Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors.

Since zinc is involved in many aspects of the hematopoietic process, zinc supplementation can reduce erythropoiesis-stimulating agents (ESAs) in patients undergoing hemodialysis. However, it remains unclear whether hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have similar reduction effects. HIF-PHI stabilizes HIF, which promotes hematopoiesis, although HIF-1α levels are downregulated by zinc. This study aimed to investigate the effect of zinc supplementation on the hematopoietic effect of HIF-PHI in patients undergoing hemodialysis. Thirty patients undergoing maintenance hemodialysis who underwent periods of treatment with roxadustat or darbepoetin alfa during the past 3 years were retrospectively observed. Participants who underwent periods with and without zinc supplementation were selected, with nine treated with darbepoetin alfa and nine treated with roxadustat. Similarly to the ESA responsiveness index (ERI), the hematopoietic effect of zinc supplementation was determined by the HIF-PHI responsiveness index (HRI), which was calculated by dividing the HIF-PHI dose (mg/week) by the patient's dry weight (kg) and hemoglobin level (g/L). Zinc supplementation significantly increased ERI (p < 0.05), but no significant change was observed (p = 0.931) in HRI. Although zinc supplementation did not significantly affect HRI, adequate zinc supplementation is required to alleviate concerns such as vascular calcification and increased serum copper during the use of HIF-PHI.

Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial.

BACKGROUND: Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. METHODS: We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 µg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. FINDINGS: Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. INTERPRETATION: Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. FUNDING: Sanquin Blood Supply. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Equivalence assessment of biotherapeutics with N- and O-glycosylation sites by sequential intact glycoform mass spectrometry (IGMS).

Glycosylation is a crucial attribute for biotherapeutics with significant impacts on quality, stability, safety, immunogenicity, pharmacokinetics, and efficacy. Therefore, to ensure consistent glycosylation, a systematic review of biotherapeutics is absolutely required including the variable glycan structure (micro-heterogeneity) and different occupancy at individual site (macro-heterogeneity) from drug design to upstream and downstream bioprocesses. Various methods have been used for glyco-characterization of biotherapeutics at the glycan, glycopeptide, and intact protein levels. In particular, intact protein analysis is considered a facile and rapid glycoform monitoring approach used throughout the product development lifecycle to determine suitable glycosylation lead candidates and reproducible product quality. However, intact glycoform characterization of diverse and complex biotherapeutics with multiple N- and O-glycosylation sites can be very challenging. To address this, a robust analytical platform that enables rapid and accurate characterization of a biotherapeutics with highly complex multiple glycosylation using two-step intact glycoform mass spectrometry has been developed. We used darbepoetin alfa, a second-generation EPO bearing multiple N- and O-glycosylation sites, as a model biotherapeutics to obtain integrated information on glycan heterogeneity and site occupancy through step-by-step MS of intact protein and enzyme-treated protein. In addition, we performed a comparative assessment of the heterogeneity from different products, confirming that our new method can efficiently evaluate glycosylation equivalence. This new strategy provides rapid and accurate information on the degree of glycosylation of a therapeutic glycoprotein with multiple glycosylation, which can be used to assess glycosylation similarity between batches and between biosimilar and reference during development and production.

Weight-based vs fixed dosing of darbepoetin alfa for anemia following kidney transplantation.

PURPOSE: Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial. METHODS: This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 µg and those who received a weight-based dose of 0.45 µg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation. RESULTS: Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 µg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups. CONCLUSION: Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.

Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial.

BACKGROUND: In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes. METHODS: Patients with an estimated glomerular filtration rate (eGFR) 8-20 ml/min/1.73 m2 without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model. RESULTS: In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m2/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups. CONCLUSIONS: In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (identifier: NCT01581073).

Treatment satisfaction with molidustat in CKD-related anemia in non-dialysis patients: a post-hoc analysis of two clinical trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa. METHODS: This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia. RESULTS: Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant. CONCLUSION: These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia. REGISTRATION OF CLINICAL TRIALS: ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017). CLINICALTRIALS: gov Identifier: NCT03350347 (November 22, 2017).

Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis.

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

Long-Term Efficacy of Erythropoiesis-Stimulating Agents in Patients with Low-Risk or Intermediate-1-Risk Myelodysplastic Syndrome: Multicenter Real-Life Data

Objective: This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life setting. Materials and Methods: A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion needs were recorded before treatment and at 12 months, 24 months, 36 months, and 48 months of treatment. Results: At the 36-month (p=0.025) and 48-month (p=0.022) visits, epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa. Transfusion needs were also significantly lower with epoetin alfa compared to darbepoetin alfa at 24 months (p=0.012) and in the low-risk group compared to the intermediate-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001). Treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-risk (29.6%, 24.1%, and 11.1%) groups were lower than those obtained at 12 months, and the values differed significantly for the 36-month and 48-month visits with values ranging from p<0.05 to p<0.001. Conclusion: This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months, revealing that treatment efficacy reached a plateau starting from the 24th month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, significantly higher hemoglobin levels and marked improvement in transfusion needs were evident in epoetin-treated patients compared to darbepoetin-treated patients and in the low-risk group compared to the intermediate-risk group.

Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014. OBJECTIVES: To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS: In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data.  AUTHORS' CONCLUSIONS: The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.

ANTECEDENTES: Los fármacos estimulantes de la eritropoyesis (FEE) se suelen utilizar para tratar la anemia en personas con nefropatía crónica. Sin embargo, su uso se ha asociado a eventos cardiovasculares. Esta es una actualización de una revisión Cochrane publicada por primera vez en 2014. OBJETIVOS: Comparar la eficacia y la seguridad de los FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi­polietilenglicol epoetina beta y FEE biosimilares) entre sí, con placebo, o ningún tratamiento, para el tratamiento de la anemia en adultos con nefropatía crónica. MÉTODOS DE BÚSQUEDA: En esta actualización, a través del contacto con el documentalista, y con el uso de términos de búsqueda pertinentes para esta revisión, se realizaron búsquedas en el Registro de estudios del Grupo Cochrane de Riñón y trasplante (Cochrane Kidney and Transplant) hasta el 29 de abril de 2022. Los estudios en el registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, en resúmenes de congresos, en el portal de búsqueda de la Plataforma de registros internacionales de ensayos clínicos (ICTRP) y en ClinicalTrials.gov. CRITERIOS DE SELECCIÓN: Se consideraron para la inclusión los ensayos controlados aleatorizados (ECA) que incluían una comparación de un FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi­polietilenglicol epoetina beta, una epoetina biosimilar o una darbepoetina alfa biosimilar) con otro FEE, placebo o ningún tratamiento en adultos con NC. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores independientes examinaron los resultados de la búsqueda y extrajeron los datos. La síntesis de los datos se realizó mediante un metanálisis pareado de efectos aleatorios (expresada como odds ratio [OR] y sus intervalos de confianza [IC] del 95%) y un metanálisis en red. Se evaluó la heterogeneidad y la inconsistencia dentro de los metanálisis con técnicas estándares y se planeó crear subgrupos y una metarregresión para explorar las fuentes de heterogeneidad o la inconsistencia. Se evaluó la certeza en las estimaciones del tratamiento para los