HIF PH inhibitors stabilize HIF and stimulate endogenous EPO production, facilitating erythropoiesis and improving iron metabolism in CKD patients. Compared to ESAs, HIF PH inhibitors maintain physiological EPO levels, decrease cardiovascular risks, and reduce need for rescue therapies like transfusions. By coordinating EPO production, iron transport, and hepcidin inhibition, HIF PH inhibitors provide a targeted approach to anemia in CKD.
2. PREVALENCE OF ANEMIA IN CKD
The prevalence of anemia (hemoglobin <12 g/dl) is :
47.7% in patients with nondialysis CKD and increases
as CKD progresses
42% of patients with stage 3 CKD
76% in stage 5 CKD.
When compared with patients without anemia (Hb >
12.5 g/dL), patients with anemia (Hb < 10.5 g/dL) had
a 2-fold increased risk of cardiovascular (CV)
hospitalization, a 5-fold increased risk of mortality,
and a 5-fold increased risk of progression to ESRD.
Kidney International Supplements (2017) 7, 157–163;
5. ANEMIA IN CKD
There are 2 key causes underlying the development of anemia in CKD: erythropoietin
(EPO) deficiency and functional iron deficiency (FID).
EPO deficiency : blunted response in EPO production to the degree of anemia.
FID : a combination of impaired iron mobilization from stores and inadequate delivery of
iron to the erythroid marrow in the setting of increased red blood cell (RBC) production
induced by pharmacologic treatment with ESAs.
Absolute iron deficiency : in patients with CKD due to inadequate provision or
absorption of dietary iron and/or blood losses.
Am J Kidney Dis. 69(6):815-826
6.
7. WHY HYPOXIA OCCURS IN CKD
Adequate oxygen is essential for all mammalian organs to fuel various bio-metabolic
processes and to maintain biological homeostasis.
The balance between oxygen consumption and supply is critical especially for kidneys,
which always stay in active metabolic condition and are in high need of oxygen supply.
Hypoxia, insufficient supply of oxygen, has been considered to be closely related to CKD
progression.
The induction of hypoxia during CKD is indeed multifactorial, including increased oxygen
consumption, malfunction of microvasculature, vascular remodeling, anemia associated
impaired oxygen delivery, impaired oxygen diffusion by extracellular matrix (ECM)
accumulation, and mitochondrial abnormality.
12. ERYTHROPOIETIN
• EPO is a proliferation and maturation factor produced in response to tissue hypoxia, as a
result of complex regulatory mechanisms.
• 90% of all EPO produced in the body originates from the kidneys and approximately 10%
is produced by the liver.
• Kidney-derived EPO is produced by cortical
peritubular fibroblasts located near the
proximal tubular cells in the outer medulla
and inner cortex in the kidney. This
production is expanded into the outer
cortex in response to hypoxia and anemia,
a region that is especially susceptible to
hypoxia. Kidney International Supplements (2017) 7, 157–163;
13. ESA AND CHALLENGES WITH ITS USE
• Treatment of anemia related to CKD with
rHuEPO and related products
(erythropoiesis-stimulating agents [ESAs])
increases hemoglobin (Hb) levels, lessens
the need for transfusion, and improves
patient quality of life.
• However, treatment to higher Hb targets
in clinical trials has resulted in higher rates
of access thrombosis, cerebrovascular
events, and cardiovascular events; earlier
requirement for kidney replacement
therapy; and higher mortality.
Kidney International Supplements (2017) 7, 157–163;
Am J Kidney Dis. 69(6):815-826
14. ESA AND CHALLENGES WITH ITS USE
• Analysis suggests high pharmacologic doses of ESAs, rather than the highly achieved
hemoglobin, may mediate harm.
• The circulating levels of EPO required to stimulate erythropoiesis is 7 to 30 mU/ml,
with higher levels required in patients with CKD and ESRD due to shortened red cell
survival.
• The unphysiologic administration of high-dose ESA for anemia of CKD and ESRD can
result in EPO levels as high as 700 mU/ml.
Kidney International Supplements (2017) 7, 157–163;
15. TARGETED APPROACH
An emerging approach to the treatment of EPO deficiency in anemic patients with
CKD is the use of agents that stimulate endogenous EPO production in renal and
nonrenal tissues.
Such a strategy might decrease adverse outcomes by allowing for a more consistent,
although not necessarily continuous, physiologic level of EPO to stimulate RBC
production rather than the high intermittent blood levels that result from
pharmacologic administration of an exogenous ESA.
Am J Kidney Dis. 69(6):815-826
16. HYPOXIA INDUCIBLE FACTOR (HIF)
HIF is a key transcription factor that produces a physiologic response to reduced tissue
oxygen levels by activating the expression of certain genes.
The purpose of this adaptive homeostatic response is to restore oxygen balance and
protect against cellular damage while oxygen levels are being restored.
HIF is a heterodimer with an α and β subunit. The HIF-α subunit joins with the β subunit in
the nucleus and binds to DNA sequences called hypoxia response elements (HREs) and thus
induces the expression target genes.
There are 3 isoforms of the a subunit:HIF-1α, HIF-2α, and HIF-3α, any of which can combine
with the β subunit to induce the expression of different combinations of target genes.
