4) Treatment of anemia has been evolving over the last 30 years.— @CKD_ce (@ckd_ce) November 2, 2022
Until recently transfusions, analogues of erythropoietin #EPO and IV/PO iron were the only treatment choices.
New understanding of the anemia pathway has led to novel therapeutics.
8) Erythropoietin (#EPO)— @CKD_ce (@ckd_ce) November 2, 2022
Produced in the corticomedullary area of kidney.
Zone of relative hypoxia, sensitive to small changes in oxygen concentration.
Anemia of #CKD thought to represent EPO deficiency but may actually be due to impaired oxygen sensing. pic.twitter.com/ZNqSpvcTlB
10) In this tweetorial we will examine:— @CKD_ce (@ckd_ce) November 2, 2022
-How do HIF-PHIs work
-What are the major side effects associated with HIF-PHIs
-What trials have been done with HIF-PHIs thus far
-When will HIF-PHIs be available in the 🇺🇸? pic.twitter.com/opX9VHkSGk
12) #HIF— @CKD_ce (@ckd_ce) November 2, 2022
3 isoforms with unique alpha & common beta subunits.
HIF-1 stimulates transcription of genes involved in iron mobilization.
HIF-2 stimulates duodenal iron absorption by ↑ transcription of genes that encode iron transport proteins.
See 🔓https://t.co/m0eEWtPudb pic.twitter.com/p84tuvEsuC
14) So, how do HIF-PHIs predominantly work?— @CKD_ce (@ckd_ce) November 2, 2022
a. Stimulating erythropoietin
b. Decreasing iron absorption
c. Stabilizing the tetramer 𝞪 subunit
d. Increasing levels of hepcidin
15b) Prolyl hydroxylase (PH) + oxygen cause HIF 𝞪 degradation.— @CKD_ce (@ckd_ce) November 2, 2022
2-oxaglutarate is a cofactor of PH that inhibits HIF-PH even with oxygen, stabilizing HIF 𝞪.
See https://t.co/WyrvklDqNt pic.twitter.com/s6Djs629e6
19) The answer is C. Let’s review.— @CKD_ce (@ckd_ce) November 2, 2022
Meta-analysis of 11 trials thru April 2021.
In CKD no difference in total adverse events vs placebo (RR = 1.02, p=0.08)
In dialysis patients no difference in adverse events vs ESA (RR= 1.22, p=0.18)
21) #Cholesterol— @CKD_ce (@ckd_ce) November 2, 2022
↓ total cholesterol LDL HDL triglycerides.
6 studies with pooled data on LDL levels.
In dialysis roxadustat ↓ LDL vs ESA patients.
No change in LDL in CKD vs placebo.
↑ lipoprotein uptake by liver.
HIF-1-induces degradation of HMG-CoA reductase.
23) Great! Now that we understand the mechanisms by which HIF-PHIs work, next tweetorial we will look at trials and meta-analyses that have been done in dialysis and non-dialysis patients. COME BACK TOMORROW! pic.twitter.com/RP2prepMgn— @CKD_ce (@ckd_ce) November 2, 2022
25) Abbreviations:— @CKD_ce (@ckd_ce) November 3, 2022
HIF = hypoxia induced factor
PHI = Prolyl hydroxylase inhibitor
ESA = erythropoietin stimulating agents
MACE = major adverse cardiac event (death, MI, stroke)
MACE+ = (includes CHF, USA, hospitalization)
CKD = chronic kidney dz
ESKD = end stage kidney dz pic.twitter.com/XQ80w60q2m
27) #Roxadustat#ANDES/#ALPS/#OLYMPUS Pooled#CKD patients with #anemia.— @CKD_ce (@ckd_ce) November 3, 2022
↑ in Hgb not affected by iron stores or CRP level.
Time to first MACE event was non-inferior to placebo.
Adverse events similar.
Hyperkalemia 10.9% versus 7.1% with placebo.https://t.co/vqZg6sBscr pic.twitter.com/G0bBxJaUhm
29) #Roxadustat— @CKD_ce (@ckd_ce) November 3, 2022
However, on 4/6/21 Fibrogen announced analysis of outcomes were adjusted after unblinding.
Reanalysis showed no MACE & MACE+ advantage in ESKD.
Roxadustat remained non-inferior to ESA in all outcomes.
This has potentially slowed HIF-PHIs @US_FDA approval.
31) Although roxadustat has been studied the most, other HIF-PHIs have also been developed.— @CKD_ce (@ckd_ce) November 3, 2022
Roxadustat is currently approved in Europe 🇪🇺 and China 🇨🇳.
In Japan 🇯🇵 #daprodustat, #roxadustat, #vadadustat & #enarodustat are approved for use in CKD/ESKD. pic.twitter.com/NqEZyjRwtZ
33) #Vadadustat#PRO2TECT 2 studies in CKD— @CKD_ce (@ckd_ce) November 3, 2022
Included ESA-naïve and ESA-treated patients
Did not meet criteria for safety noninferiority for MACE
All increase of #MACE was seen outside the US 🇺🇸, unclear causeshttps://t.co/48Toeydm4l
35) #Daprodustat#ASCEND studies in #CKD/#ESKD— @CKD_ce (@ckd_ce) November 3, 2022
Noninferior to ESAs for hgb goals and #CV outcomes in ESKD
Similar in CKD vs #ESA for target Hgb and CV outcomes
See 🔓 https://t.co/pkWbFrSxqF pic.twitter.com/3skE3qvcih
37) #Thrombosis Risks— @CKD_ce (@ckd_ce) November 3, 2022
Japanese PMDA 🇯🇵
Safety warning: risks of PE, DVT & vascular access thrombosis, cerebral/myocardial infarction
Higher thrombosis (11.3% vs 3.9%) roxadustat vs darbepoetin in pooled study of dialysis pts.
38b) In contrast pooled data of roxadustat (n=2438) suggested benefit in GFR ⬇️ (1 yr: -2.8 vs -4.4 w/ placebo).— @CKD_ce (@ckd_ce) November 3, 2022
41) There you have it! Please go pick up your 🆓0.5h CE/#CME certificate at https://t.co/dDvMsvKe8A & FOLLOW US for more on this topic of HIF-PHIs. I am @brian_rifkin.— @CKD_ce (@ckd_ce) November 3, 2022
👉 @edgarlerma @eric_weinhandl @sophia_kidney @salinaro17 @Nephro_Sparks @hswapnil @Jwaitz @scoca1 @DrDanMO