Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease
Abstract
:1. Introduction
2. Materials and Methods
3. Anemia Treatment in CKD
4. Guidelines of Anemia Treatment in CKD
5. Hypoxia-Inducible Factor (HIF) System
6. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIF-PHIs)
6.1. Roxadustat (FG-4592)
6.2. Vadadustat (AKB-6548)
6.3. Daprodustat (GSK-1278863)
6.4. Molidustat (BAY-85-3934)
7. Comparison of the Effectiveness of Different HIF-PHIs
8. Additional Actions of HIF-PHIs
9. Potential Adverse Effects of HIF-PHIs
9.1. Cardiovascular Complications
9.2. Tumorogenesis
9.3. Hyperkalemia
9.4. Retinopathy
10. Conclusions and Future Perspectives
Funding
Conflicts of Interest
References
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Iron Deficiency Diagnosis | Iron Supply | EPO Treatment Start | Hb Target | SF and TSAT under Iron Treatment | |
---|---|---|---|---|---|
ERBP (2009) | SF < 100 ng/mL, TSAT < 20% if ESA naive; SF ≤ 300 ng/mL, TSAT ≤ 30% if ESA treated | Oral iron > 3 months (ND-CKD and mild-moderate anemia), iv iron (ND-CKD and severe anemia), or oral iron ineffective | Hb < 10 g/dL; Avoid Hb > 12 g/dL | 10–12 g/dL; high-risk patients Hb around 10 g/dL | Avoid SF > 500 ng/mL and TSAT > 30% |
KDIGO (2012) | SF ≤ 100 ng/mL, TSAT ≤ 20% | ND-CKD: a trial of iv iron or a 1–3-month trial of oral iron; DD-CKD: preference for iv iron | ND-CKD: Hb < 10 g/dL; DD-CKD: Hb 9–10 g/dL Avoid Hb < 9 g/dL | Hb ≤ 11.5 g/dL; Higher Hb if QoL improves and the patient accepts risks; Avoid > 13 g/dL | Stop iron supplementations if SF > 500 ng/mL |
Consider the Use of HIF-PHIs |
---|
NDD-CKD and PD patients |
|
Hemodialysis patients |
|
Use with caution |
|
Avoid or use with extreme caution |
|
Administration key points |
|
Monitoring key points |
|
Study Name, Reference | HIF-PHI | Comparator | Baseline Hb (g/dL) | Hb Increase (g/dL) | Iron iv (%) | Transfusions (%) |
---|---|---|---|---|---|---|
ALPS [64] | roxadustat | placebo | 9.1 | 1.98 versus 0.4 | 5.4 versus 5.9 | 8 versus 16.7 |
ANDES [65] | roxadustat | placebo | 9.1 | 2.02 versus 0.18 | 2.5 versus 4.9 | 5.6 versus 15.4 |
ASCEND-ND [88] | daprodustat | darbepoietin α | 9.9 | 0.74 versus 0.66 | 11.7 versus 11.8 | 2.8 versus 13.5 |
PRO2TECT [89] | vadadustat | darbepoietin α | 9.1 | 1.43 versus 1.38 | 2.5 versus 2.3 | 5.1 versus 4.4 |
OLYMPUS [66] | roxadustat | placebo | 9.1 | 1.75 versus 0.4 | 4.3 versus 7.9 | 13 versus 23 |
DOLOMITES [67] | roxadustat | darbepoietin α | 9,5 | 2.5 versus 2.3 | NA | NA |
DIALOGUE 1 [85], Phase 2 study | molidustat | placebo | 9.5 | 1.8 versus 0.3 | NA | NA |
DIALOGUE 2 [85], Phase 2 study | molidustat | darbepoetin α | 10.8 versus 10.9 | 0.6 versus 0.1 | NA | NA |
Study Name, Reference | HIF-PHI | Comparator | Baseline Hb (g/dL) | Hb Increase (g/dL) | Iron iv (%) | Transfusions (%) |
---|---|---|---|---|---|---|
ROCKIES [60] | roxadustat | epoietin α | 10.2 versus 10.3 | 0.77 versus 0.68 | NA | 9.8 versus 13.2 |
PYRENEES [61] | roxadustat | epoietin α or darbepoietin α | 10.8 | 0.51 versus 0.29 | 25.2 versus 56 | 9.2 versus 12.9 |
SIERRAS [62] | roxadustat | epoietin α | 10.3 | 0.39 versus 0.09 | 17.1 versus 37 | 12.5 versus 21.1 |