Am J Kidney Dis. 69(6):815-826
17. HOW HIF EPO PATHWAY WORKS
In CKD, EPO production is relatively insufficient because the HIF expression and function in damaged kidneys are
insufficient to respond to their hypoxic condition, which is caused by oxidative stress , inflammation and uremic toxins
Kidney360 August 2020, 1 (8) 855-862; DOI:
https://doi.org/10.34067/KID.000144202
18. HYPOXIA INDUCIBLE FACTOR
The primary means of HIF activity regulation is hydroxylation at 2 proline residues by a
family of HIF-PH enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, of
which there are 3 members: PHD1, PHD2, and PHD3.
PHD2 is the main regulator of HIF activity in normoxia.
HIF-2α is the main subunit involved in upregulating EPO gene expression and iron
transport in hypoxia.
HIF-2α is expressed in peritubular fibroblasts, which are thought to be the primary site of
renal EPO production.
HIF-2α appears to be a key element in the hypoxic response; however, in certain situations,
HIF-1α controls the early response to hypoxia.
Am J Kidney Dis. 69(6):815-826
19. HYPOXIA INDUCIBLE FACTOR
In normoxia, HIF-PH activity leads to
rapid degradation of HIF.
During hypoxia, HIF-PH activity is
suppressed, allowing HIF to accumulate
and directly stimulate endogenous EPO
production, upregulate transferrin
receptor expression, increase iron uptake
by proerythrocytes, and promote
maturation of erythrocytes replete with
Hb. Am J Kidney Dis. 69(6):815-826
20. HYPOXIA INDUCIBLE FACTOR
Oxygen dependent regulation of HIF mainly
involves the degradation of HIF-α subunits, which
starts with hydroxylation of HIF-α by HIF-PH
enzymes.
HIF-PH enzymes require oxygen for their catalytic
activity to regulate HIF. Thus, when oxygen levels
decrease, prolyl hydroxylation does not occur,
which allows HIF-α to dimerize with its partner
HIF-β and accumulate in the nucleus to regulate
HIF target genes. HIF stabilization increases gene
transcription by binding to HREs, thus
upregulating EPO and other genes.
21. HIF ROLE IN ERYTHROPOIESIS
HIF upregulates transferrin, ceruloplasmin, and transferrin receptor 1, the latter facilitating
increased plasma transport of iron to tissues.
HIF-2α boosts intestinal absorption of iron by upregulating duodenal cytochrome b and
divalent metal transporter 1, 2 important genes in iron uptake and export.
EPO production induced by HIF leads to the production by erythroblasts of erythroferrone,
which limits the gene expression of liver hepcidin.
These functions of HIF complement its effect on erythropoiesis by coordinating EPO-
stimulated RBC production with increased available iron
Am J Kidney Dis. 69(6):815-826
26. COMPARED TO ESA....IS IT BETTER?
Although parenteral ESA treatment produces high levels of the ESA in blood, treatment with
HIF-PH inhibitors results in a relatively small increase in EPO blood levels. This may confer a
potential advantage to HIF-PH inhibitors because they lead to endogenous EPO levels close to
the physiologic range and adequately stimulate the high-affinity receptor responsible for
hematopoiesis.
Increases the availability of iron for effective erythropoiesis.
Lowering hepcidin level and beneficial effect on iron metabolism
27. COMPARED TO ESA...IS IT BETTER?
Use of these agents consistently results in dose-related increases in Hb levels, while
decreasing hepcidin and ferritin levels and decreasing TSAT by increasing total iron-binding
capacity.
Potential benefit in EPO resistant patients
Potential blood pressure lowering effect
Potential protection from ischemic events
Potential anti-inflammatory effects
28. TO SUMMERIZE......
Facilitates intestinal iron absorption by promoting the expression of divalent metal
transporter 1 and duodenal cytochrome B
Stimulates erythropoiesis by upregulating endogenous EPO production
Enhances iron uptakes by proerythrocytes by raising the expression transferrin receptor
Propels the recycling of iron in phagocytosed erythrocytes
Improves chronic inflammatory status by elevating erythroferrone and inhibiting hepcidin
Compared to ESAs, comprehensive effect on replenishing endogenous EPO, decreasing
hepcidin, and improving the bioavailability of iron
Reduces the cardiovascular risks by maintaining a physiological elevation of EPO and avoiding
hemoglobin overshoot brought by ESAs.
Reduces rescue therapy like blood transfusion or iv iron need.
29. REFERENCES
1.Nupur Gupta, MD, and Jay B. Wish, MD Hypoxia-Inducible Factor Prolyl Hydroxylase
Inhibitors: A Potential New Treatment for Anemia in Patients With CKD Am J Kidney Dis.
69(6):815-826.
2.DW Coyne et al.: New options for the anemia of CKD Kidney International
Supplements (2017) 7, 157–163
3.https://www.medscape.org/viewarticle/925208_print
4.Joshua M. Kaplan , Neeraj Sharma and Sean Dikdan Hypoxia-Inducible Factor and Its
Role in the Management of Anemia in Chronic Kidney Disease Int. J. Mol. Sci. 2018, 19,
389; doi:10.3390/ijms19020389