desenlaces principales (prevención de transfusiones de sangre y muerte [por cualquier causa]) mediante el método Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTADOS PRINCIPALES: En esta actualización se incluyeron 62 nuevos estudios (9237 participantes), por lo que la revisión incluye ahora 117 estudios con 25 237 participantes. La mayoría de los estudios tuvieron riesgo alto o incierto de sesgo en la mayoría de los dominios metodológicos. En general, los resultados siguen siendo similares en esta actualización en comparación con la revisión anterior de 2014. Para prevenir la transfusión de sangre, la epoetina alfa (OR 0,28; IC del 95%: 0,13 a 0,61; evidencia de certeza baja) y la epoetina beta (OR 0,19; IC del 95%: 0,08 a 0,47; evidencia de certeza baja) podrían ser superiores al placebo, y la darbepoetina alfa fue probablemente superior al placebo (OR 0,27; IC del 95%: 0,11 a 0,67; evidencia de certeza moderada). La metoxi­polietilenglicol epoetina beta (OR 0,33; IC del 95%: 0,11 a 1,02; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,34; IC del 95%: 0,11 a 1,03; evidencia de certeza muy baja) y una darbepoetina alfa biosimilar (OR 0,37; IC del 95%: 0,07 a 1,91; evidencia de certeza muy baja) tuvieron efectos inciertos sobre la prevención de la transfusión de sangre en comparación con el placebo. Los efectos comparativos de los FEE comparados con otro FEE sobre la prevención de las transfusiones de sangre fueron inciertos, en evidencia de certeza baja a muy baja. Los efectos sobre la mortalidad (por cualquier causa) fueron inciertos para la epoetina alfa (OR 0,79; IC del 95%: 0,51 a 1,22; evidencia de certeza baja), la epoetina beta (OR 0,69; IC del 95%: 0,40 a 1,20; evidencia de certeza baja), la metoxi­polietilenglicol epoetina beta (OR 1,07; IC del 95%: 0,67 a 1,71; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,80; IC del 95%: 0,47 a 1,36; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,63; IC del 95%: 0,51 a 5,23; evidencia de certeza muy baja) en comparación con el placebo. Es probable que no hubiera diferencias entre la darbepoetina alfa y el placebo en las probabilidades de muerte (por cualquier causa) (OR 0,99; IC del 95%: 0,81 a 1,21; evidencia de certeza moderada). Los efectos comparativos de los FEE comparados con otro FEE sobre la mortalidad (por cualquier causa) fueron inciertos en evidencia de certeza baja a muy baja. Es probable que la epoetina beta aumentara el riesgo de hipertensión en comparación con el placebo (OR 2,17; IC del 95%: 1,17 a 4,00; evidencia de certeza moderada). En comparación con el placebo, la epoetina alfa (OR 2,10; IC del 95%: 1,22 a 3,59; evidencia de certeza muy baja), la epoetina beta (OR 1,88; IC del 95%: 1,12 a 3,14; evidencia de certeza baja) y la metoxi­polietilenglicol epoetina beta (OR 1,98; IC del 95%: 1,05 a 3,74; evidencia de certeza baja) podrían aumentar las probabilidades de hipertensión, pero una epoetina biosimilar (OR 1,88; IC del 95%: 0,96 a 3,67; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,98; IC del 95%: 0,84 a 4,66; evidencia de certeza baja) tuvieron efectos inciertos sobre la hipertensión. Los efectos comparativos de todos los FEE comparados con otro FEE, placebo o ningún tratamiento sobre la mortalidad cardiovascular, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal y la disnea fueron inciertos. El análisis en red para el cansancio no fue posible debido a los pocos datos disponibles. CONCLUSIONES DE LOS AUTORES: Los efectos comparativos de los diferentes FEE sobre las transfusiones de sangre, la mortalidad (por cualquier causa y cardiovascular), los eventos cardiovasculares mayores, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal, el cansancio y la disnea fueron inciertos.

Nociception Control of Bilateral Single-Shot Erector Spinae Plane Block Compared to No Block in Open Heart Surgery-A Post Hoc Analysis of the NESP Randomized Controlled Clinical Trial.

