scholarly journals Hypoxia-inducible factor prolyl hydroxylase domain inhibitor may maintain hemoglobin synthesis at lower serum ferritin and transferrin saturation levels than darbepoetin alfa

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252439
Author(s):  
Chie Ogawa ◽  
Ken Tsuchiya ◽  
Naohisa Tomosugi ◽  
Kunimi Maeda
Keyword(s):  
Iron Deficiency ◽  
Serum Ferritin ◽  
Darbepoetin Alfa ◽  
Reference Group ◽  
Hypoxia Inducible Factor ◽  
Transferrin Saturation ◽  
Prolyl Hydroxylase ◽  
Logistic Analysis ◽  
Cutoff Values ◽  
Prolyl Hydroxylase Domain

Background Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors, which have recently become clinically available for treating renal anemia, are attracting attention for their novel mechanisms of action. Methods Relationships of reticulocyte hemoglobin content (CHr), which reflects recent Hb synthesis, with serum ferritin (s-ft) and transferrin saturation (TSAT) were examined in 30 patients on hemodialysis after switching from darbepoetin alfa (DA) to roxadustat (Rox). Iron deficiency was defined as CHr < 32.0 pg. Cutoff values of s-ft and TSAT were determined using receiver operating characteristic curves for the endpoint CHr ≥ 32.0 pg. Logistic analysis was performed with the reference group having s-ft or TSAT below the corresponding cutoff value (low vs high). Results With the endpoint CHr ≥ 32.0 pg on Day 0, cutoff values for s-ft and TSAT were respectively 49.7 ng/mL and 21.6% on Day 0 and 35.5 ng/mL and 16.2% on Day 28. With the endpoint CHr ≥ 32.0 pg on Day 28, cutoff values for s-ft and TSAT on Day 0 were 81.6 ng/mL and 23.9%, respectively. According to multivariable logistic analysis, the odds ratios of CHr ≥ 32.0 pg on Day 0 were significantly higher for high TSAT on Day 0 [34.7 (95% CI 2.42–131.0), p<0.003] and Day 28 [24.8 (95% CI 2.75–224.0), p = 0.004]. There were no significant differences by s-ft. Odd ratios of CHr ≥ 32.0 pg on Day 28 were also significantly higher for high s-ft on Day 0 [16.0 (95% CI 1.57–163.0), p = 0.019] and high TSAT on Day 0 [13.5 (95% CI 1.24–147.0), p<0.033]. Conclusions Our results suggest Hb synthesis was maintained with lower TSAT and s-ft during Rox therapy compared with DA therapy. To avoid iron deficiency during the 4 weeks after switching DA to Rox, ideal s-ft and TSAT levels before the switch are 81.6 ng/mL and 23.9%, respectively.

scholarly journals Enhancement of Angiogenesis Through Stabilization of Hypoxia-inducible Factor-1 by Silencing Prolyl Hydroxylase Domain-2 Gene

2008 ◽  
Vol 16 (7) ◽  
pp. 1227-1234 ◽  
Author(s):  
Shourong Wu ◽  
Nobuhiro Nishiyama ◽  
Mitsunobu R Kano ◽  
Yasuyuki Morishita ◽  
Kohei Miyazono ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factor 1 ◽  
Prolyl Hydroxylase Domain

Abstract 396: Inhibition of Prolyl Hydroxylase Domain-containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Toshihiro Ichiki
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Prolyl Hydroxylase ◽  
Ang Ii ◽  
Prolyl Hydroxylase Domain

