AIMS:Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis.MATERIALS AND METHODS:All-cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non-users and in multivariable proportional hazards models.RESULTS:There were 591 individuals who used metformin at baseline and 3447 non-users. Among propensity-matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non-users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all-cause mortality (HR, 0.49; 95% CI, 0.36-0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32-0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51-0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61-0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65-1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed.CONCLUSIONS:Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.

RATIONALE & OBJECTIVE:Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes.STUDY DESIGN:Post hoc analysis of a randomized controlled trial.SETTING & PARTICIPANTS:Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).EXPOSURE:Randomized treatment assignment (darbepoetin vs placebo).OUTCOMES:All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation.ANALYTICAL APPROACH:Proportional hazards regression.RESULTS:Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7).LIMITATIONS:Post hoc analyses of a subgroup of study participants.CONCLUSIONS:Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation.

BACKGROUND:How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain.STUDY DESIGN:Observational study.SETTING & PARTICIPANTS:4,022 patients with type 2 diabetes, anemia, and chronic kidney disease from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).PREDICTOR:Postrandomization CV events.OUTCOMES:ESRD (defined as initiation of dialysis for >30 days, kidney transplantation, or refusal or nonavailability of renal replacement therapy) and post-ESRD mortality within 30 days and during overall follow-up after an intercurrent CV event.LIMITATIONS:Population limited to clinical trial participants with diabetes and anemia.RESULTS:155 of 652 (23.8%) ESRD cases occurred after an intercurrent CV event; 110 (16.9%) cases followed heart failure, 28 (4.3%) followed myocardial infarction, 12 (1.84%) followed stroke, and 5 (0.77%) followed multiple CV events. ESRD rate was higher within 30 days in individuals with an intercurrent CV event compared with those without an intercurrent event (HR, 22.2; 95% CI, 17.0-29.0). Compared to no intercurrent CV events, relative risks for ESRD were higher after the occurrence of heart failure overall (HR, 3.4; 95% CI, 2.7-4.2) and at 30 days (HR, 20.1; 95% CI, 14.5-27.9) than after myocardial infarction or stroke (P<0.001). Compared with individuals without pre-ESRD events, those with ESRD following intercurrent CV events were older, were more likely to have prior CV disease, and had higher (24.4 vs 23.1mL/min/1.73m2; P=0.01) baseline estimated glomerular filtration rates (eGFRs) and higher eGFRs at last measurement before ESRD (18.6 vs 15.2mL/min/1.73m2; P<0.001), whereas race, sex, and medication use were similar. Post-ESRD mortality was similar (P=0.3) with and without preceding CV events.CONCLUSIONS:Most ESRD cases occurred in individuals without intercurrent CV events who had lower eGFRs than individuals with intercurrent CV events, but similar post-ESRD mortality. Nevertheless, intercurrent CV events, particularly heart failure, are strongly associated with risk for ESRD. These findings underscore the need for kidney-specific therapies in addition to treatment of CV risk factors to lower ESRD incidence in diabetes.

Background Although clear evidence shows that chronic kidney disease is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of chronic kidney disease to end‐stage renal disease. We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with chronic kidney disease, diabetes, and anemia. Methods and Results Using the previously described Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) population, we compared baseline characteristics of patients with and without CAD. Cox proportional hazards models were used to assess the association between CAD and the outcomes of end‐stage renal disease and the composite of death or end‐stage renal disease. Of the 4038 patients, 1791 had a history of known CAD. These patients were older (mean age 70 versus 65 years, P<0.001) and more likely to have other cardiovascular disease. CAD patients were less likely to have marked proteinuria (29% versus 39%, P<0.001), but there was no significant difference in estimated glomerular filtration rate between the 2 groups. After adjusting for age, sex, race, estimated glomerular filtration rate, proteinuria, treatment group, and 14 other renal risk factors, patients with CAD were significantly more likely to progress to end‐stage renal disease (adjusted hazard ratio 1.20 [95% CI 1.01–1.42], P=0.04) and to have the composite of death or end‐stage renal disease (adjusted hazard ratio 1.15 [95% CI 1.01–1.30], P=0.03). Conclusions In patients with chronic kidney disease, diabetes, and anemia, a history of CAD is an independent predictor of progression to dialysis. In patients with diabetic nephropathy, a history of CAD contributes important prognostic information to traditional risk factors for worsening renal disease.

BACKGROUND:The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified.STUDY DESIGN:Retrospective analysis of prospective randomized clinical trial.SETTING & PARTICIPANTS:We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo.PREDICTORS:Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR).OUTCOMES:Cause of death as adjudicated by a blinded committee.RESULTS:Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles.LIMITATIONS:Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available.CONCLUSIONS:In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Background The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD.Methods TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level <= 11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes.Results Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics.Conclusion Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.

