Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”
Abstract
:1. Introduction
2. Anemia in Chronic Kidney Disease
2.1. EPO Deficiency
2.2. Functional Iron Deficiency
2.3. HIF Regulation in CKD
3. Management of Anemia in CKD
4. Use of HIF Stabilizers in ESKD
4.1. Roxadustat
4.2. Vadadustat
4.3. Other Drug Agents
5. HIF Stabilizers in Personalized Medicine Era
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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First Author | Patients | Study | Randomization | Primary Endpoint | Follow-Up | Results |
---|---|---|---|---|---|---|
Besarab, 2015 [53] | 117 NDD-CKD | Correction | 3:1 (placebo) | Change in Hb from baseline and proportion of Hb responders (Change in Hb ≥ 1.0 g/dL) | 4 weeks | Roxadustat significantly increased endogenous erythropoietin and decreased hepcidin |
Besarab, 2016 [56] | 60 ESA-naive incident to HD or PD | Correction | no iron oral iron iv iron | Mean ± SEM maximal change in Hb from baseline | 12 weeks | Roxadustat corrected Hb levels in patients undergoing dialysis and reduced hepcidin, regardless of baseline iron status |
Provenzano, 2016 [42] | 90 HD (Epo alfa) | Maintenance | 3:1 (epoetin alfa) | Change in Hb of ≥ 0.5 g/dL from baseline (part 1) and mean Hb level ≥ 11.0 g/dL during the last 4 treatment weeks (part 2) | 19 weeks | Response rate was higher in Roxadustat than in epoetin alfa arm. Roxadustat was well tolerated |
Chen, 2017 [70] | 91 NDD-CKD | Correction | 2:1 (placebo) | The maximum Hb change from baseline | 8 weeks | Maintenance of Hb levels was reached more frequently with Roxadustat than epoetin alfa |
Chen, 2017 [70] | 47 DD-CKD (HD) | Maintenance | 3:1 (placebo) | % of subjects with an Hb level maintained at no < 0.5 g/dL below mean baseline value | 8 weeks | Maintenance of Hb levels was reached more frequently with Roxadustat than epoetin alfa |
Clinicaltrials.Gov Identifier | Start/End-Date | Patients | Study Design | Intervention | Primary Endpoint |
---|---|---|---|---|---|
NCT02174731 | June 2014/December 2019 | 2133 DD-CKD | Multicenter, randomized, open-label, active controlled | Roxadustat Epoetin alfa | Mean change in Hb from baseline to week 52 MACE |
NCT02273726 | December 2014/September 2018 | 741 DD-CKD | Multicenter, randomized, open-label, active controlled | Roxadustat Epoetin alfa | Hb change from baseline |
NTC02174627 | June 2014/December 2019 | 2781 ND-CKD | Multicenter, randomized, double-blind, placebo-controlled | Roxadustat Placebo | MACE |
NCT02021318 (DOLOMITES) | December 2013/May 2021 | 616 ND-CKD | Randomized, open-label, active-controlled | Roxadustat Darbepoetin alfa | Hb response without the use of rescue therapy |
NCT01887600 (ALPS) | June 2013/December 2020 | 594 ND-CKD | Randomized, double-blind, placebo-controlled | Roxadustat Placebo | Hb response without the use of rescue therapy |
NCT02052310 (HIMALAYAS) | February 2014/September 2020 | 1043 incident dialysis patients | Multicenter, randomized, open-label, active-controlled | Roxadustat Epoetin alfa | Mean Hb change from baseline to week 52 |
NCT02278341 (PYRENEES) | October 2014/February 2021 | 838 DD-CKD | Randomized, open-label, active controlled | Roxadustat Epoetin alfa Darbepoetin alfa | Hb change from baseline to week 36 without rescue therapy |
NCT01750190 | December 2012/November 2019 | 922 ND-CKD | Randomized, double-blind, placebo-controlled | Roxadustat Placebo | Efficacy in anemia correction and maintenance |
NCT02779764 | May 2016/January 2020 | 164 DD-CKD | Long-Term Study | Roxadustat | Hb response rate from week 18 to week 24 |
NCT02780141 | May 2016/January 2020 | 75 ESA-naives HD patient | Multicenter, randomized, 2-arm, open-label | Roxadustat | Hb response rate |
NCT02780726 | May 2016/December 2019 | 56 PD patients | Multicenter, open-label, parallel group | Roxadustat low dose, high dose and previously treated with ESA | Hb response rate from week 18 to week 24 |
NCT02952092 | November 2016/January 2020 | 303 HD patients | Multicenter, randomized, 2-arm parallel, double-blind, active comparator | Roxadustat Darbepoetin alfa | Hb change from baseline to 24 week |
NCT02964936 | November 2016/April 2021 | 100 ESA-naives ND-CKD | Multicenter, randomized, 2-arm, open-label | Roxadustat | Hb change from baseline to week 24 |
NCT02988973 | December 2016/March 2021 | 334 ND-CKD | Multicenter, randomized, open-label, active-comparator conversion study | Roxadustat Darbepoetin alfa | Hb change from baseline to week 24 |
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Crugliano, G.; Serra, R.; Ielapi, N.; Battaglia, Y.; Coppolino, G.; Bolignano, D.; Bracale, U.M.; Pisani, A.; Faga, T.; Michael, A.; et al. Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”. Int. J. Mol. Sci. 2021, 22, 12590. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212590
Crugliano G, Serra R, Ielapi N, Battaglia Y, Coppolino G, Bolignano D, Bracale UM, Pisani A, Faga T, Michael A, et al. Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”. International Journal of Molecular Sciences. 2021; 22(22):12590. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212590
Chicago/Turabian StyleCrugliano, Giuseppina, Raffaele Serra, Nicola Ielapi, Yuri Battaglia, Giuseppe Coppolino, Davide Bolignano, Umberto Marcello Bracale, Antonio Pisani, Teresa Faga, Ashour Michael, and et al. 2021. "Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”" International Journal of Molecular Sciences 22, no. 22: 12590. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212590