Background: Prolyl hydroxylase domain-containing protein (PHD) mediates hydroxylation of hypoxia-inducible factor (HIF)-1α and thereby induces proteasomal degradation of HIF-1α. Inhibition of PHD by hypoxia or hypoxia mimetics such as cobalt chloride (CoCl2) stabilizes HIF-1 and increases the expression of target genes such as vascular endothelial growth factor (VEGF). Although hypoxia activates the systemic renin angiotensin system (RAS), the role of PHD in regulating RAS remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin (Ang) II type 1 receptor (AT1R) and its signaling. Methods and Results: Hypoxia (1% O2), CoCl2 (100-300 μmol/L), and dimethyloxalylglycine (0.25-1.0 mmol/L), all known to inhibit PHD, reduced AT1R expression by 37.7±7.6, 39.6±8.4-69.7±9.9, and 13.4±6.1-25.2±7.0%, respectively (p<0.01) in cultured vascular smooth muscle cell. The same stimuli increased the expression of nuclear HIF-1α and VEGF (p<0.05), suggesting that PHD activity is inhibited. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression by 55.3±6.0% (p<0.01). CoCl2 decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms (p<0.01 and <0.05, respectively). CoCl2 and PHD2 knockdown diminished Ang II-induced ERK phosphorylation (P<0.01). Over-expression of the constitutively active HIF-1α did not impact the AT1R gene promoter activity. Oral administration of CoCl2 (14 mg/kg/day) to C57BL/6J mice receiving Ang II infusion (490 ng/kg/min) for 4 weeks significantly reduced the expression of AT1R in the aorta by 60.9±11.3% (p<0.05) and attenuated coronary perivascular fibrosis by 85% (p<0.01) without affecting blood pressure. However, CoCl2 did not affect Ang II-induced renal interstitial fibrosis. Conclusion: PHD inhibition downregulates AT1R expression independently of HIF-1α, reduces the cellular response to Ang II, and attenuates profibrotic effect of Ang II on the coronary arteries. PHD inhibition may be beneficial for the treatment of cardiovascular diseases, in which activation of RAS plays a critical role.

MO559ASCEND-ND: STUDY DESIGN AND BASELINE CHARACTERISTICS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Vlado Perkovic ◽  
Allison Blackorby ◽  
Borut Cizman ◽  
Kevin Carroll ◽  
Alexander Cobitz ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Darbepoetin Alfa ◽  
Trial Design ◽  
Rescue Therapy ◽  
Transferrin Saturation ◽  
Statistical Testing ◽  
Efficacy And Safety ◽  
Primary Endpoints ◽  
History Of ◽  
Baseline Characteristics

Abstract Background and Aims The Anemia Study in Chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Non-Dialysis (ASCEND-ND; NCT02876835) trial is evaluating the efficacy and safety of daprodustat when compared with darbepoetin alfa in CKD patients with anaemia not requiring dialysis. We report the trial design as well as key baseline characteristics of participants. Method Eligible patients from 39 countries were adults with CKD stages 3–5 who were able to provide informed consent and demonstrated adherence to daprodustat placebo tablets and study procedures during the run-in period. Patients were eligible if (1) they were not using erythropoiesis stimulating agents (ESAs) and had a screening haemoglobin (Hb) 8 to 10 g/dL or if (2) they were receiving ESAs with screening Hb of 8 to 12 g/dL. Patients were required to be iron replete [transferrin saturation (TSAT) &gt;20% and serum ferritin &gt;100 ng/mL] at screening. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open-label (sponsor-blind) trial design with blinded endpoint assessment. An IDMC conducts regular reviews of unblinded safety and efficacy data and makes recommendations for additions or adjustments. An external, independent and blinded Clinical Events Classification (CEC) group, led by the Duke Clinical Research Institute, in collaboration with George Clinical, adjudicate predefined events. During the study, both groups had randomised treatment adjusted using a protocol-defined algorithm targeting a Hb range of 10 to 11 g/dL. Participants also followed protocol-defined iron management criteria to ensure they remained iron replete. Additionally, an anaemia rescue algorithm was in place to minimise the risk of extended periods of inadequate Hb response and to ensure consistent application of rescue therapy across the study. The co-primary endpoints are mean change in Hb between baseline and Evaluation Period (EP; Weeks 28 to 52, inclusive) and time to first adjudicated major adverse cardiovascular event (MACE; composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke). The study has more than 99% power for the Hb non-inferiority (NI) test with an NI margin of -0.75 g/dL for the treatment difference of mean change in Hb between baseline and EP, and approximately 90% power to exclude the NI margin of 1.25 for time to first adjudicated MACE, for daprodustat compared with darbepoetin alfa. Conditional on both co-primary endpoints achieving NI at the one-sided 2.5% level, statistical testing will progress to evaluate MACE and the principal secondary endpoint of CKD progression for superiority. These tests will be multiplicity adjusted. Results A total of 3872 patients were randomised (median age 67 years, 56% female; 55% white, 28% Asian, and 10% black). The median baseline Hb was 9.8 g/dL, serum ferritin was 274 ng/mL, TSAT 30%, and eGFR 18 mL/min/1.73 m2. Among randomised patients, 54% were ESA non-users, 57% reported a history of diabetes mellitus and 36% a history of cardiovascular disease. Median blood pressure was 135/74 mmHg. Sixty percent of participants were taking angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, while 57% were taking lipid modifying agents at baseline. The trial is expected to complete during 2021. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not requiring dialysis.

