BackgroundCurrent anemia therapies for patients with non–dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis.MethodsIn this double-blind phase 3 study, we randomized patients with non–dialysis-dependent CKD stages 3–5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28–52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events.ResultsThe study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%).ConclusionsRoxadustat effectively increased hemoglobin in patients with non–dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo.Clinical Trial registry name and registration number:Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627

BackgroundConcerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability.MethodsIn this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, −0.75 g/dl). Adverse events (AEs) were assessed.ResultsAmong 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively.ConclusionsRoxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa.Clinical Trial registry name and registration number:Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis. ClinicalTrials.gov Identifier: NCT02174731.

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Oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors have recently been added to the nephrologist's armament against renal anemia. Many studies confirmed the efficacy and the relatively safe profile of this new class of drugs. The recently published results from a randomized phase 3 trial about roxadustat for treating anemia in patients with CKD, not on dialysis, confirmed its efficacy and safety. However, in the same study, the event rate of urinary tract infection and pneumonia appeared higher for roxadustat than the placebo group. According to the authors, there is no clear biologic mechanism for this observation. 1 Interestingly, randomized phase 3 trials, with a smaller sample size and a shorter duration, for treating anemia in patients on chronic dialysis with roxadustat detected a higher incidence of upper respiratory infection in the roxadustat group than in the epoetin alfa or darbepoetin alfa group. 2,3 Oral HIF prolyl hydroxylase inhibitors affect erythropoietin production and iron metabolism by increasing HIF-2a and HIF-1a, respectively. However, HIFs are expressed in any cell type and transcribe too many genes. Experimental data support that roxadustat might increase certain infections by affecting the adaptive immune response through HIF-1a upregulation. Upon T-cell activation, HIF-1a is upregulated even in the absence of anoxia and affects cell metabolism, proliferation, and differentiation toward various effector or regulatory phenotypes. 4 In the human mixed-lymphocyte reaction, an established experimental model of alloimmunity, roxadustat increased HIF-1a and HIF-2a levels in CD4+ T cells, decreased their proliferation, and induced apoptosis. In parallel, roxadustat facilitated CD4+ T-cell differentiation toward a T helper 2 (Th2) cell phenotype instead of a Th1 phenotype, and into a regulatory T cell phenotype instead of a Th17 phenotype. Finally, roxadustat suppressed humoral alloimmunity, as assessed by alloantibody production. 5 Thus, in our opinion, the increased incidence of certain infections in the patients treated with roxadustat might be the result of its effect on the adaptive immune response. The pleiotropic effects and possible side effects of HIF prolyl hydroxylase inhibitors should be evaluated further. DISCLOSURESV. Liakopoulos reports receiving research funding from Baxter and Genesis, and serving as a member of the World Kidney Day Steering Committee. All remaining authors have nothing to disclose.

In Vietnam, continuous ambulatory peritoneal dialysis (CAPD) with a straight line and one bag was first used in 1998. Because the complication rate, mainly as a result of catheter obstruction and peritonitis, was very high (50%), treatment was stopped after the first 10 cases. Use of the modality resumed only in 2001. However, because of skepticism and concern on both the part of physicians and patients about the effectiveness of peritoneal dialysis (PD) and about the infection risk, CAPD developed very slowly. Until late 2004, patient numbers were very limited, and there was only one PD unit in the entire country. Since then, CAPD using Y-set and two-bag system—plus routine omentectomy during catheter insertion and better patient selection and training in bag exchange—has resulted in much better outcomes with fewer complications, and the technique has been developing far faster. This success, together full insurance coverage of both dialysis and erythropoietin since 2005, has led to a steep rise in the number of patients on PD and the number of PD units. As a result, despite the initial difficulty, the number of PD patients increased to nearly 700 in just 3 years (2004 – 2007), while it took more than 20 years before more than 3000 patients were receiving hemodialysis. Automated PD and icodextrin are not yet available in Vietnam.