Introduction: Cardiovascular disease (CVD) is the leading cause of death in patients with type 2 diabetes mellitus (T2DM) and in those with chronic kidney disease (CKD). Although there is clear evidence that CKD is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of CKD to end stage renal disease (ESRD). Hypothesis: We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with CKD, T2DM, and anemia. Methods: Using the previously described TREAT population, we evaluated differences in baseline characteristics and outcomes in patients with and without a history of CAD (based on a self-reported history of CAD, MI, CABG, or PCI). Cox proportional hazards models were used to assess the association between CAD and time to ESRD and time to ESRD or death. Results: Of the 4038 patients, 1791 had a history of CAD. Patients with CAD were significantly older (mean age 70 vs 65 years, p 1 (29% vs 39%, p 2 , p=0.93). After adjusting for age, race, eGFR, proteinuria, albumin, and 12 other renal risk factors, patients with CAD were significantly more likely to progress to ESRD (adj HR 1.20 [1.01-1.42], p=0.04) and to have the composite of ESRD or death (adj HR 1.14 [1.01-1.30], p=0.03). See Figure. Conclusions: In patients with CKD, T2DM, and anemia, we found that a history of CAD is an independent predictor of progression to dialysis. Thus, in patients with diabetic nephropathy, a history of CAD contributes important prognostic information to traditional risk factors for worsening renal disease.

The Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO) was born in Ohrid on October 9, 1993. The war in former Yugoslavia negatively affected the development of nephrology and also the connections among the nephrologists from the Balkans. However, there was willingness for further mutual collaboration between the nephrologists from the Balkans. The war in Yugoslavia created hate among people, between the newly established countries, and there were problems with the recognition of the names of the new countries, and so, the nephrologists decided to apply the ancient principle of using the names of the cities, instead of the countries, as the founders of the Association. The main goal of BANTAO is to promote scientific and technical cooperation in the fields of renal disease and artificial organs between the regions on the Balkan Peninsula and the world, to give an opportunity for exchange of experience and knowledge among the experts in the area and to engage in collaborative projects in order to demonstrate that cooperation is possible even on the turbulent Balkan Peninsula. The I BANTAO congress was held in Varna from September 22 to 24th, 1995 (President--D. Nenov, Varna). The II congress of BANTAO was held from September 6th to 10th, 1997 in Struga, (President--M. Polenakovic, Skopje). The III BANTAO congress was held in Belgrade from September 18th to 20th, 1998 (President--Lj. Djukanović, Belgrade). The IV congress of BANTAO was held in Izmir from 14th to 16th November 1999 (President--A. Akcicek, Izmir). The V Congress of BANTAO was held in Thessaloniki from September 30th to October 3rd, 2001 (President--P. Stathakis, Athens). The VI Congress of BANTAO was held for the second time in Varna from 6th to 9th October 2003 (President--D. Nenov, Varna). The VII congress of BANTAO was held from September 8th to 11th, 2005 in Ohrid, (President--M. Polenakovic, Skopje). The VIII BANTAO congress was held in Belgrade, 16-19 September 2007 (President--V. Nesic, Belgrade). The IX BANTAO congress was held in Antalya, 18-22 November 2009 (President--A. Basci, Izmir). The X BANTAO congress was held from 13 to 15 October 2011 in Chalkidiki (President--D. Tsakiris, Thessaloniki). The XI BANTAO congress is being held on 26-29 September 2013 in Timisoara (President--A. Schiller, Timisoara). At the VII BANTAO Congress for the first time a CME Course was organized by ERA/EDTA and ISN/COMGAN entitled "Frontiers in Nephrology" with seven distinguished speakers. Very important event in the existence of BANTAO is the appearance of the BANTAO journal in 2003. The BANTAO journal has been published biannually since 2003. In the past 10 years, 20 regular issues; 2 supplements (Antalia and Chalkidiki congresses) have been published. Editors of the journal were as follows: 2003-2005--D. Nenov, Editor; 2005-2009--A. Basci, Editor; 2009--Goce Spasovski, Editor. Until now 332 papers have been published. The BANTAO journal is on EBSCO, DOAJ, SCOPUS. After the First Congress of BANTAO, F. Valderrábano, chairman of the EDTA--ERA Registry, at that time, wrote in Nephrology Dialysis Transplantation (1996) 11:740: "Nephrologists of the Balkan countries meet across political frontiers and war fronts--an example to politicians!BANTAO:a new European Medical Association overcomes Political obstacles." Despite the difficulties imposed by major events, such as devastating wars and catastrophic earthquakes in many countries of the Balkan Peninsula BANTAO has made considerable progress. The BANTAO Congress was established as the major scientific and institutional forum for Balkan nephrologists, with its own journal, indicating our will to communicate, to collaborate, to get to know each other and to share our difficulties. Now, we expect further successful work of BANTAO.