scholarly journals Prevalence and pattern of Iron deficiency in patient with heart failure with reduced ejection fraction

2019 ◽  
Vol 7 (2) ◽  
pp. 10-16
Author(s):  
Aditya Mahaseth ◽  
Jay Narayan Shah ◽  
Bikash Nepal ◽  
Biplave Karki ◽  
Jeet Ghimire ◽  
...  
Keyword(s):  
Heart Failure ◽  
Iron Deficiency ◽  
Ejection Fraction ◽  
Serum Ferritin ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Functional Iron Deficiency ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
Absolute Iron Deficiency

Background and Objectives: Iron Deficiency is the commonest nutritional deficiency worldwide, affecting more than one-third of the population, its association with Heart Failure with or without anemia is of growing interest. As iron supplementation improves prognosis in patients with Heart Failure, Iron Deficiency is an attractive therapeutic target – a hypothesis that has recently been tested in clinical studies. This study is designed to estimate the prevalence and pattern of iron deficiency (ID) in heart failure (HF) with reduced ejection fraction patients with or without anemia. Material and methods: It was a single center hospital based cross sectional observational study. A total of 60 male and female patients with diagnosis of heart failure based on the Framingham Criteria, who gave consent for the study were included. They underwent laboratory evaluation including hemoglobin concentration, serum iron, transferrin saturation percentage, serum ferritin, total iron binding capacity. Serum ferritin <100 μg/l was used to diagnose absolute ID. Functional ID was defined as a serum ferritin level of 100–300 μg/l and a transferrin saturation of <20 %. Anemia was defined as hemoglobin (Hb) <13 g/dl for males and <12 g/dl for females, based on World Health Organization definition. Results: Using the above definitions iron deficiency was found in 28 (46.67%) patients. 36.67% patients had absolute iron deficiency and 10% patients had functional iron deficiency. Females had a higher non statistically significant iron deficiency than males 63.16% vs 39.02%. 15 patients (48.38%) with iron deficiency did not have anemia, and 11 (35.5%) of those patients had absolute iron deficiency. Conclusion: Iron deficiency is prevalent in patients with heart failure and reduced ejection fraction irrespective of anemia and hemoglobin levels. Many of those patients can have functional iron deficiency. Measurement of iron status should be a routine during workup of heart failure patients and further studies are needed to determine the prognostic value of iron status measurement and the influences of treatment of iron deficiency in heart failure patients. Many such trials are now underway.  

Serum iron and total iron-binding capacity compared with serum ferritin in assessment of iron deficiency.