Background and Objectives: The erector spinae plane block (ESPB) is an analgesic adjunct demonstrated to reduce intraoperative opioid consumption within a Nociception Level (NOL) index-directed anesthetic protocol. We aimed to examine the ESPB effect on the quality of intraoperative nociception control evaluated with the NOL index. Materials and Methods: This is a post hoc analysis of the NESP (Nociception Level Index-Directed Erector Spinae Plane Block in Open Heart Surgery) randomized controlled trial. Eighty-five adult patients undergoing on-pump cardiac surgery were allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 42). Both groups received general anesthesia. Preoperatively, group 2 received bilateral single-shot ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Until cardiopulmonary bypass (CPB) was initiated, fentanyl administration was individualized using the NOL index. The NOL index was compared at five time points: pre-incision (T1), post-incision (T2), pre-sternotomy (T3), post-sternotomy (T4), and pre-CPB (T5). On a scale from 0 (no nociception) to 100 (extreme nociception), a NOL index > 25 was considered an inadequate response to noxious stimuli. Results: The average NOL index across the five time points in group 2 to group 1 was 12.78 ± 0.8 vs. 24.18 ± 0.79 (p < 0.001). The NOL index was significantly lower in the ESPB-to-Control group at T2 (12.95 ± 1.49 vs. 35.97 ± 1.47), T3 (13.28 ± 1.49 vs. 24.44 ± 1.47), and T4 (15.52 ± 1.49 vs. 34.39 ± 1.47) (p < 0.001) but not at T1 and T5. Compared to controls, significantly fewer ESPB patients reached a NOL index > 25 at T2 (4.7% vs. 79%), T3 (0% vs. 37.2%), and T4 (7.1% vs. 79%) (p < 0.001). Conclusions: The addition of bilateral single-shot ESPB to general anesthesia during cardiac surgery improved the quality of intraoperative nociception control according to a NOL index-based evaluation.

The long-range interaction between two GNAS imprinting control regions delineates pseudohypoparathyroidism type 1B pathogenesis.

Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes pseudohypoparathyroidism type 1B (PHP1B), a prototype of mammalian end-organ hormone resistance. Hypomethylation at the maternally methylated GNAS A/B region is the only shared defect in patients with PHP1B. In autosomal dominant (AD) PHP1B kindreds, A/B hypomethylation is associated with maternal microdeletions at either the GNAS NESP55 differentially methylated region or the STX16 gene located approximately 170 kb upstream. Functional evidence is meager regarding the causality of these microdeletions. Moreover, the mechanisms linking A/B methylation and the putative imprinting control regions (ICRs) NESP-ICR and STX16-ICR remain unknown. Here, we generated a human embryonic stem cell model of AD-PHP1B by introducing ICR deletions using CRISPR/Cas9. With this model, we showed that the NESP-ICR is required for methylation and transcriptional silencing of A/B on the maternal allele. We also found that the SXT16-ICR is a long-range enhancer of NESP55 transcription, which originates from the maternal NESP-ICR. Furthermore, we demonstrated that the STX16-ICR is an embryonic stage-specific enhancer enabled by the direct binding of pluripotency factors. Our findings uncover an essential GNAS imprinting control mechanism and advance the molecular understanding of PHP1B pathogenesis.

Changes of biomarkers for erythropoiesis, iron metabolism, and FGF23 by supplementation with roxadustat in patients on hemodialysis.

This study aimed to confirm changes in biomarkers of erythropoiesis and iron metabolism and serum fibroblast growth factor 23 (FGF-23) during darbepoetin-α treatment and then switching to the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat. A total of 28 patients on hemodialysis who received weekly doses of darbepoetin-α were switched to roxadustat. Biomarkers for erythropoiesis and iron metabolism and intact and C-terminal FGF-23 were measured in blood samples collected before the HD session on days - 7 (darbepoetin-α injection), - 4, and - 2, and days 0 (switch to roxadustat treatment, three times weekly), 3, 5, 7, 14, 21, and 28. Erythropoietin and erythroferrone levels were elevated on day - 4 by darbepoetin-α injection and decreased to baseline levels at day 0. Levels of erythropoietin were not significantly increased by roxadustat supplementation, but erythroferrone levels were continuously elevated, similar to darbepoetin-α treatment. Hepcidin-25 and total iron binding capacity were significantly decreased or increased in patients treated with roxadustat compared with darbepoetin-α. Changes of intact and C-terminal FGF-23 levels were parallel to changes of phosphate levels during roxadustat treatment. However, the actual and percentage changes of intact FGF-23 and C-terminal FGF-23 in patients with low ferritin levels were greater than those in patients with high ferritin levels. Roxadustat might stimulate erythropoiesis by increasing iron usage through hepcidin-25, which was suppressed by erythroferrone in the physiological erythropoietin condition. Changes of intact FGF-23 and C-terminal FGF-23 levels might be affected by roxadustat in patients on hemodialysis, especially those with a low-iron condition.

