Cagliari, 2Pediatry, University of Cagliari,3Nephrology ,Brotzu Hospital

Introduction and Aims: In Cardiorenal Syndrome type 4 (CRS 4), chronic renalfailure is responsible for heart failure. Anaemia is a complication of both conditionsand is associated with an increased risk of mortality, but the possible correlationbetween clinical outcome and hemoglobin (Hb) levels still remains unclear. The aimof our study was to analyse the influence of the severity of anaemia on the long-termsurvival of our patients affected by CRS 4.Methods: Among all the patients admitted to our department between January 2001and January 2008 (n = 7,768), we selected those who met the following criteria uponadmission: signs and symptoms of systolic heart failure, left ventricular ejectionfraction (LVEF) <40%, Glomerular Filtration Rate (GFR) MDRD Study <60 ml/min,Hb <13.5 in males and <12.0 in females. 76 patients (0.97%)(M=52, F=24) met theinclusion criteria, and baseline characteristics are shown in Table 1. The primaryoutcome was all-cause mortality and all patients were followed-up for at least 18months after discharge (mean=23 months). Based on Hb levels, patients werestratified into two subgroups (1 and 2), that were homogeneous for gender, age andco-morbidities (1 = Hb =10.5, 2 = Hb >10.5 g/dl). Univariate analyses of survivalwere performed using Kaplan-Meier estimation and long-rank tests.Results: Overall survival was 67% after 6 months from admission, 52% after 12months, 42% after 24 months and 20% after 60 months (Fig .1). 60-month survivalwas 20% and 25% in groups 1 and 2, respectively (Fig.2) .The difference between thesurvival curves in the 2 groups was not statistically significant (Log Rank Test =0.82).Conclusions: Although it was a single centre, retrospective study, and consideringthat limited data are available in this field from routine clinical practice, we foundthat the association between CRS 4 and anaemia was characterized by severeprognosis. In agreement with literature data, we found that more than half of ourpatients died after 2 years of follow-up. We did not observe a significant correlation



between the severity of anaemia and mortality risk, likely related to the highmortality rates of these patients as a result of old age and the presence of seriousco-morbidities. In conclusion, further studies are needed, not only to betterunderstand the overall burden of disease, but also for risk stratification and toidentify potential targets for intervention.

FP215 EVALUATION OF HYPOXIA-INDUCIBLE FACTOR PROLYLHYDROXYLASE INHIBITOR FG-4592 FOR HEMOGLOBINCORRECTION AND MAINTENANCE IN NONDIALYSISCHRONIC KIDNEY DISEASE PATIENTS FOR 16 AND 24WEEKS

Anatole Besarab1, Diogo Belo2, Susan Diamond3, Edouard Martin4, Chao Sun5,Tyson Lee6, Khalil Saikali6, Marietta Franco6, Robert Leong7, Thomas Neff6 andKin-Hung Peony Yu61Henry Ford Hospital, Detroit, USA, 2California Institute of Renal Research, ChulaVista, USA, 3San Antonio Kidney Disease Center, San Antonio, USA, 4SouthFlorida Research Institute, Lauderdale Lakes, USA, 5Apex Research, Riverside,USA, 6Fibrogen, Inc., San Francisco, USA, 7Fibrogen, Inc. San Francisco, USA