1981 ◽  
Vol 27 (2) ◽  
pp. 276-279 ◽  
Author(s):  
F Peter ◽  
S Wang
Keyword(s):  
Iron Deficiency ◽  
Serum Ferritin ◽  
Serum Iron ◽  
Binding Capacity ◽  
Transferrin Saturation ◽  
Total Iron ◽  
Iron Binding ◽  
Total Iron Binding Capacity ◽  
Iron Deficient ◽  
Iron Binding Capacity

Abstract Ferritin values for 250 selected sera were compared with values for iron, total iron-binding capacity (TIBC), and transferrin saturation, to assess the potential of the ferritin assay for the detection of latent iron deficiency. The specimens were grouped (50 in each group) according to their values for iron and TIBC. In Group 1 (low iron, high TIBC) the saturation and ferritin values both indicated iron deficiency in all but one. In the 100 specimens of Groups 2 (normal iron, high TIBC) and 4 (normal iron, high normal TIBC), the saturation values revealed 16 iron-deficient cases, the ferritin test 55. For Groups 3 (low iron, normal TIBC) and 5 (low iron, low TIBC), the ferritin test revealed fewer cases of iron deficiency than did the saturation values (37 cases vs 51 cases, in the 100 specimens). Evidently the ferritin test detects iron deficiency in many cases for whom the serum iron and TIBC tests are not positively indicative. The correlation of serum ferritin with iron, TIBC, and transferrin saturation in the five groups was good only in the case of specimens for which the TIBC was normal; if it was abnormal the correlation was very poor.

scholarly journals Iron Status in Hypogammaglobulinemia

1985 ◽  
Vol 78 (10) ◽  
pp. 838-841
Author(s):  
Hasan I Atrah
Keyword(s):  
Iron Deficiency ◽  
General Population ◽  
Intravenous Immunoglobulin ◽  
Serum Ferritin ◽  
Iron Status ◽  
Transferrin Saturation ◽  
The State ◽  
Serum Samples ◽  
Serum Igg

Iron, transferrin and ferritin were measured in serum samples from 16 patients with primary hypogammaglobulinemia. Transferrin saturation was low in 12 patients (75%) and serum ferritin was low in 9 patients (56.25%). Both parameters were low, confirming the state of iron deficiency, in 6 patients (37.5%). These figures are highly significant ( P < 0.01) when compared with the prevalence of iron deficiency in the general population. Eight patients were maintained on intravenous immunoglobulin infusions and the rest on intramuscular immunoglobulin injections, their mean serum IgG being 4.4 g/l and 2.6 g/l respectively. There was no difference in the prevalence of iron deficiency between the two groups.

scholarly journals The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lihong Fan ◽  
Jia Li ◽  
Zefeng Yu ◽  
Xiaoqian Dang ◽  
Kunzheng Wang
Keyword(s):  
Cell Fate ◽  
Bone Repair ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Bone Tumours ◽  
Cell Fate Decisions ◽  
Tightly Coupled ◽  
Hif Pathway ◽  
Prolyl Hydroxylase Domain

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-αvia inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

scholarly journals Evaluation of the iron status of a population

Blood ◽  
1976 ◽  
Vol 48 (3) ◽  
pp. 449-455 ◽  
Author(s):  
JD Cook ◽  
CA Finch ◽  
NJ Smith
Keyword(s):  
Iron Deficiency ◽  
Serum Ferritin ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Red Cell ◽  
Adult Males ◽  
Packed Red Blood Cells ◽  
Iron Deficient ◽  
Menstruating Women ◽  
Prevalence Of Anemia

Abstract The iron status of a population of 1564 subjects living in the northwestern United States was evaluated by measurements of transferrin saturation, red cell protoporphyrin, and serum ferritin. The frequency distribution of these parameters showed no distinct separation between normal and iron-deficient subjects. When only one of these three parameters was abnormal (transferrin saturation below 15%, red cell protoporphyrin above 100 mug/ml packed red blood cells, serum ferritin below 12 ng/ml), the prevalence of anemia was only slightly greater (10.9%) than in the entire sample (8.3%). The prevalence of anemia was increased to 28% in individuals with two or more abnormal parameters, and to 63% when all three parameters were abnormal. As defined by the presence of at least two abnormal parameters, the prevalence of iron deficiency in various populations separated on the basis of age and sex ranged from 3% in adolescent and adult males to 20% in menstruating women. It is concluded that the accuracy of detecting iron deficiency in population surveys can be substantially improved by employing a battery of laboratory measurements of the iron status.

