Roxadustat for anemia in patients with end-stage renal disease incident to dialysis.

BACKGROUND: We evaluated the efficacy and safety of roxadustat versus epoetin alfa for the treatment of chronic kidney disease-related anemia in patients new to dialysis. METHODS: HIMALAYAS was a Phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were incident to hemodialysis/peritoneal dialysis for 2 weeks to ≤4 months prior to randomization and had mean hemoglobin (Hb) ≤10.0 g/dL. Primary endpoints were mean Hb (g/dL) change from baseline averaged over Weeks 28-52 regardless of rescue therapy [non-inferiority criterion: lower limit of 95% confidence interval (CI) for treatment difference >-0.75] and percentage of patients achieving an Hb response between Weeks 1 and 24 censored for rescue therapy (non-inferiority margin for between-group difference -15%). Adverse events were monitored. RESULTS: The intent-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (standard deviation) Hb changes from baseline averaged over Weeks 28-52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior [least squares mean difference: 0.18 (95% CI 0.08, 0.29)] to epoetin alfa. Percentages of patients with an Hb response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups, respectively. Roxadustat was non-inferior to epoetin alfa [treatment-group difference 3.5% (95% CI -0.7%, 7.7%)]. Adverse event rates were comparable between treatment groups. CONCLUSIONS: Roxadustat was efficacious for correcting and maintaining Hb levels compared with epoetin alfa. Roxadustat had an acceptable safety profile.

Peginesatide in patients with anemia undergoing hemodialysis.

BACKGROUND: Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).

Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis.

BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis. METHODS: In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 µg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point. RESULTS: In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide. CONCLUSIONS: The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).

Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.

BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. STUDY DESIGN: Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. SETTING & PARTICIPANTS: Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. INTERVENTION: Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. OUTCOMES: Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). MEASUREMENTS: Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). RESULTS: Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. LIMITATIONS: Short treatment duration and small sample size. CONCLUSIONS: In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients.

BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects. METHODS: NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity. RESULTS: Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo. CONCLUSIONS: Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial. CLINICAL TRIALS REGISTRATION: Clintrials.gov #NCT00761657.

Prospective analysis of Hemodialysis Reliable Outflow (HeRO) vascular access graft vs. cuffed catheter access in hemodialysis.

The Hemodialysis Reliable Outflow (HeRO) graft was compared to the cuffed catheter in end-stage renal disease patients. All consented patients were evaluated for HeRO graft placement. Eligible patients that did not receive a graft were enrolled in the control group. Participants who had not exhausted peripheral venous access sites suitable for fistulas and grafts were excluded. Differences in quality of life and incidence of bacteremia, vascular interventions, hospitalizations, and death were evaluated over one year. In thirty-three patients included in the analysis--16 HeRO, 17 control--significantly fewer bacteremia events (93.8% vs. 64.7%) and a significantly increased number of vascular interventions (64.7% vs. 25%) were reported for the HeRO versus Control group. The increased interventions in the HeRO group may be due to the two-step placement process.

Association of risk stratification score with dialysis vascular access stenosis.

BACKGROUNDS: Clinical monitoring is the recommended standard for identifying dialysis access dysfunction; however, clinical monitoring requires skill and training, which is challenging for understaffed clinics and overburdened healthcare personnel. A vascular access risk stratification score was recently proposed to assist in detecting dialysis access dysfunction. PURPOSE: Our objective was to evaluate the utility of using vascular access risk scores to assess venous stenosis in hemodialysis vascular accesses. METHODS: We prospectively enrolled adult patients who were receiving hemodialysis through an arteriovenous access and who had a risk score ⩽3 (low-risk) or ⩾8 (high-risk). We compared the occurrence of access stenosis (>50% on ultrasonography or angiography) between low-risk and high-risk groups and assessed clinical monitoring results for each group. RESULTS: Of the 38 patients analyzed (18 low-risk; 20 high-risk), 16 (42%) had significant stenosis. Clinical monitoring results were positive in 39% of the low-risk and 60% of the high-risk group (p = 0.19). The high-risk group had significantly higher occurrence of stenosis than the low-risk group (65% vs 17%; p = 0.003). Sensitivity and specificity of a high score for identifying stenosis were 81% and 68%, respectively. The positive predictive value of a high-risk score was 65%, and the negative predictive value was 80%. Only 11 (58%) of 19 subjects with positive clinical monitoring had significant stenosis. In a multivariable model, the high-risk group had seven-fold higher odds of stenosis than the low-risk group (aOR = 7.38; 95% CI, 1.44-37.82; p = 0.02). Positive clinical monitoring results and previous stenotic history were not associated with stenosis. Every unit increase in the score was associated with 34% higher odds of stenosis (aOR = 1.34; 95% CI, 1.05-1.70; p = 0.02). CONCLUSIONS: A calculated risk score may help predict the development of hemodialysis vascular access stenosis and may provide a simple and reliable objective measure for risk stratification.

Retraction notice to "Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis." Kidney Int Rep. 2021;6:613-623.

[This retracts the article DOI: 10.1016/j.ekir.2020.12.018.].

