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*Corresponding author: E-mail: mohdnaveedk97@gmail.com; 
 
Cite as: Gupta, Nikita, Mohd Naveed Khan, Varda Farooqui, Guntoju Poojitha, and Thipparam Kavya. 2024. “A Review on 
Vadadustat: Hope in Treatment of Anemia Patients Having Chronic Kidney Disease”. Asian Journal of Immunology 7 (1):302-
15. https://doi.org/10.9734/aji/2024/v7i1153. 
 

 
 

Asian Journal of Immunology 
 
Volume 7, Issue 1, Page 302-315, 2024; Article no.AJI.127402 
 

 
 

 

 

A Review on Vadadustat: Hope in 
Treatment of Anemia Patients Having 

Chronic Kidney Disease 
 

Nikita Gupta a, Mohd Naveed Khan a*, Varda Farooqui a, 
Guntoju Poojitha a and Thipparam Kavya a 

 
a Department of Pharmacy Practice, St. Pauls College of Pharmacy, Hyderabad, Telangana-510, 

India. 
 

Authors’ contributions  
 

This work was carried out in collaboration among all authors. All authors read and approved the final 
manuscript. 

 
Article Information 

 
DOI: https://doi.org/10.9734/aji/2024/v7i1153  

 
Open Peer Review History: 

This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers,  
peer review comments, different versions of the manuscript, comments of the editors, etc are available here: 

https://www.sdiarticle5.com/review-history/127402  

 
 

Received: 09/10/2024 
Accepted: 12/12/2024 
Published: 21/12/2024 

 
 

ABSTRACT 
 

Vadadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, may offer an oral alternative to 
injectable erythropoiesis-stimulating agents (ESAs) to treat anemia in patients undergoing 
peritoneal dialysis. Current standard of care for anemia linked to chronic kidney disease (CKD) is 
the use of ESAs. Targeting the HIFs-the basic elements of RBC production-presents an oral 
alternative to the standard ESAs. Due to their low oxygen environment, HIF transcription factors 
are, by nature, constitutively activated at high altitude, which enhances iron mobilization and boosts 
production of endogenous erythropoietin (EPO). While clinical trials have demonstrated safety and 
efficacy for vadadustat, whether it will promote cancer is still a topic under investigation. In fact, 
research has suggested that activation of HIFs promotes tumor growth due to stimulation of 

Review Article 

https://doi.org/10.9734/aji/2024/v7i1153
https://www.sdiarticle5.com/review-history/127402


 
 
 
 

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303 

 

angiogenesis through vascular endothelial growth factor (VEGF). The HIF system includes two 
subunits, α and β. Under low-oxygen conditions, the HIF-1α subunit accumulates and translocates 
to the cell nucleus, where it binds to HIF-β to form the heterodimer HIF-1αβ. This complex initiates 
the expression of sensitive hypoxic genes, including the EPO gene, whose production is increased 
under such conditions. Three isoforms of the HIF-α subunit exist: HIF-1α, HIF-2α, and HIF-3α, all of 
which can dimerize with HIF-β and activate the transcription of other genes besides EPO. In the 
intestine, duodenal cytochrome b (DCYTB) reduces ferric iron (Fe3+) to ferrous iron (Fe2+), which 
is then taken into enterocytes by the divalent metal transporter-1 (DMT1). HIF-2 controls both 
DCYTB and DMT1. Iron is exported from cells by ferroportin (FPN), and this export is repressed by 
hepcidin but stimulated by HIF. In blood, iron is transported in a complex with transferrin (TF) to the 
liver, RES cells, bone marrow, and other tissues. The increased erythropoietic activity in the 
marrow leads to the production of growth differentiation factor 15 (GDF15) and erythroferrone, 
which are known to inhibit hepcidin in liver cells. The inflammatory cytokine relates with increased 
hepcidin production in the liver, whose action is mediated by decreased ferroportin expression on 
the cell surface and lower blood iron levels. Vadadustat has HIF stabilized for the promotion of the 
secretion of EPO but does not seem to have an effect on the production of VEGF. It is also 
reported that increased activity of HIF results in an antitumor effect. Results from clinical trials 
support the use of vadadustat without genotoxicity, facilitating the treatment of anemia in patients 
with chronic kidney disease.  
 

 
Keywords: Vadadustat; anaemia; chronic kidney disease; hypoxia-inducible factor; erythropoiesis 

stimulating agents. 