Introduction and Aims: The need for novel therapy for anemia of chronic kidneydisease (CKD) has been underscored by growing concern over safety oferythropoiesis-stimulating agents (ESAs), which has resulted in changes to ESA labelsreducing hemoglobin (Hb) correction targets. Consequently, mean Hb concentrationat initiation of end-stage-renal-disease therapy is decreasing. FG- 4592 is an oralhypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI) in developmentfor the treatment of anemia in CKD. The HIF system has been shown to act as aniron sensor and a regulator of erythropoiesis. In an ongoing phase 2b, randomized,open- label, multicenter study, we are evaluating safety and efficacy of the HIF-PHI,FG-4592, in nondialysis CKD patients, using a range of starting doses, dosefrequencies, and dose adjustment guidelines. Data from Cohorts A-D were reportedpreviously (N=96, intent-to- treat population). We additionally report interim resultsof Cohorts E and F (N=48, intent-to- treat population).Methods: A total of 144 adult patients with stage 3 or 4 CKD and stable Hb =10.5 g/dL who were not on dialysis and had not been treated with ESAs within the previous12 weeks were randomized to six FG-4592 treatment cohorts (Table). Cohortsenrolled in parallel: A and B, followed by C and D, followed by E andF. Cohort-specific dose adjustments were allowed every 4 weeks. IV ironsupplementation was not allowed during the treatment period.Results: Treatment is complete in Cohorts A-D. For 94 efficacy-evaluable patients(treated for =2 weeks and for whom baseline and at least one post-baseline Hbvalues were available) in Cohorts A-D, mean±SD baseline Hb was 9.7±0.70 g/dL, and44 (47%) were not iron replete (i.e., ferritin <100 ng/mL and/or TSAT <20%). Mean±SD Hb increased in a dose-dependent manner, ranging from 1.4 ± 0.99 g/dL to 2.4±1.00 g/dL at the end of treatment (all p-values <0.0001 baseline vs. end oftreatment). Hb increased similarly whether or not patients were iron replete atbaseline. Preliminary data from 40 efficacy evaluable patients in Cohorts E (n=21)and F (n=19) indicate that after 4 weeks of treatment, Hb increased significantly by amean±SD of 0.94±0.86 g/dL (p<0.01 week 5 vs. baseline) and 0.66±0.83 g/dL(p<0.004 week 5 vs. baseline), respectively. Taking into account Cohorts E and F asof Dec 22, 2011of 144 randomized patients, 95 (66%) reported at least one adverseevent (AE). Twenty-three (16%) patients reported 32 treatment-emergent seriousAEs, none of which were judged by investigators to be related to FG-4592. In CohortA-D patients treated with FG-4592, a significant reduction from baseline meanarterial pressure was observed at the end of treatment (mean±SD decrease of 2.6±9.6mmHg, p=0.03). There were no sustained elevations of liver enzymes or totalbilirubin.Conclusions: A range of starting doses and dose frequencies of FG-4592 were welltolerated and effectively corrected and maintained Hb in patients with CKD-relatedanemia. The results suggest that FG-4592 may offer CKD patients a convenient oraltreatment for anemia, without need for exogenous ESA and IV iron. The potential

FP215 Table 1 FG-4592 Dosing Scheme

FP214 Table 1 Baseline characteristics of 76 patients

FP214 Fig.1: Kaplan Meier Overall survival plot.

FP214 Fig.2: Kaplan Meier survival plot for Group 1 (Hb =10.5 g/dl) and Group 2 =(Hb >10.5 g/dl)



for this novel erythrogenic HIF mechanism to avoid risks of serious side effectsassociated with ESA treatment, including hypertension and thrombotic events, alsomerits further study.

FP216 RECHALLENGE WITH INTRAVENOUS RECOMBINANTHUMAN ERYTHROPOIETIN (R-HUEPO) CAN SUCCESSFULLYTREAT ANTI-RECOMBINANT ERYTHROPOIETINASSOCIATED PRCA

Khajohn Tiranathanagul1, Kearkiat Praditpornsilpa2, Pisut Katavetin1,Talerngsak Kanjanabuch1, Yingyos Avihingsanon1, Kriang Tungsanga1 andSomchai Eiam-Ong11Chulalongkorn University, Bangkok, Thailand, 2Division of Nephrology, Faculty ofMedicine, Chulalongkorn University, Bangkok, Thailand

Introduction and Aims: Anti recombinant human erythropoietin (r-HuEpo)associated PRCA is an immunologic adverse effect of using subcutaneous r-HuEpo.Immunosuppressive agents has been suggested as treatment of this seriouscomplication. After the reversal of anti-r-HuEpo antibody, patients will continue tohave renal anemia and require long-term blood transfusion, albeit less frequentlythan when the antibody was positive. It is skeptical whether rechallenging thepatients with r-HuEpo is appropriate because rechallenging may cause thereappearance of the antibody. This study aimed to evaluate the effect of intravenousr-HuEpo rechallenge after a successful reversal of antibody.Methods: Five anti-r-HuEpo associated PRCA successfully treated by prednisolone incombination with cyclophosphamide were recruited in the study. The anti-r-HuEpowas assayed by 125I-radioimmunoprecipitaion test and was confirmed negative priorto r-HuEpo rechallenge. Intravenous dose of r-HuEpo 5000 unit per week wasstarted and dose was adjusted to achieve Hb of 10 g/dL. The absolute reticulocytecount and anti-r-HuEpo assay were done each month to monitor for relapse. Allpatients were followed for at least 6 months after rechallenge.Results: The mean age of the patients was 48.8 years. The r-HuEPO antibody wasreversed after an average of 5.4 months of the immunosuppression (Table1). Theduration after the reversal of antibody was 2.4 months before rechallenge. Twopatients were immediately rechallenged as soon as the antibodies reversed. Afterrechallenge of intravenous r- HuEpo, all patients responsed to r-HuEpo. Target Hbwas attained at mean Hb of 10.2 g/dL without the need for blood transfusions. Theabsolute reticulocyte was maintained > 39,000/uL and anti-r-HuEpo was consistentlynegative for 6 consecutive months .Conclusions: To balance the risk of anti-r-HuEpo antibody reappearance and therisk of long-term blood transfusion complications, intravenous r-HuEpo re-challengeseemed to be prudent in managing this dilemma since anti-r-HuEpo associatedPRCA case via intravenous administration has never been reported. Our study

showed that by rechallenging the patients with intravenous r-HuEpo was safe andeffective in treating renal anemia. We did not see the reappearance of anti-r-HuEpoantibodies, even after 6 months post- rechallenge.