Oligopeptide Transporters of Nonencapsulated Streptococcus pneumoniae Regulate CbpAC and PspA Expression and Reduce Complement-Mediated Clearance.

Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious disease, but there has been an increase in the prevalence of nonencapsulated S. pneumoniae (NESp). Previously, it was thought that a capsule was necessary to cause invasive disease. NESp strains expressing the oligopeptide transporters AliC and AliD have been isolated from patients with invasive disease. The AliC and AliD oligopeptide transporters regulate the expression of several genes, including choline binding protein AC (CbpAC) (a homolog of PspA), which aids in reducing C3b deposition. It is hypothesized that by altering CbpAC expression, AliC and AliD provide protection from classical complement-mediated clearance by reducing C-reactive protein (CRP) binding. Our study demonstrates that AliC and AliD regulate CbpAC expression in NESp and that AliD found in certain serotypes of encapsulated strains regulates PspA expression. C3b deposition was increased in the NESp ΔaliD and encapsulated mutants in comparison to the wild type. NESp strains expressing AliC and AliD have a significant decrease in C1q and CRP deposition in comparison to the ΔaliC ΔaliD mutant. The complement protein C1q is required for NESp clearance in a murine model and increases opsonophagocytosis. By regulating CbpAC expression, NESp inhibits CRP binding to the bacterial surface and blocks classical complement activation, leading to greater systemic survival and virulence. Due to the increase in the prevalence of NESp, it is important to gain a better understanding of NESp virulence mechanisms that aid in establishing disease and persistence within a host by avoiding clearance by the immune system. IMPORTANCE Streptococcus pneumoniae (pneumococcus) can cause a range of diseases. Although there is a robust pneumococcal vaccination program that reduces invasive pneumococcal disease by targeting various polysaccharide capsules, there has been an increase in the isolation of nonvaccine serotypes and nonencapsulated S. pneumoniae (NESp) strains. While most studies of pneumococcal pathogenesis have focused on encapsulated strains, there is little understanding of how NESp causes disease. NESp lacks a protective capsule but contains novel genes, such as aliC and aliD, which have been shown to regulate the expression of numerous genes and to be required for NESp virulence and immune evasion. Furthermore, NESp strains have high transformation efficiencies and harbor resistance to multiple drugs. This could be deleterious to current treatment strategies employed for pneumococcal disease as NESp can be a reservoir of drug resistance genes. Therefore, deciphering how NESp survives within a host and facilitates disease is a necessity that will allow the fabrication of improved, broad-spectrum treatments and preventatives against pneumococcal disease. Our study provides a better understanding of NESp virulence mechanisms during host-pathogen interactions through the examination of genes directly regulated by the NESp proteins AliC and AliD.

Subcutaneous C.E.R.A. for the Maintenance Treatment of Anemia in Pediatric Patients With CKD: A Phase 2, Open-Label, Single-Arm, Multicenter Study.

RATIONALE & OBJECTIVE: The optimum starting dose of intravenous continuous erythropoietin receptor activator (C.E.R.A.) has been previously determined; this study ascertains the optimum starting dose of subcutaneous C.E.R.A. administration in pediatric patients. STUDY DESIGN: Phase 2, open-label, single-arm, multicenter study. SETTING & PARTICIPANTS: Patients aged 3 months to 17 years with renal anemia and chronic kidney disease (CKD; including those treated with maintenance dialysis and those not treated with dialysis) who were receiving maintenance treatment with erythropoiesis-stimulating agents (ESAs). INTERVENTION: Subcutaneous C.E.R.A. administration every 4 weeks (starting dose was based on defined conversion factors). OUTCOME: The primary outcome was the change in hemoglobin concentration between the baseline and evaluation period for each patient. Secondary efficacy measures and safety were also evaluated. RESULTS: Forty patients aged 0.4-17.7 years were enrolled. The study achieved its primary outcome: the mean change in hemoglobin concentration was an increase of 0.48g/dL; the 95% confidence interval (0.15-0.82) and standard deviation (±1.03) were within the prespecified boundaries (-1 to 1g/dL and<1.5g/dL, respectively). Mean hemoglobin concentrations were maintained within the target 10-12g/dL range in 24 of 38 patients and within±1g/dL of the baseline in 19 of 38 patients, and the median C.E.R.A. subcutaneous dose decreased over time. Efficacy in key subgroups (age group, dialysis type, prior ESA treatment) was consistent with the primary outcome. Thirty-eight patients completed the core period; 25 chose to enter the safety extension period. Safety was consistent with prior studies, with no new signals. LIMITATIONS: Single-arm and open-label study; small sample size. CONCLUSIONS: Pediatric patients with anemia secondary to CKD who were on, or not on, dialysis could be safely and effectively switched from maintenance ESAs to subcutaneous C.E.R.A. administered every 4 weeks, using defined dose-conversion factors to determine the optimum starting dose. FUNDING: F. Hoffmann-La Roche Ltd. TRIAL REGISTRATION: The SKIPPER trial registered at ClinicalTrials.gov with study number NCT03552393. PLAIN-LANGUAGE SUMMARY: Anemia, a complication of chronic kidney disease, is associated with poor quality of life and an increased risk of hospitalization and mortality. The current treatments for anemia include iron therapy and erythropoiesis-stimulating agents (ESAs); however, the relatively short half-lives of the ESAs epoetin alfa/beta or darbepoetin alfa may require more frequent dosing and hospital visits compared with the ESA known as continuous erythropoietin receptor activator (C.E.R.A.). A previous study demonstrated that children aged 5 years or more with anemia associated with chronic kidney disease who were on hemodialysis could be switched to intravenous C.E.R.A. from their existing epoetin alfa/beta or darbepoetin alfa treatment. This study provides evidence that subcutaneous C.E.R.A. can safely and effectively treat anemia in children, including those aged<5 years and regardless of whether they were on dialysis or the type of dialysis they received (peritoneal dialysis or hemodialysis).

Epoetin-alfa induced pruritic maculopapular eruption: Case report and literature review.

BACKGROUND: Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse events, the complications have been previously reported. OBJECTIVE: To report and review the characteristics and management of ESA hypersensitivities. METHODS: Case reports and related articles associated with ESA use, published between January 1999 and December 2018, were retrieved through Electronic databases (MEDLINE® and PubMed®). RESULTS: Forty-seven ESA patients with various immediate and delayed hypersensitivity reactions caused by epoetin and pharmaceutical excipients were identified from nineteen studies and one case report in this paper. Fatal hypersensitivity to ESA and ESA-allergic cross-reactivities have been documented. Desensitization or change of EPO molecular structure has been reported as successful methods of re-introducing the drug. CONCLUSIONS: ESA hypersensitivity in the various allergic reactions and cross-reactivity have been documented. Desensitization and Epoetin structural changes could be successful methods to re-introduce the drug.

Efficacy and safety of vadadustat compared to darbepoetin alfa on anemia in patients with chronic kidney disease: a meta-analysis.

OBJECTIVE: As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). METHODS: Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). RESULTS: Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). CONCLUSION: Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.

Comparison of darbepoetin alpha and recombinant human erythropoietin for treatment of anemia in pediatric chronic kidney disease: a non-inferiority trial from India.

