2) This #accredited #tweetorial series on #kidneydisease #aCKD is supported by an independent educational grant from GSK plc and is intended for healthcare providers.
β @CKD_ce (@ckd_ce) November 2, 2022
4) Treatment of anemia has been evolving over the last 30 years.
β @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.
πhttps://t.co/Cx1d2VlFP3 pic.twitter.com/WpygidKqtD
6) A quick knowledge βοΈ!
β @CKD_ce (@ckd_ce) November 2, 2022
Treatment of anemia in CKD/ESKD improves:
a. Quality of life (#QoL)
b. #CV disease outcomes
c. #CKD progression
d. Need for transfusions
8) Erythropoietin (#EPO)
β @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:
β @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 πΊπΈ? pic.twitter.com/opX9VHkSGk
12) #HIF
β @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 β transcription of genes that encode iron transport proteins.
See πhttps://t.co/m0eEWtPudb pic.twitter.com/p84tuvEsuC
14) So, how do HIF-PHIs predominantly work?
β @CKD_ce (@ckd_ce) November 2, 2022
a. Stimulating erythropoietin
b. Decreasing iron absorption
c. Stabilizing the tetramer πͺ subunit
d. Increasing levels of hepcidin
15b) Prolyl hydroxylase (PH) + oxygen cause HIF πͺ degradation.
β @CKD_ce (@ckd_ce) November 2, 2022
2-oxaglutarate is a cofactor of PH that inhibits HIF-PH even with oxygen, stabilizing HIF πͺ.
See https://t.co/WyrvklDqNt pic.twitter.com/s6Djs629e6
17) All medications have risks and benefits. Letβs examine the adverse events (#AE) and benefits outside of anemia for HIF-PHIs. pic.twitter.com/FjrjdYobDT
β @CKD_ce (@ckd_ce) November 2, 2022
19) The answer is C. Letβs review.
β @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)
See πhttps://t.co/NAcKfDesLF
21) #Cholesterol
β @CKD_ce (@ckd_ce) November 2, 2022
β total cholesterol LDL HDL triglycerides.
6 studies with pooled data on LDL levels.
In dialysis roxadustat β LDL vs ESA patients.
No change in LDL in CKD vs placebo.
Mechanism:
β 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
β @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
β 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 πͺπΊ and China π¨π³.
In Japan π―π΅ #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-naΓ―ve and ESA-treated patients
Did not meet criteria for safety noninferiority for MACE
All increase of #MACE was seen outside the US πΊπΈ, 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 π https://t.co/pkWbFrSxqF pic.twitter.com/3skE3qvcih
37) #Thrombosis Risks
— @CKD_ce (@ckd_ce) November 3, 2022
Japanese PMDA π―π΅
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.
(https://t.co/E2jnhZRTAS)
38b) In contrast pooled data of roxadustat (n=2438) suggested benefit in GFR β¬οΈ (1 yr: -2.8 vs -4.4 w/ placebo).
— @CKD_ce (@ckd_ce) November 3, 2022
See πhttps://t.co/gu3vfCqPbV
39b) Cardiovascular and Renal Drug Advisory Committee reviewed #daprodustat Oct, 2022.
— @CKD_ce (@ckd_ce) November 3, 2022
They voted 13-3 to approve β for patients on #dialysis, but voted against use in #CKD 11-5.https://t.co/TEkMuVEUL5
41) There you have it! Please go pick up your π0.5h 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
π @edgarlerma @eric_weinhandl @sophia_kidney @salinaro17 @Nephro_Sparks @hswapnil @Jwaitz @scoca1 @DrDanMO