Evaluation of the Effect of the PMMA Dialysis Membrane on the Level of Inflammation in Patients on Hemodialysis.

INTRODUCTION: The inflammation syndrome is typical for chronic kidney disease (CKD) and increases with the progression of CKD. It is extremely important to monitor the markers of inflammation in patients with CKD, as there is a clear relationship between the level of inflammation and mortality in these patients. Currently, there is no single approach to the treatment of chronic inflammation in patients with CKD. METHODS: This was a prospective open cohort study. We studied 31 patients on hemodialysis from March 1, 2020, to August 1, 2021, in 2 Moscow clinics (No. 7 and S.P. Botkin). Inclusion criteria for patients in the study were an adequate dialysis according to the KT/V index ≥1.4, absence of an active inflammatory process or infections, age over 18 years, standard hemodialysis regimen of 3 times per week, at least 4 h, levels of interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP) above the reference values. Patients were transferred from hemodialysis performed using a standard polysulfone (PS) membrane to a polymethylmethacrylate (PMMA) membrane (Filtryzer BK-2.1F). For dialysis treatment in patients, blood flow rates of 250-350 mL/min were used, and the flow rate of the dialysis solution was set at 500 mL/min. The control group consisted of 19 patients, with similar inclusion parameters, who continued their treatment with hemodialysis using a PS membrane. The aim of the research was to study the effect of the dialysis membrane (Filtryzer BK-2.1F) on the level of inflammation in routine practice compared to a PS membrane. Adverse events were monitored. RESULTS: By the end of the study, after 12 months, the levels of cytokines significantly decreased only in patients who had treatment with PMMA membrane, starting from the 3rd month of treatment, and became close to normal levels: IL-6 from 16.9 ± 8.0 to 8.5 ± 4.8 pg/mL (p ≤ 0.0001); IL-8 from 78.5 ± 11.4 to 43.6 ± 11.6 pg/mL (p ≤ 0.0001); and CRP from 10.33 ± 2.83 to 6.15 ± 1.57 mg/L (p ≤ 0.0001). Values of inflammation markers did not change in control group. CONCLUSION: In our study, we demonstrated for the first time a significant reduction in the level of inflammation in patients on standard hemodialysis in routine practice due to the use of PMMA membranes.

Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS).

BACKGROUND: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia. METHODS: This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3-5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)-hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration-change in Hb from BL to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. RESULTS: A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48-58.93] and change in Hb from BL [roxadustat - placebo: +1.692 (95% CI 1.52-1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). CONCLUSIONS: Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable.

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.

Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients.

Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb≤10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean±SD baseline Hb was 8.3±1.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by ≥2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean±SEM maximal change in Hb from baseline (ΔHb(max)), the primary endpoint, was 3.1±0.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, ΔHb(max) was similar and larger than in the no-iron group. Hb response (increase in Hb of ≥1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

BACKGROUND: In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). OBJECTIVES: This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. METHODS: Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. RESULTS: A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. CONCLUSIONS: In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360).

Biosimilar erythropoietin in anemia treatment (BEAT)-Efficacy and safety of a 1:1 dose conversion from EPREX® to EPIAO® in patients with end-stage renal disease on hemodialysis: A prospective, randomized, double blind, parallel group study.

BACKGROUND: EPREX®/ERYPO®/PROCRIT® (epoetin alfa, Janssen-Cilag GmbH) was the first available recombinant human erythropoietin (rHuEPO) and was universally reference product as per the recommendation provided by European Medicines Agency. EPIAO® is a biosimilar formulation of EPREX®, and making it a 1:1 dose conversion from EPREX® according to recommendation of European Medicines Agency. This study evaluated the clinical efficacy and safety of EPIAO® in subjects with end-stage renal disease receiving hemodialysis after intravenous administration. METHODS: This study was a multicenter, prospective, randomized, double-blind, parallel-group, 2-cohort, maintenance phase, therapeutic equivalence study to evaluate a 1:1 dose conversion from EPREX® to EPIAO® in terms of clinical efficacy and safety that was conducted at 20 sites in 2 countries in patients with end-stage renal disease on hemodialysis. Eligible subjects were treated with EPREX® (reference product of epoetin) for a period of at least 3 months before the treatment period, and then were randomly assigned to the group of EPREX® or EPIAO®. Primary endpoints were mean absolute change in hemoglobin level and mean absolute change in weekly epoetin dosage from baseline to 6 months after treatment with EPIAO®/EPREX® in parallel groups. RESULTS: A total of 200 people received the random intervention and were included in the safety set. After 6, 9, and 12 months of treatment with EPIAO® or EPREX®, there were no significant differences in the hemoglobin levels of the 2 groups compared with baseline. The 95% confidence interval for the treatment difference was within the predetermined acceptable range: ±0.5 g/dL. There were no significant differences in the epoetin dosage of the 2 groups compared with the baseline. The 95% confidence interval for the treatment difference was within the predetermined acceptable range: ± 45 IU/kg. There were no significant differences in the incidence of adverse events between the EPIAO® and EPREX® groups. Most adverse events were mild to moderate and were reverted/resolved. CONCLUSION: EPIAO® demonstrated promising effectiveness and manageable safety in patients with end-stage renal disease on hemodialysis.

The Benefit of a Glucose-Sparing PD Therapy on Glycemic Control Measured by Serum Fructosamine in Diabetic Patients in a Randomized, Controlled Trial (IMPENDIA).

BACKGROUND/AIMS: Poor glycemic control can lead to increased morbidity and mortality in peritoneal dialysis (PD) patients. Serum fructosamine may be a more reliable marker of glycemic control than HbA1c in dialysis patients. METHODS: We evaluated the effects of a glucose-sparing PD regimen on serum fructosamine. In the multicenter, controlled IMPENDIA trial, eligible diabetic PD patients were randomized (1:1) to a 24-hour combination of a glucose sparing regimen (n = 89) or a glucose-based therapy (n = 91). Serum fructosamine and HbA1c were measured at baseline, 3 months and 6 months; fructosamine measurements were corrected for serum albumin (AlbF). RESULTS: Serum fructosamine decreased from 297 to 253 µmol/l in the glucose-sparing group (95% confidence interval [CI] for the difference, -26 to -68, p < 0.001), and increased from 311 to 314 µmol/l in the glucose-only group (95% CI for the difference, -23 to +19, p = 0.87). The mean difference in change of fructosamine levels between groups at 6 months was 64 µmol/l (95% CI 29-99, p < 0.001). HbA1c decreased versus baseline in both groups (treatment difference 0.3%, p = 0.07). The correlation between AlbF and baseline fasting serum glucose was stronger than that seen between HbA1c and baseline fasting serum glucose (r = 0.47, p < 0.0001 and r = 0.31, p < 0.0001, respectively). CONCLUSION: A glucose-sparing regimen (P-E-N) improved glycemic control as measured by serum fructosamine. Further studies are needed to establish fructosamine targets that will reduce the morbidity risk related to hyperglycemia in PD patients.