To determine whether or not Darbepoetin alpha (DA) was non-inferior to recombinant human erythropoietin (rHuEPO) in the treatment of anemia in children with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis). This was a randomized, open-label, two-arm, parallel group, active-controlled, non-inferiority trial conducted at a tertiary care center in New Delhi, India. Fifty patients of either gender (aged 1-18 years) with CKD stage 3-5 (on or not on dialysis) who had baseline hemoglobin (Hb) between 9 and 12 g/dL and were on stable erythropoietin therapy for at least 8 weeks were randomized (1:1) to either continue rHuEPO or switch to DA therapy for a period of 28 weeks. Doses were titrated in the initial 23 weeks to maintain the Hb between 11 and 12 g/dL, and efficacy was assessed between weeks 24 and 28. The primary efficacy outcome was the mean change in Hb between baseline and the evaluation period. In the intention-to-treat population (n = 50), the adjusted between-group difference in mean Hb change between the baseline and the evaluation period was 0.131 g/dL (95% CI: - 0.439 to 0.719, p = 0.629). The lower limit of the two-sided 95% CI for the difference in the mean change in Hb between the two treatment groups was well above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar pattern of non-inferiority was seen for per protocol population. The safety profile of DA and rHuEPO was also comparable (injection site pain:rHuEPO-3, DA-7; p-0.296).   Conclusion: DA is non-inferior to rHuEPO for the treatment of anemia of CKD (stage 3-5) in pediatric population with a comparable safety profile.   Trial registration: ClinicalTrials.gov Identifier: NCT04959578 (retrospectively registered), Date: July 13, 2021. What is Known: • Limited studies showing darbepoetin alpha is effective in children as an erythropoiesis stimulating agent. • No RCT from Indian subcontinent addressing this topic. What is New: • Darbepoetin alpha is non inferior to recombinant human erythropoietin for treatment of anemia in children with CKD stage 3-5 (on or not on dialysis) with safety comparable to recombinant human erythropoietin. • A cost reduction of approximately 8.6% per patient by shifting to darbepoetin alpha.

Nucleated Red Blood Cell Emergence-Time in Newborn Lambs Following a Dose of Darbepoetin Alfa.

BACKGROUND: Nucleated red blood cells (NRBC) are very uncommon in the blood of children and adults, but small numbers are not rare in neonates on the day of birth. Elevated NRBC counts in neonates can be seen following erythropoietin dosing. Limited studies in human neonates suggest the time-interval between erythropoietin dosing and the first appearance of NRBC in the blood (the "NRBC emergence-time") is in excess of 24 hours. METHODS: We made serial blood counts (Sysmex veterinary analyzer) on ten newborn lambs; five were dosed with darbepoetin (10 µg/kg), and five were dosed with a vehicle-control to assess the NRBC emergence time under relatively controlled laboratory conditions. RESULTS: The first appearance of NRBC was at 24 h (2757 ± 3210 NRBC/µL vs. 0/µL in controls). Peak was 48-72 h (16,758 ± 8434/µL vs. 0/µL in controls), followed by fewer at 96 hours (7823 ± 7114/µL vs. 0/µL in controls). Similarly, reticulocytes peaked at 48-72 h (113,094 ± 3210/µL vs. 10,790 ± 5449/µL in controls), with no changes in platelets or leukocytes. CONCLUSION: The NRBC emergence time in newborn lambs is similar to reports from newborn humans. By extrapolation, if a neonate has a high NRBC at birth, the erythropoietic stimulus likely occurred within the interval 24 to perhaps 96+ hours prior to birth.

Longitudinal Assessment of Preterm Infants Treated with Erythropoiesis Stimulating Agents.

OBJECTIVE: We previously reported improved neurodevelopment at 2 and 4 years among preterm infants treated with erythropoietin or darbepoetin, known as erythropoiesis-stimulating agents (ESAs). We now characterize longitudinal outcomes through 6 years. METHODS: Children randomized to ESAs or placebo were evaluated at 6 years. Healthy-term children served as controls. Tests of cognition and executive function (EF) were performed. RESULTS: Cognitive/EF scores remained similar between 4 and 6 years within each group (ESA: 43 children; placebo: 17 children; term: 21 children). ESA recipients scored higher than placebo on Full-Scale IQ (94.2 ± 18.6 vs. 81.6 ± 16.7, p = 0.022), and Performance IQ (97.3 ± 16.2 vs. 81.7 ± 15.2, = 0.005). Aggregate EF trended better for the ESA group. Term controls scored better than placebo on all measures. ESA and term controls scored similarly on cognitive and EF tests. CONCLUSION: ESA recipients had better outcomes than placebo recipients, and were similar to term children. ESAs may improve long-term cognition and executive function in preterm infants.