 
1. INTRODUCTION 
 

1.1 Vadadustat 
 
Vadadustat is an experimental oral inhibitor of 
hypoxia-inducible factor prolyl-hydroxylase, 
which stimulates the natural production of 
erythropoietin. Currently, erythropoiesis-
stimulating agents are the first-line treatment for 
anemia associated with chronic kidney disease. 
All ESAs effectively treat anemia caused by CKD 
as they compensate for the deficit of EPO 
produced by failing kidneys. HIF-PHIs have been 
differentiated from ESAs by the fact that they 
activate the HIF pathway and result in 
downstream effects on the EPO gene 
transcription, expression of genes involved in 
erythropoiesis and iron metabolism. The 
conventional management of anemia in the CKD 
patient is intravenous ESA, either as 
monotherapy or with IV or oral iron 
supplementation. Although ESAs are highly 
effective for many patients with CKD, they do 
come with significant limitations. Many CKD 
patients have a diminished ability to produce 
EPO and absorb and mobilize iron. The 
production of Hb is largely dependent on the 
supply of iron, which is controlled by both the 
liver, the kidneys, and the bone marrow through 
synchronized signals. Normally, EPO stimulates 
erythroblasts to produce Erythroferrone, a 
protein that acts to inhibit the production of 
hepcidin in the liver [1]. 

“Hypoxia-inducible factor is a transcription factor 
that controls the expression of many low oxygen-
regulated genes, including EPO, which is an 
important stimulator of erythropoiesis. HIF levels 
are controlled by oxygen-dependent degradation 
at the proteasome, a process mediated by a 
family of prolyl hydroxylases that serve as 
oxygen sensors. HIF-prolyl hydroxylase 
inhibitors or HIF-PHIs are novel drugs that 
stabilize HIF and promote the expression of EPO 
and may correct anemia related to CKD. On the 
other hand, because initiation of HIF and its 
downstream genes results in a global response 
to hypoxia, there is, in theory, a potential risk for 
adverse events including neoplasia due to 
activation of the HIF pathway. The oxygen 
dependent hydroxylation of HIF-α is catalyzed by 
PHD1, PHD2, and PHD3 that function as oxygen 
sensors within the HIF pathway. PHDs are part 
of a large family of 2OG-dependent 
dioxygenases, with more than 60 members. 
Dioxygenases catalyze the hydroxylation 
reaction by using molecular oxygen, thereby 
linking oxygen, intermediary metabolism, and 
amino acid metabolism to a variety of cellular 
functions, including HIF regulation, hypoxia 
responses, collagen synthesis, epigenetic gene 
regulation, and fatty acid metabolism. Systemic 
activation of HIF reduces hepcidin production in 
the liver, thereby improving iron uptake and 
mobilization. The anemia of CKD is caused by a 
relative lack of renal production of EPO, together 
with functional or absolute iron deficiency and 



 
 
 
 

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resistance to EPO signaling, often in the context 
of inflammation. Activation of HIF signaling by 
pharmacological agonists may provide a more 
physiologic and holistic treatment strategy for 
renal anemia than administration of recombinant 
EPO alone. 
 
While initial reports suggested a direct role for 
HIF-1 in suppressing the transcription of 
hepcidin, subsequent mouse models with global 
or liver-specific HIF activation showed that 
suppression of hepcidin depends upon EPO-
induced stimulation of erythropoiesis. which 
would argue that HIF itself does not play a role in 
suppressing hepcidin transcription [2]. 
 

1.2 Anemia 
 
Anemia is the most common disorder diagnosed 
in most patients with chronic kidney disease. It 
could significantly affect a patient's quality of life 
if left unappropriately managed. There are 
multiple reasons for anemia in this patient 
population. In addition to drugs and dietary 
restrictions, patients may develop anemia due to 
iron deficiency resulting from a decrease in the 
renal capability. This leads to lowering the 
amount of iron available for the bone marrow to 
produce various blood elements. Chronic 
patients with kidney diseases can hardly utilize 
their body's iron stores, and many of them, 
especially those who are hemodialysed, develop 
an increased need for additional iron therapy 
which has been primarily delivered by infusions. 
 