Prediction of Response to Recombinant Erythropoietin Plus Granulocyte-Colony Stimulating Factor Following a Single Subcutaneous Bolus in Patients with Myelodysplastic Syndromes; a Randomised Placebo Controlled Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1435-1435
Author(s):  
David Bowen ◽  
Ann Hyslop ◽  
Norene Keenan ◽  
Michael Groves ◽  
Dominic Culligan ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Haemoglobin Concentration ◽  
Controlled Study ◽  
Therapeutic Trial ◽  
Recombinant Erythropoietin ◽  
Baseline Serum ◽  
Functional Iron Deficiency ◽  
Erythroid Response

Abstract Recombinant Erythropoietin (+/− G-CSF) is an effective therapy for the anaemia of selected patients with MDS. Validated response prediction models are available, but response rates are only 60% in the “high” predicted response group. Furthermore, half of the total cost of one year’s therapy for a cohort of patients selected for intermediate / high predicted response, is incurred within the initial 12-week therapeutic trial (Cassadeval et al, Blood 2004,104;321). Our hypothesis was that the erythroid response to a single bolus of EPO + G-CSF (Part 1) may predict for sustained response to a therapeutic trial (Part 2). 21 MDS patients (<10% blasts) were randomised in Part 1 to receive either a single s.c. bolus of EPO 18 000 units (NeoRecormon) plus G-CSF (Lenograstim) 263 mcg (n=10), or two vials s.c. placebo (n=11). Serum EPO, haemoglobin concentration and reticulocytes (Sysmex SE9000) were assayed daily from Days 1–8. 20 patients proceeded to Part 2 and received an 8 week therapeutic trial of s.c. EPO 9000 units thrice weekly (tiw), weeks 1–4, escalating to 18 000 units tiw weeks 5–8 if no response, plus titrated s.c. G-CSF tiw. Responders were changed to once weekly (qw) EPO dosing from weeks 12–20 at the total weekly responding dose. 6 patients had erythroid response by study response criteria and 7 by IWG criteria (2HI-E major, 5 HI-E minor). 4/7 RARS patients responded. Incremental change in absolute reticulocyte counts between Day 1 and Day 8 of Part 1 discriminated responders (median increment = 40x109/l, range 31–81, n=6), who received bolus EPO/G-CSF, from non-responders who also received bolus EPO/GSCF (median increment = 1.5x109/l, range −14 to 6, n=4) and from patients receiving placebo (median increment = 5x109/l, range −21 to 18, n=11)(ANOVA P=.002). An incremental increase of >30x109/l was 100% predictive of subsequent response. In patients with erythroid response in Part 2, haemoglobin concentration at qw EPO either did not change compared to tiw dosing (P>.05, n=5), or increased (P=.002, n=1). Serum ferritin, transferrin saturation, CHr (Bayer Advia) and serum transferrin receptor (TfR)concentrations were assayed weekly. Two patients became biochemically iron deficient during weeks 1–8, both of whom had baseline serum ferritin <100mg/l. No iron supplementation was given, and one patient still had an erythroid response. No clear evidence for functional iron deficiency was seen in patients with serum ferritin >100 mg/l. Serum non-transferrin bound iron concentration correlated closely with transferrin saturation both at baseline (n=21 patients), and on treatment (n=4 responders and 4 non-responders). In Part 2, neither ΔHb, nor ΔTfR at weeks 1 or 2 predicted response. No baseline erythroid parameters differed between responders and non-responders. New observations: 1. Absolute reticulocyte increment at Day 8 post s.c. bolus EPO/G-CSF predicts for therapeutic response in this small study, 2. Once weekly EPO is as effective as thrice weekly EPO in similar doses, 3. Functional iron deficiency may impair response in MDS patients with iron-limited erythropoiesis.

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