ASCEND-ID [81] | daprodustat | darbepoietin α | 9.5 | 1.02 versus 1.12 | NA | 12 versus 14 |
HIMALAYAS [63] | roxadustat | epoietin α | 8.4 versus 8.5 | 2.57 versus 1.27 | 58 versus 89 | 7.3 versus 6.4 |
ASCEND-D [90] | daprodustat | epoietin α | 10.4 | 0.28 versus 0.1 | NA | 15.7 versus 18.3 |
INNO2VATE [91] | vadadustat | darbepoietin α | 9.4 versus 9.2 | 1.26 versus 1.58 | 10.5 versus 4,8 | 5.1 versus 4.4 |
DIALOGUE 4 [85], Phase 2 | molidustat | epoetin α | 10.5 versus 10.6 | −0.2 versus −0.1 | NA | NA |
HIF-PHI | Side Effects | Source |
---|---|---|
Roxadustat | The most common side effects of roxadustat (which may affect more than 1 in 10 people) are hypertension, vascular access thrombosis, diarrhea, peripheral edema (swelling especially of the ankles and feet), hyperkalemia, and nausea. The most common serious side effects (which may affect up to 1 in 10 people) are sepsis, hyperkalemia, hypertension, and deep vein thrombosis. Roxadustat must also not be used in women who are breastfeeding or during the third trimester of pregnancy. https://www.ema.europa.eu/en/medicines/human/EPAR/evrenzo (Accessed on 19 July 2024) | European Medicines Agency |
Vadadustat | Increased risk of death, myocardial infarction (MI), stroke, venous thromboembolism, and thrombosis of vascular access Hepatotoxicity Hypertension Seizures Gastrointestinal erosion Serious adverse reactions in patients with anemia due to chronic kidney disease and not on dialysis Malignancy https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215192s000lbl.pdf (Accessed on 19 July 2024) | The US Food and Drug Administration |
Daprodust | Increased risk of death, myocardial infarction (MI), stroke, venous thromboembolism, and thrombosis of vascular access Risk of hospitalization for heart failure: increased in patients with a history of heart failure. Hypertension: worsening hypertension, including a possibility of hypertensive crisis occurring. Monitor blood pressure. Adjust antihypertensive therapy as needed. Gastrointestinal erosion: gastric or esophageal erosions and gastrointestinal bleeding have been reported. Not indicated for treatment of anemia of CKD in patients who are not dialysis-dependent Malignancy: may have unfavorable effects on cancer growth https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216951s000lbl.pdf (Accessed on 19 July 2024) | The US Food and Drug Administration |
Roxadustat | Thromboembolism Hypertension Hepatic dysfunction Malignant tumors Retinal hemorrhage https://www.pmda.go.jp/files/000234811.pdf (Accessed on 19 July 2024) | Pharmaceuticals and Medical Devices Agency of Japan |
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Bartnicki, P. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease. Biomedicines 2024, 12, 1884. https://doi.org/10.3390/biomedicines12081884
Bartnicki P. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease. Biomedicines. 2024; 12(8):1884. https://doi.org/10.3390/biomedicines12081884
Chicago/Turabian StyleBartnicki, Piotr. 2024. "Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease" Biomedicines 12, no. 8: 1884. https://doi.org/10.3390/biomedicines12081884