FP217 A PROSPECTIVE, IMMUNOGENICITY SURVEILLANCEREGISTRY (PRIMS) TO ESTIMATE THE INCIDENCE OFERYTHROPOIETIN ANTIBODY-MEDIATED PURE RED CELLAPLASIA AMONG SUBJECTS WITH CHRONIC RENALFAILURE AND SUBCUTANEOUS EXPOSURE TORECOMBINANT ERYTHROPOIETIN PRODUCTS

Iain C. Macdougall1, Nicole Casadevall2, Paul Percheson3, Anna Potamianou3,Arnaud Foucher3, Daniel Fife3, Els Vercammen3 and Prims Study Group4

1Renal Unit, King's College Hospital, 2Sce D'immunologie Et HématologieBiologiques,Hôpital Saint Antoine, Paris, France, 3Janssen, PharmaceuticalCompanies of Johnson & Johnson, 4.

Introduction and Aims: The aim of the PRIMS registry was to estimate theexposure-adjusted incidence rate of erythropoietin antibody-mediated pure red cellaplasia (PRCA) in patients receiving subcutaneous (sc) EPREX for the treatment ofanaemia associated with chronic renal failure (CRF), and to compare this incidencerate with two other innovative ESAs: epoetin beta [NeoRecormon], and darbepoetinalfa [Aranesp], marketed at the start of the registry.Methods: This multicentre, multinational, non-interventional, immunogenicitysurveillance registry was conducted between 2006 and 2010 in 751 centers in Europeand Australia. In this prospective, parallel group, cohort design study, subjects weretreated with sc ESA for anemia of CRF according to standard practice consistent withthe terms of the marketing authorisation. The planned registry accrual was 20,000person-years (PY) of sc exposure to EPREX and 20,000 PY of sc exposure to twoother ESAs combined. Subjects were observed for up to 3 years. Data collectedincluded exposure to ESAs, cause and stage of CRF, treatment modality for CRF,ESAs handling and storage information, and hemoglobin level. Cases of unexplainedloss or lack of effect (LOE) with an administered ESA product, including cases ofsuspected PRCA, were reported as serious adverse events. For cases suspected ofPRCA, EPO antibody testing was recommended.Results: Between June 2006 and December 2010, when patient follow-up wasstopped, a total of 15,333 subjects were enrolled. Enrollment in the registry endedprior to the target accrual because of very slow recruitment rate due to changes inthe ESAs environment. A total of 9,602 (62.6%) subjects completed the registry. Mostsubjects had stage 4 or 5 CKD (76.3%), predialysis (80.5%).The median age was 73years. Subject demographics were comparable across all treatments. Overall, 6,525subjects received EPREX with a mean exposed time of 15.4 months and total 8,377PY exposure; 9,925 subjects received either Aranesp or NeoRecormon with a meanexposed time of 17.3 months and total 14,286 PY of exposure. During the studyperiod 3 cases of PRCA were reported for Eprex, 1 case for Aranesp and 1 case forNeoRecormon. The rate for EPO Ab-mediated PRCA with EPREX was 35.8/100,000PY and the rate for Aranesp/NeoRecormon was 14.0/100,000 PY. The rate ratio was2.6 (95% CI: 0.43, 15.31). The limited number of EPO Ab-positive PRCA casesavailable for these analyses is reflected in the wide confidence interval. Nostatistically significant difference was noted in the EPREX rate compared with otherESAs, p > 0.15, but the small numbers and wide confidence interval contributed tothis negative result. Drug-related serious adverse events were reported in 25 subjects.A review of adverse events and serious adverse events did not reveal any new orunexpected safety concerns among the 3 ESAs.Conclusions: In this large, multinational, non-interventional, prospective surveillanceregistry, EPO antibody mediated PRCA occurred at a very low incidence with thetherapeutic use of EPREX and other ESAs. No statistically significant difference inEPO antibody mediated PRCA rate was noted between EPREX treatment and thetwo other ESAs evaluated. No new, unexpected, or unusual safety signals were notedduring the conduct of the registry.

FP216 Table 1 Clinical data of 5 patients rechallenged with intravenous r-HuEpoafter the reversal of anti-r-HuEpo antibody



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RENAL ANAEMIA - CKD 1-5

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