Artificial OrgansVolume 37, Issue 5 p. 421-422 Invited Editorial 2011 Burl Osborne Pioneer Organ Replacement Hero Award and the 2011 Osborne-IFAO Prizes for Outstanding Scientific Achievement Peter Ivanovich MD, FRCP, Peter Ivanovich MD, FRCP [email protected] Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Jesse Brown VA Medical Center, 820 S. Damen Street, Chicago, IL, 60612 USASearch for more papers by this author Peter Ivanovich MD, FRCP, Peter Ivanovich MD, FRCP [email protected] Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Jesse Brown VA Medical Center, 820 S. Damen Street, Chicago, IL, 60612 USASearch for more papers by this author First published: 23 April 2013 https://doi.org/10.1111/aor.12096Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume37, Issue5May 2013Pages 421-422 RelatedInformation

Artificial OrgansVolume 37, Issue 5 p. 419-420 In Memoriam Celebration of the Life of Burl Osborne Peter Ivanovich MD, FRCP, Peter Ivanovich MD, FRCP [email protected] Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Jesse Brown VA Medical Center, 820 S. Damen Street, Chicago, IL, 60612 USASearch for more papers by this author Peter Ivanovich MD, FRCP, Peter Ivanovich MD, FRCP [email protected] Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Jesse Brown VA Medical Center, 820 S. Damen Street, Chicago, IL, 60612 USASearch for more papers by this author First published: 23 April 2013 https://doi.org/10.1111/aor.12088Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Reference 1 Ivanovich P. The first pioneer organ replacement hero award. Artif Organs 1997; 21: 1160–1162. Volume37, Issue5May 2013Pages 419-420 ReferencesRelatedInformation

BACKGROUND Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents. STUDY DESIGN Prospective clinical trial cohort. SETTING & PARTICIPANTS 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL. OUTCOMES & MEASUREMENTS Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL. RESULTS 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level. LIMITATIONS Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD. CONCLUSIONS In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.

Background— More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. Methods and Results— A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4–2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5–2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4–2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. Conclusions— The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00093015.

BACKGROUND:Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS:We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. RESULTS:Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). CONCLUSIONS:A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

BACKGROUND:Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.METHODS:In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.RESULTS:Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.CONCLUSIONS:The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Artificial OrgansVolume 33, Issue 12 p. 1045-1047 Invited Editorial 2009 Burl Osborne Pioneer Organ Replacement Hero Award and the 2009 Osborne-IFAO Prizes for Outstanding Scientific Achievement Peter Ivanovich MD, FRCP, Peter Ivanovich MD, FRCP Jesse Brown VA Medical Center 820 S. Damen StreetChicago, IL 60612 USAE-mail: [email protected]Search for more papers by this author Peter Ivanovich MD, FRCP, Peter Ivanovich MD, FRCP Jesse Brown VA Medical Center 820 S. Damen StreetChicago, IL 60612 USAE-mail: [email protected]Search for more papers by this author First published: 15 December 2009 https://doi.org/10.1111/j.1525-1594.2009.00968.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 Ivanovich P. The first pioneer organ replacement hero award. Artif Organs 1997; 21: 1160–2. 2 Osborne B, Berry PH. Burl Osborne pioneer organ replacement hero award presentation. Artif Organs 2000; 24: 320–1. 3 Matsuda K. Presidential address: highlights of the 13th World Congress of the International Society for Artificial Organs. Artif Organs 2003; 27: 125–46. 4 Ivanovich P. 2003 Burl Osborne pioneer organ replacement hero award. Artif Organs 2004; 28: 518–9. 5 Ivanovich P. 2005 Burl Osborne pioneer organ replacement hero award. Artif Organs 2006; 30: 82–5. 6 Yamazaki K, Kurosawa H, Saito S, et al. 2-years survival and come back to work were achieved in a Japanese feasibility study with next generation LVAD “EVAHEART. Artif Organs 2007; 31: A38. 7 Ivanovich P. 2007 Burl Osborne pioneer organ replacement hero award and the 2007 Burl Osborne best paper award. Artif Organs 2008; 32: 89–90. 8 Green R. The Nicholas Green Foundation Website. Available at: http://www.nicholasgreen.org/. Accessed October 2, 2009. Citing Literature Volume33, Issue12December 2009Pages 1045-1047 ReferencesRelatedInformation

BACKGROUND Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes. STUDY DESIGN Randomized trial. SETTING & PARTICIPANTS 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries. INTERVENTION Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo. OUTCOMES TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point. CONCLUSIONS With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia.