scholarly journals Novel Compound Induces Erythropoietin Secretion through Liver Effects in Chronic Kidney Disease Patients and Healthy Volunteers

2018 ◽  
Vol 48 (3) ◽  
pp. 157-164 ◽  
Author(s):  
Aya Shinfuku ◽  
Toshiharu Shimazaki ◽  
Masanori Fujiwara ◽  
Fumihiko Sato ◽  
Hirotaka Watase ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Healthy Volunteers ◽  
Hypoxia Inducible Factor ◽  
Correlation Coefficients ◽  
Two Phase ◽  
New Strategy ◽  
The Mean ◽  
Oral Doses ◽  
Dose Dependent

Background: TP0463518 is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor developed to aid in the treatment of anemia associated with chronic kidney disease (CKD) and is expected to increase erythropoietin (EPO) derived from liver. Two phase I studies were conducted in healthy volunteers (HV) and CKD patients undergoing hemodialysis (i.e., HD patients) or those not undergoing dialysis (i.e., ND patients). Methods: Pharmacokinetics, pharmacodynamics, and safety profiles of TP0463518 were assessed. Forty HV received single oral doses of TP0463518 at 3, 6, 11, 20, and 36 mg or placebo. Twenty ND patients received single doses of TP0463518 at 1, 6, and 11 mg and 9 HD patients received TP0463518 at 1 and 11 mg doses. To identify the source organ of EPO, glycosylation patterns were determined using percentage migrated isoform (PMI) values. Results: Declining renal function slowed elimination of TP0463518 and increased the mean AUC0–∞. ∆Emax of serum EPO in 11-mg groups of HV, ND patients, and HD patients were 24.37 ± 11.37, 201.57 ± 130.34, and 1,324.76 ± 1,189.24 mIU/mL respectively. A strong correlation was ­observed between logarithm conversions of ∆Emax and AUC0–∞ with correlation coefficients of 0.945. PMI values of blood after TP0463518 administration were elevated to similar or higher levels in comparison with those of umbilical cord blood, which mainly contains liver-derived EPO. Conclusions: TP0463518 induced dose-dependent EPO production, mainly derived from the liver in HV and CKD patients. These results suggest that TP0463518 is a new strategy for treating anemia in CKD, which can be used regardless of renal functions.

scholarly journals Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies

2019 ◽  
Vol 49 (4) ◽  
pp. 271-280 ◽  
Author(s):  
Tadao Akizawa ◽  
Iain C. Macdougall ◽  
Jeffrey S. Berns ◽  
Thomas Bernhardt ◽  
Gerald Staedtler ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Efficacy And Safety ◽  
Open Label ◽  
Multicenter Studies ◽  
Parallel Group ◽  
The Mean ◽  
Term Management

Background: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. Methods: Both studies were parallel-group, open-label, multicenter studies of ≤36 months’ duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). Results: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient’s overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. Conclusions: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.

Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, for treatment of anemia of chronic kidney disease: two randomized Phase 2 trials in Japanese patients

2020 ◽  
Author(s):  
Masaomi Nangaku ◽  
Youssef M K Farag ◽  
Emil deGoma ◽  
Wenli Luo ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Japanese Patients ◽  
Prolyl Hydroxylase ◽  
Fixed Dose ◽  
Primary Efficacy ◽  
Phase 2 ◽  
Prolyl Hydroxylase Inhibitor ◽  
Dose Dependent

Abstract Background Vadadustat is an investigational, oral hypoxia-inducible factor prolyl hydroxylase inhibitor in development in Japan for the treatment of chronic kidney disease (CKD)-induced anemia. Methods Two Phase 2, multicenter, double-blind, placebo-controlled studies randomized Japanese patients with nondialysis-dependent (NDD, n = 51) or dialysis-dependent (DD, n = 60) CKD-induced anemia to once-daily vadadustat (150, 300 or 600 mg) or placebo. A 6-week, fixed-dose primary efficacy period was followed by a 10-week vadadustat dose adjustment/maintenance period. The primary endpoint was the mean change in hemoglobin (Hb) level from pretreatment to Week 6. Results Statistically significant (P < 0.01) dose-dependent increases in mean Hb values were observed at Week 6 in all vadadustat groups versus placebo [placebo and vadadustat 150, 300 and 600 mg: −0.47, 0.43, 1.13 and 1.62 (NDD-CKD) and −1.48, −0.28, 0.08 and 0.41 (DD-CKD), respectively]. By Week 16, 91% (NDD-CKD) and 71% (DD-CKD) of vadadustat-treated participants achieved target Hb levels (10.0–12.0 g/dL) and significant dose-dependent changes in iron utilization and mobilization biomarkers were observed with vadadustat. During the primary efficacy period, the incidence of treatment-emergent adverse events (AEs) with placebo and vadadustat 150, 300 and 600 mg was 36, 33, 58 and 54% (NDD-CKD) and 40, 53, 73 and 40% (DD-CKD), respectively. The most common AEs during the primary efficacy period were nausea and hypertension (NDD-CKD) and diarrhea, nasopharyngitis and shunt stenosis (DD-CKD). Of 23 serious AEs in 18 patients, 1 was deemed related (hepatic function abnormal); no deaths were reported. Conclusions The efficacy and safety results from these studies support the development of vadadustat for the treatment of anemia in patients with CKD.

scholarly journals A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study

2021 ◽  
pp. 1-9
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Takuhiro Yamaguchi ◽  
Ryosuke Koretomo ◽  
Kazuo Maeda ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Hypoxia Inducible Factor ◽  
Intravenous Iron ◽  
Target Range ◽  
Maintenance Hemodialysis ◽  
Phase 3 ◽  
Evaluation Period ◽  
The Mean

<b><i>Introduction:</i></b> Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis. <b><i>Methods:</i></b> Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to &#x3c;12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20–24 (noninferiority margin: −1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0–4. <b><i>Results:</i></b> The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was −0.12 g/dL (95% CI: −0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA. <b><i>Discussion/Conclusion:</i></b> Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.

scholarly journals MO541HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH NON--DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Mark Koury ◽  
Pablo E Pergola ◽  
Prabir Roy-Chaudhury ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Darbepoetin Alfa ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Phase 3 ◽  
Two Phase ◽  
Prolyl Hydroxylases ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be &lt;10.0 g/dL, and for the ESA-treated NDD-CKD trial (NCT02680574), the range had to be from 8.0-11.0 g/dL in the United States (US) and from 9.0-12.0 g/dL non-US. In the ESA-untreated trial, patients received no ESA within 8 weeks before randomization; in the ESA-treated trial, patients were maintained on ESA therapy, with ≥1 dose received within 6 weeks prior to or during screening. The vadadustat starting dose was 300 mg/day for all patients, whereas the initial darbepoetin alfa dose depended on each patient’s prior dose or the product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) both during the primary (PEP; weeks 24-36) and secondary (SEP; weeks 40-52) evaluation periods. Herein, we present topline results from the PEP and SEP endpoints, in addition to more detailed erythrocyte parameters. Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase &gt;1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry.

Correlation of Serum Sclerostin Levels with Carotid Intima Media Thickness in Chronic Kidney Disease Hemodialysis

2020 ◽  
Vol 6 (1) ◽  
pp. 18-26
Author(s):  
Adhi Permana ◽  
Ian Effendi ◽  
Taufik Indrajaya
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Ultrasound Examination ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Media Thickness ◽  
The Mean ◽  
Sclerostin Level ◽  
Hemodialysis Duration

Chronic kidney disease is associated with a high mortality rate, especially cardiovascular disease associated with mineral and bone disorders. Sclerostin is an inhibitor of Wnt signaling which has the effect of increasing the occurrence of vascular calcification in patients with chronic kidney disease. There are several studies that show different results. Carotid intima media thickness ultrasound examination is a tool to identify atherosclerosis which is part of vascular calcification. The aim of this study is to look at the correlation of sclerostin with carotid intima media thickness (CIMT) in patients with chronic kidney disease undergoing hemodialysis. In this cross section, the concentration of sclerostin was measured by examination of enzymed linked immunosorbent assay. CIMT measurement by ultrasound mode B examination. There were 40 patients in this study. The mean sclerostin level was 256.68 ± 127.76 pg / ml. Sclerostin levels are declared high if above 162 pg / ml there are 30 people. CIMT thickening was present in 11 patients. There was no significant correlation of serum sclerostin with CIMT in patients with chronic kidney disease undergoing hemodialysis (r-0.32 p0,847). In multivariate linear regression, hemodialysis duration is an independent factor that is significantly significant with CIMT. There was no significant correlation of serum sclerostin with CIMT in patients with chronic kidney disease undergoing hemodialysis.

scholarly journals Plasma natriuretic peptide level is an independent determinant of major clinical outcomes in atrial fibrillation patients without heart failure: the Fushimi AF Registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hamatani ◽  
M Iguchi ◽  
Y Aono ◽  
K Ishigami ◽  
S Ikeda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Outcomes ◽  
Prognostic Marker ◽  
Oral Anticoagulants ◽  
Systemic Embolism ◽  
The Mean

Abstract Background Atrial fibrillation (AF) increases the risk of death, stroke/systemic embolism and heart failure (HF). Plasma natriuretic peptide (NP) level is an important prognostic marker in HF patients. However, little is known regarding the prognostic significance of plasma NP level in AF patients without HF. Purpose The aim of this study is to investigate the relationship between plasma NP level and clinical outcomes such as all-cause death, stroke/systemic embolism and HF hospitalization during follow-up period in AF patients without HF. Methods The Fushimi AF Registry is a community-based prospective survey of AF patients in our city. The inclusion criterion of the registry is the documentation of AF at 12-lead electrocardiogram or Holter monitoring at any time, and there are no exclusion criteria. We started to enroll patients from March 2011, and follow-up data were available for 4,466 patients by the end of November 2019. From the registry, we excluded 1,220 patients without a pre-existing HF (defined as having one of the following; prior hospitalization for HF, New York Heart Association class ≥2, or left ventricular ejection fraction &lt;40%). Among 3,246 AF patients without HF, we investigated 1,189 patients with the data of plasma BNP (n=401) or N-terminal pro-BNP (n=788) level at the enrollment. We divided the patients according to the quartile of each plasma BNP or NT-pro BNP level and compared the backgrounds and outcomes between these 4 groups stratified by plasma NP level. Results Of 1,189 patients, the mean age was 72.1±10.2 years, 454 (38%) were female and 684 (58%) were paroxysmal AF. The mean CHADS2 and CHA2DS2-VASc score were 1.6±1.1 and 2.9±1.5, respectively. Oral anticoagulants were prescribed in 671 (56%) at baseline. The median (interquartile range) BNP and N-terminal pro-BNP level were 84 (38, 176) and 500 (155, 984) pg/ml, respectively. Patients with high plasma NP level were older, and demonstrated lower prevalence of paroxysmal AF, higher CHADS2 and CHA2DS2-VASc scores and higher prevalence of chronic kidney disease and oral anticoagulants prescription (all P&lt;0.01). A total of 165 all-cause death, 114 stroke/systemic embolism and 103 HF hospitalization occurred during the median follow-up period of 5.0 years. Kaplan-Meier curves demonstrated that higher plasma NP level was significantly associated with the incidences of all-cause death, stroke/systemic embolism and HF hospitalization in AF patients without HF (Figure 1A). Multivariable Cox regression analysis revealed that plasma NP level could stratify the risk of clinical outcomes even after adjustment by type of AF, CHA2DS2-VASc score, chronic kidney disease and oral anticoagulant prescription (Figure 1B). Conclusion Plasma NP level is a significant prognostic marker for all-cause death, stroke/systemic embolism and HF hospitalization in AF patients without HF, suggesting the importance of measuring plasma NP level in AF patients even without HF. Figure 1 Funding Acknowledgement Type of funding source: None

scholarly journals Associations among Heavy Metals and Proteinuria and Chronic Kidney Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 282
Author(s):  
Hui-Ju Tsai ◽  
Chih-Hsing Hung ◽  
Chih-Wen Wang ◽  
Hung-Pin Tu ◽  
Chiu-Hui Li ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
General Population ◽  
Estimated Glomerular Filtration Rate ◽  
Synergistic Effects ◽  
Blood Lead ◽  
Southern Taiwan ◽  
The Mean ◽  
Traditional Risk Factors

Background: The prevalence of chronic kidney disease (CKD) is increasing annually in Taiwan. In addition to traditional risk factors, heavy metals contribute to the development of CKD. The aim of this study was to investigate associations among heavy metals and proteinuria and CKD in the general population in Southern Taiwan. We also explored the interaction and synergetic effects among heavy metals on proteinuria. Methods: We conducted a health survey in the general population living in Southern Taiwan between June 2016 and September 2018. Seven heavy metals were measured: blood lead (Pb) and urine nickel (Ni), chromium (Cr), manganese (Mn), arsenic (As), copper (Cu), and cadmium (Cd). Proteinuria was measured using reagent strips. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Results: The mean age of the 2447 participants was 55.1 ± 13.2 years and included 977 males and 1470 females. Participants with high blood Pb and high urine Ni, Mn, Cu, and Cd were significantly associated with proteinuria. Interactions between blood Pb and urine Cr, and between urine Cd and Cu, had significant effects on proteinuria. The participants with high blood Pb and high urine Cu were significantly associated with an eGFR of <60 mL/min/1.73 m2. Conclusion: High blood Pb and high urine Cu may be associated with proteinuria and an eGFR of <60 mL/min/1.73 m2. High urine Ni, Mn, and Cd were significantly associated with proteinuria. Co-exposure to Cd and Cu, and Pb and Cr, may have synergistic effects on proteinuria.

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