1b) Our expert guest faculty is #nephrologist @DrBobPro1 of @waynemedicine.#nephtwitter @MedTweetorials @ISNkidneycare @goKDIGO @KIRepors. Earn more ๐ CE/#CME in #renal medicine from #blogposts at https://t.co/Zap2Al75YO pic.twitter.com/TOTFxUeI6w
— @CKD_ce (@ckd_ce) November 29, 2023
3a) Key numbers:
— @CKD_ce (@ckd_ce) November 29, 2023
๐ซ ~ 700 million people worldwide & 50 million in the ๐บ๐ธ (approx. 15% of the population) are estimated to have #CKD. That means 1 in 7 Americans have CKD.
See ๐ https://t.co/IGepJZd0SK
4) Prior to the introduction of recombinant #erythropoietin (#EPO) to treat #aCKD, HCPs relied upon blood transfusions resulting in many complications
— @CKD_ce (@ckd_ce) November 29, 2023
– #Hemosiderosis
– Porphyria cutanea tarda
– Infections
– Fluid overload
– #Transfusion reactions
๐ https://t.co/NI7LK1HsM4
5b) #aCKD results from 1โฃ inflammation, which
— @CKD_ce (@ckd_ce) November 29, 2023
๐ reduces #EPO production
๐ shortens #RBC lifespan
๐ accumulation of #uremic toxins
๐ increases levels of #hepcidin, which โฌ๏ธ available plasma iron, also โฌ๏ธ#erythropoiesis pic.twitter.com/8SKnR6FNGn
5d) So we give #iron during dialysis & we give #ESAs, but โฌ๏ธhepcidin works against us, โฌ๏ธing Fe #GI absorption, โฌ๏ธing Fe release from the liver, & โฌ๏ธing release of Fe from #splenic #macrophages. pic.twitter.com/IK8vyDgkbN
— @CKD_ce (@ckd_ce) November 29, 2023
6a) So let's talk about the "#HIF #Pathway":
— @CKD_ce (@ckd_ce) November 29, 2023
Turns out there's a whole family ๐จโ๐ฉโ๐งโ๐ฆof oxygen-sensitive proteins that manage cells' response to #hypoxia. And these proteins are the central regulators of #erythropoeisis in response to #hypoxia. pic.twitter.com/Z9mkYZpvnj
6c) HIF-ฮฑ can then bind with HIF-ฮฒ, get translocated into the nucleus, and then ๐ฏgene expression that โฌ๏ธ#erythropoiesis. pic.twitter.com/U4miyCRr3d
— @CKD_ce (@ckd_ce) November 29, 2023
7b) #HIF_PHIs also stimulate the #duodenum to transport Fe from #enterocytes and make it available to #transferrin, which then carries it to the #erythroid marrow to enhance #erythropoiesis. They also โฌ๏ธtransferrin stores. pic.twitter.com/szYOdV2E3c
— @CKD_ce (@ckd_ce) November 29, 2023
7d) So we have an elegant, physiologic, #Nobel ๐-winning mechanism for treating #anemia of #CKD #aCKD! pic.twitter.com/8ckTx8s56J
— @CKD_ce (@ckd_ce) November 29, 2023
9a) So are there clinical data to suggest that #HIF_PHI inhibitors might fare better? For example, #Roxadustat is an orally administered HIF-PHI. Back in 2018 and 2019 it was shown to . . . .
— @CKD_ce (@ckd_ce) November 29, 2023
10a) But in August 2021, @US_FDA rejected #roxadustat for use in #CKD_NDD & #CKD_DD patients.
— @CKD_ce (@ckd_ce) November 29, 2023
๐It is approved in EU member states ๐ช๐บ, Iceland ๐ฎ๐ธ, Norway ๐ณ๐ด, Liechtenstein ๐ฑ๐ฎ, United Kingdom ๐ฌ๐ง, Netherlands ๐ณ๐ฑ, Japan ๐ฏ๐ต, China ๐จ๐ณ, Chile, ๐จ๐ฑ and South Korea ๐ฐ๐ท.
11) 3โฃ #HIF_PHI agents continue under development in ๐บ๐ธ: #roxadustat, #vadadustat, & #daprodustat. All are dosed orally and all are reversible. pic.twitter.com/sCbP4ce34s
— @CKD_ce (@ckd_ce) November 29, 2023
12b) The #NDD patients (all in ๐จ๐ณ) were randomized to #roxadustat or placebo. Roxadustat group had higher mean hemoglobin level than those in the placebo group after 8 wks; efficacy continued in 18-week open-label extension.
— @CKD_ce (@ckd_ce) November 29, 2023
12d) The #CKD_DD patients in a trial also conducted in ๐จ๐ณ were randomized to #roxadustat or #epoetin_alfa for treatment of #aCKD. Pts had been on #dialysis & #ESA for at least 6 weeks.
— @CKD_ce (@ckd_ce) November 29, 2023
13a) #Vadadustat: here are data on that HIF-PHI inhibitor vs #darbepoietin in #CKD_DD patients.https://t.co/bE0HKsGRdD
— @CKD_ce (@ckd_ce) November 29, 2023
On the left below are incident #DD pts, on #dialysis < 3mos, and on R are prevalent #DD pts. pic.twitter.com/IbfGatR52a
13c) #Vadadustat was initially rejected by @US_FDA but has been resubmitted for #CKD_DD populations.#PDUFA date early 2024–so stay tuned.
— @CKD_ce (@ckd_ce) November 29, 2023
15) So what are the clinical benefits of this class?
— @CKD_ce (@ckd_ce) November 29, 2023
๐ correction of #anemia with lower #EPO levels–? lower risk of thrombosis?
๐โฌ๏ธhepcidin levels improves Fe metabolism
๐other potential benefits as per ๐ https://t.co/kDdUBKYv2J
๐ must note potential downsides pic.twitter.com/Bo7P5kMlEx
17a) So what have you learned? Complete this sentence: HIF-PHIs promote erythropoiesis by stimulating endogenous EPO production and increasing iron availability via inhibition of _____:
— @CKD_ce (@ckd_ce) November 29, 2023
a. transferrin
b. erythroferrone
c. propyl hydroxylase
d. hepcidin
18a) Which of the following #HIF_PHI agents has been approved by @US_FDA for #aCKD?
— @CKD_ce (@ckd_ce) November 29, 2023
a. daprodustat in dialysis-dependent patients
b. roxadustat
c. daprodustat in non-dialysis-dependent patients
d. vadadustat
19) You just earned 0.5hr ๐CE/#CME! Claim your certificate at https://t.co/Xleji8g9Hl, then ๐ฑ๏ธ right back here to FOLLOW @ckd_ce for more highest-quality #MedEd delivered wholly on X, formerly (and perhaps always best) known as Twitter.
— @CKD_ce (@ckd_ce) November 29, 2023
Thanks to @DrBobPro1!