C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis.

BACKGROUND: No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients. METHODS: Patients were randomized (1:1) to receive either 1.2 µg/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-week evaluation period. Two primary end points were assessed: the haemoglobin (Hb) response rate and the change in average Hb concentration between baseline and evaluation. RESULTS: The Hb response rate for C.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate [95% confidence interval (CI): 89.1, 97.3; P < 0.0001] and comparable with darbepoetin alfa (93.5%; 95% CI: 88.4, 96.8; P < 0.0001). C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similar mean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa [39 patients (25.8%) versus 72 patients (47.7%); P < 0.0001]. Adverse event rates were comparable between the treatment groups. CONCLUSION: C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended target range in non-dialysis CKD patients.

Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials.

BACKGROUND AND OBJECTIVES: We evaluated the efficacy and cardiovascular safety of roxadustat versus placebo by analyzing data pooled from three phase 3 studies of roxadustat in patients with non-dialysis-dependent CKD and CKD-related anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the three phase 3, double-blind studies of roxadustat versus placebo evaluating the treatment of CKD-related anemia in patients not requiring dialysis, the primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy. The primary cardiovascular safety end point was a composite measure of major adverse cardiovascular events (MACE; all-cause mortality, myocardial infarction, stroke). MACE plus (MACE+; MACE plus unstable angina and heart failure requiring hospitalization) and all-cause mortality were key secondary safety end points. These safety end points were adjudicated. RESULTS: A total of 4277 patients with non-dialysis-dependent CKD were randomized (roxadustat, n=2391; placebo, n=1886). Baseline characteristics were comparable between groups; the mean (SD) hemoglobin was 9.1 (0.7) g/dl and mean eGFR was 20 (12) ml/min per 1.73 m2. Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7 (95% confidence interval [95% CI], 1.7 to 1.8). Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively; hazard ratio [HR], 0.26; 95% CI, 0.21 to 0.32). There were no increased risks of MACE (HR, 1.10; 95% CI, 0.96 to 1.27), MACE+ (HR, 1.07; 95% CI, 0.94 to 1.21), all-cause mortality (HR, 1.08; 95% CI, 0.93 to 1.26), or individual MACE+ components in patients treated with roxadustat versus those treated with placebo. CONCLUSIONS: Roxadustat was more effective than placebo at increasing hemoglobin in patients with non-dialysis-dependent CKD and anemia, while decreasing transfusion rate and being noninferior to placebo with respect to risk of MACE. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study of FG-4592 for the Treatment of Anemia in Chronic Kidney Disease Patients Not Receiving Dialysis, NCT01750190; Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS), NCT01887600; Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis, NCT02174627.

Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis.

INTRODUCTION: Erythropoiesis-stimulating agents are associated with increased cardiovascular risk when higher doses are used toward higher hematocrit targets. Patients new to dialysis are at higher risk for morbidity and mortality. Systematic evaluation of this population was predefined in the roxadustat clinical development program. Roxadustat is a hypoxia-inducible prolyl hydroxylase inhibitor. METHODS: Data were pooled from 3 phase 3, randomized, open-label, active-controlled trials. Eligible adults had kidney failure and initiated dialysis for 2 weeks to ≤ 4 months prior to randomization to roxadustat or epoetin alfa. Efficacy was assessed as mean change in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy. Key cardiovascular safety endpoints were major adverse cardiovascular events (MACE; all-cause mortality [ACM], myocardial infarction, and stroke), and MACE+ (MACE plus unstable angina or congestive heart failure requiring hospitalization), and ACM. RESULTS: This study included 1530 patients with kidney failure incident to dialysis. Mean (SD) changes in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy, were 2.12 (1.45) versus 1.91 (1.42) g/dl in the roxadustat and epoetin alfa groups (least-squares mean difference: 0.22; 95% CI, 0.05 to 0.40; P = 0.0130). Risks of MACE and MACE+ were lower in the roxadustat group (hazard ratio [HR], 0.70; 95% CI, 0.51 to 0.96) than the epoetin alfa group (HR, 0.66; 95% CI, 0.50 to 0.89); the HR for ACM was 0.76 (95% CI, 0.52 to 1.11). CONCLUSION: Roxadustat was at least as efficacious as epoetin alfa. Roxadustat had a lower risk of MACE/MACE+ in patients new to dialysis.

Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for Treatment of Anemia in Chronic Kidney Disease: A Placebo-Controlled Study of Pharmacokinetic and Pharmacodynamic Profiles in Hemodialysis Patients.

Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). Patients received single doses of roxadustat (1 or 2 mg/kg) or placebo 1 hour after hemodialysis on day 1 and 2 hours before dialysis on day 8. Maximum plasma concentration and area under the plasma concentration-time curve for patients receiving roxadustat were slightly more than dose proportional and elimination half-life ranged from 14.7 to 19.4 hours. Roxadustat was highly protein bound (99%) in plasma, and dialysis contributed a small fraction of the total clearance: only 4.56% and 3.04% of roxadustat recovered from the 1 and 2 mg/kg dose groups, respectively. Roxadustat induced transient elevations of endogenous erythropoietin that peaked between 7 and 14 hours after dosing and returned to baseline by 48 hours after dosing. Peak median endogenous erythropoietin levels were 96 mIU/mL and 268 mIU/mL for the 1- and 2-mg/kg doses, respectively, within physiologic range of endogenous erythropoietin responses to hypoxia at high altitude or after blood loss. No serious adverse events were reported, and there were no treatment- or dose-related trends in adverse event incidence.

