1/14
🎤“Don’t make a change too complicated, just begin.”
🔊 We have a chance to make a ‘change for good’ in anemia Rx in CKD.
👥Let’s discuss hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), the probable champions🏆 of NephMadness 2021. #AnemiaRegion
🎤“Don’t make a change too complicated, just begin.”
🔊 We have a chance to make a ‘change for good’ in anemia Rx in CKD.
👥Let’s discuss hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), the probable champions🏆 of NephMadness 2021. #AnemiaRegion
2/ 📖Hypoxia Inducible Factor (HIF) - Physiology
- Present in all tissues.
- Has O2 regulated 𝞪 (3 isoforms) and constitutively expressed 𝛃 subunits.
- HIF-2𝞪 is expressed in the peritubular fibroblasts, mainly involved in the upregulation of EPO gene.
- Present in all tissues.
- Has O2 regulated 𝞪 (3 isoforms) and constitutively expressed 𝛃 subunits.
- HIF-2𝞪 is expressed in the peritubular fibroblasts, mainly involved in the upregulation of EPO gene.
3/
🗝️↓ Hypoxia, HIF 𝞪 heterodimerizes with 𝛃 subunit in the nucleus → the complex binds with DNA sequences called hypoxia response elements → Gene activation → ↑ RBC production by ↑ essential protein synthesis linked with iron and EPO pathways. mdpi.com/1422-0067/19/2…
🗝️↓ Hypoxia, HIF 𝞪 heterodimerizes with 𝛃 subunit in the nucleus → the complex binds with DNA sequences called hypoxia response elements → Gene activation → ↑ RBC production by ↑ essential protein synthesis linked with iron and EPO pathways. mdpi.com/1422-0067/19/2…
4/👉 HIF-prolylhydroxylases {also known as prolyl hydroxylase domains (PHDs)}
- ↓ Normal O2, PHDs ✂ HIF-𝞪 by proteosomal degradation, mainly PHD2.
- PHDs are non-heme iron-containing dioxygenases.
- Co-substrates - O2 & oxoglutarate; Co-factors - Iron & ascorbate.
- ↓ Normal O2, PHDs ✂ HIF-𝞪 by proteosomal degradation, mainly PHD2.
- PHDs are non-heme iron-containing dioxygenases.
- Co-substrates - O2 & oxoglutarate; Co-factors - Iron & ascorbate.
5/🤔What do HIF-PHIs do?
- Inhibit HIF-prolylhydroxylases → Enhance HIF regulated gene expression.
- Stimulate EPO production.
- ↑ Iron utilization (HIF-2𝞪 upregulates iron metabolism genes in the liver and ↑ intestinal iron absorption by ↑ duodenal cytochrome b and DMT)
- Inhibit HIF-prolylhydroxylases → Enhance HIF regulated gene expression.
- Stimulate EPO production.
- ↑ Iron utilization (HIF-2𝞪 upregulates iron metabolism genes in the liver and ↑ intestinal iron absorption by ↑ duodenal cytochrome b and DMT)
6/💥HIF-PHIs currently being studied - Roxadustat, Vadadustat, Daprodustat.
✔ None of them are currently approved by the US-FDA.
✔ Roxadustat is accepted for a new drug application, currently needs additional clinical data.
✔ None of them are currently approved by the US-FDA.
✔ Roxadustat is accepted for a new drug application, currently needs additional clinical data.
7/💊Roxadustat:
- Half-life 12-13 hrs; dosed 3 times/week.
- RCT in Chinese patients on dialysis showed it is non-inferior to EPO 𝞪 as Rx for anemia. pubmed.ncbi.nlm.nih.gov/31340116/
- ↑ Hb in patients with high CRP → perhaps helpful in Rx anemia even with inflammation.
- Half-life 12-13 hrs; dosed 3 times/week.
- RCT in Chinese patients on dialysis showed it is non-inferior to EPO 𝞪 as Rx for anemia. pubmed.ncbi.nlm.nih.gov/31340116/
- ↑ Hb in patients with high CRP → perhaps helpful in Rx anemia even with inflammation.
8/😀↑ Hb significantly in patients with CKD not on dialysis as well.
😀Decreases the requirement of blood transfusion.
😒More frequent hyperkalemia & upper respiratory tract infections in the Roxadustat group.
😀Decreases the requirement of blood transfusion.
😒More frequent hyperkalemia & upper respiratory tract infections in the Roxadustat group.
9/💊Daprodustat:
- Half life - 4hrs; Daily oral administration.
- ↑ iron binding and ↓ hepcidin.
- May be effective in Rx of patients with EPO hyporesponsiveness.
- Phase 3 RCT in Japanese patients with CKD - non-inferior to darbapoetin 𝞪. pubmed.ncbi.nlm.nih.gov/32723804/
- Half life - 4hrs; Daily oral administration.
- ↑ iron binding and ↓ hepcidin.
- May be effective in Rx of patients with EPO hyporesponsiveness.
- Phase 3 RCT in Japanese patients with CKD - non-inferior to darbapoetin 𝞪. pubmed.ncbi.nlm.nih.gov/32723804/
10/💊Vadadustat:
- Approved in Japan.
- PRO2TECT trials → non-inferiority of vodadustat to darbapoetin 𝞪 in mean change in Hb at 52 weeks in patients with NDD-CKD.
- Was inferior to darbepoetin 𝞪 in time to 1st occurrence of major adverse cardiovascular events.
- Approved in Japan.
- PRO2TECT trials → non-inferiority of vodadustat to darbapoetin 𝞪 in mean change in Hb at 52 weeks in patients with NDD-CKD.
- Was inferior to darbepoetin 𝞪 in time to 1st occurrence of major adverse cardiovascular events.
11💊Molidustat:
- In animal models, shown to be effective in Rx of anemia of CKD and inflammatory anemia.
- Blood-pressure lowering effect noted in animal models (HIF participates in vasomotor control).
- Currently in active phase 2 trials.
- In animal models, shown to be effective in Rx of anemia of CKD and inflammatory anemia.
- Blood-pressure lowering effect noted in animal models (HIF participates in vasomotor control).
- Currently in active phase 2 trials.
12/🎌Advantages and disadvantages:
13/🌟HIF-PHIs have been a major breakthrough in the Rx of anemia in CKD.
Let's make a wise decision and push the revolutionary 🔥 HIF-PHIs for the win. #Nephmadness 2021 #AnemiaRegion.
Let's make a wise decision and push the revolutionary 🔥 HIF-PHIs for the win. #Nephmadness 2021 #AnemiaRegion.
14/14
Thanks: @NSMCInternship @Nephro_Sparks @drM_sudha @docanjuyadav @captainchloride @amyaimei and The Team Tubules!!
ajkdblog.org/2021/03/01/nep…
Thanks: @NSMCInternship @Nephro_Sparks @drM_sudha @docanjuyadav @captainchloride @amyaimei and The Team Tubules!!
ajkdblog.org/2021/03/01/nep…
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