Role of aldosterone in left ventricular hypertrophy among African-American patients with end-stage renal disease on hemodialysis.

AIMS: Recently, serum aldosterone levels have been reported to play a significant role in cardiac hypertrophy. One study of Japanese patients correlated aldosterone levels with the degree of left ventricular hypertrophy (LVH) in those undergoing hemodialysis. However, the role of aldosterone in LVH in non-Japanese patients with end-stage renal disease (ESRD) has not been established. MATERIALS AND METHODS: Researchers evaluated 42 [29 African-Americans (69%), 11 Caucasians (26%), and 2 other (5%)] male ESRD patients on dialysis for more than 6 months. Pre- and postdialysis, blood pressures and aldosterone and renin concentrations were measured. Transthoracic echocardiography was performed and left ventricular mass (LVM) index was calculated using the Devereaux formula. Medications were reviewed. RESULTS: There were no differences noted in medications prescribed for African-Americans and for Caucasians. Additionally, data from diabetic patients showed no statistically significant correlation between LVM index and any of the variables, including pre- and postdialysis blood pressure, serum potassium, renin, and aldosterone levels, for African-Americans compared to Caucasians. Data from nondiabetic patients showed a positive correlation between LVM and plasma aldosterone concentration in African-Americans (n = 10). Data from nondiabetic Caucasians were disregarded because only one was studied. CONCLUSION: LVM and aldosterone correlate in African-American males with ESRD on hemodialysis without diabetes. This has important implications for the etiology of, and therapy for LVH in this population. Larger studies are needed to determine whether the same associations exist in females and Caucasians.

The Economics of Late-Stage Chronic Kidney Disease.

Health care reimbursement is undergoing a fundamental change from volume-driven to value-driven care. The Patient Protection and Affordable Care Act is marshaling this change and empowering hospitals through Accountable Care Organizations to accept risk. ESRD care/nephrology was awarded the only disease-specific Accountable Care Organization, ESRD Seamless Care Organizations. Dialysis providers in partnership with nephrologists will be exploring how ESRD Seamless Care Organizations will drive improvement in care. CKD care and economics will no longer be isolated from ESRD but possibly more closely linked to global patient outcomes. Preparation for these changes will require unique co-operation and collaboration between nephrologists, dialysis providers, payers, and hospitals/health care systems. Early pilot trials, demonstration projects, and special need programs have suggested value care can be delivered. Whether these results are scalable needs to be determined.

Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.

BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Epoetin alfa. Clinical evolution of a pleiotropic cytokine.

Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.

Paying fairly for good outcomes: which formula works?

I see the single-based payment systems moving more toward the middle, toward an American-style system using competitive bidding with outcomes-based focus. The American system is moving in the opposite direction despite knowledge of the flaws of a single-payment system. Modernizing our payment system by desegregating Medicare Part A and Part B, applying information technology, and value-based reimbursement along with a bold move toward an HSA methodology could empower patients and physicians, reinvigorate our system with cost savings, and move us in the direction that all industries in a free market system should have the freedom to move.

A single center experience in the use of polyurethaneurea arteriovenous grafts.

BACKGROUND: Polytetrafluoroethylene (PTFE) grafts often require temporary catheters, which increase costs as well as risk of infection, bleeding, and poor blood flow. Polyurethaneurea (PUU) grafts can be cannulated within 24 hours of placement, avoiding the need for temporary catheters. METHODS: Hemodialysis patients who were not candidates for arteriovenous fistula (AVF) were eligible for the study. Those requiring urgent (<48 hours) hemodialysis access received PUU grafts; all others received PTFE grafts. One surgeon performed all implantations. RESULTS: 133 PUU grafts were implanted, 31 (24%) patients died (unrelated to graft placement). Within the first 4 days after graft placement, 108 of 133 grafts (81%) were cannulated. None required a temporary catheter. Of 102 surviving patients, 50 (49%) had graft thrombosis; 47/50 (94%) underwent successful percutaneous thrombectomy (PT). Primary patency at 6 months and at 1 year was 51% and 33%, respectively. Secondary patency at 6 months and 1 year was 78% and 61%, respectively. Mean bleeding time (after withdrawal of dialysis needle) was 4.0 (range 1-14) minutes in PUU grafts vs. 9.2 (1-30) minutes in PTFE grafts. CONCLUSIONS: Polyurethane graft placement allowed early graft cannulation without temporary catheters. Patency rates are comparable with previous reports. Decreased bleeding time with PUU grafts reduced aggregate blood exposure for patients and staff, lowering the risk of infection and anemia exacerbation and speeding time between treatments.