“The erythropoietic system maintains the 
balance in the supply of red blood 
cells, therefore, ensuring an adequate tissue 
oxygenation4. In order to maintain this 
balance, senescent erythrocytes are replaced by 
new cells. Hypoxia is important in stimulating 
erythrocyte production through its interaction 
with the HIF (hypoxia-inducible factor) system. 
The HIF is a heterodimer, consisting of two 
subunits: alpha and beta. The production of HIF-
alpha continues, but its degradation occurs in 
the absence of tissue hypoxia. On the opposite 
situation, alpha and beta subunits join and bind 
in the nucleus of the cell, a DNA sequence 
called hypoxia-responsive elements. Thus, the 
production of erythropoietin is stimulated” [3]. 
 
Erythropoietin, on the other hand, is a molecule 
of 165 amino acids and 4 chains of 
carbohydrates. Mainly produced in the interstitial 
cells of the renal cortex, the production of the 
liver significantly increases with reduction in 

glomerular filtration. The half-life of 
erythropoietin is 5 to 12 hours, and it acts like a 
true hormone that binds to the receptors of bone 
marrow cells to produce erythrocytes. 
 

“Although reduction in erythropoietin production 
is one of the main causes of anemia in CKD, 
other causes include iron deficiency. It is 
assumed that iron loss varies between 1 and 3 
gram per year in patients on hemodialysis. Also, 
in the absence of dialysis, depletion in iron is 
observed in most patients4. This might be 
related to frequent phlebotomies, blood loss in 
the hemodialysis apparatus, and impairment in 
its absorption. The initiation of treatment with 
erythropoietin analogs demonstrated how 
frequent iron deficiency is among CKD patients” 
[4]. 
 

“Iron deficiency is usually a functional deficiency 
and is often characterized by low TSI and normal 
or increased ferritin. Ferritin can be raised in the 
presence of inflammation, infection, liver 
disease, and malignancy. The systemic 
homeostasis of iron, being regulated and 
managed by hepcidin 9.10, is also produced in 
the liver. It mediates degradation of ferroportin in 
duodenal enterocytes, hepatocytes and 
macrophages, which mainly prevents proper 
absorption and usage of iron. Inflammatory 
cytokines can induce the transcription of 
hepcidin5.6, and its increase has been reported 
in patients with CKD5. 
 

Anemia in CKD therefore is a multi-factorial 
process with three major factors being deficiency 
of erythropoietin, reduction in the life span of 
erythrocytes of poorly defined etiology, and 
changes in homeostasis of iron” [5]. 
 

Anemia is associated with several symptoms 
that lead to reduced quality of life, such as 
fatigue, dyspnea, insomnia, and headache. It is 
also related to reduced cognitive capacity. In 
addition, as kidneys fail, patients may require 
erythropoietin - a stimulus to bone marrow to 
produce more blood. This hormone is naturally 
produced by the kidneys but becomes relatively 
limited in chronic disease of the kidneys. 
 

Most patients will come to require erythropoietin 
or equivalent injectable products. The two main 
treatments for anemia are erythropoiesis-
stimulating agents and iron replacement. 
However, despite these treatments, an important 
proportion of children remain anemic. Increasing 
the ESA dose to achieve higher hemoglobin 
levels has been associated with adverse 
outcomes in adults; this association has not 



 
 
 
 

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been examined in children. Hemoglobin may be 
hard to keep within a narrow range using 
conservative ESA dosing. Careful administration 
of iron supplements may enhance ESA’s 
efficacy, yet the commonly applied markers of 
iron storage in the clinical setting lack the 
sensitivity to identify which patients can benefit 
the most from supplemental iron. Other agents 
that target the HIF pathway, such as hypoxia-
inducible factor stabilizers and prolyl hydroxylase 
inhibitors, and iron supplements delivered via 
dialysis are, therefore under investigation and 
may provide alternative management. 
Nonetheless, the effectiveness and safety of 
these treatments in children with CKD have not 
been reported yet [6]. 
 
For those with GFR < 30 ml/minute, it is fair to 
assume that anemia is secondary to renal 
failure. Nonetheless, it is important to rule out 
iron deficiency among others since the disease 
can be easily reversed. If anemia appears 
disproportionate to the level of kidney 
dysfunction, further investigation should be 
made. In such cases, an example-like 
hemoglobin at 9 g/dl with serum creatinine of 
200 μmol/l should be investigated. Further. Type 
2 diabetes and hypertension are the 
predominant causes of CKD in the developed 
world and increase the risk of developing 
cardiovascular disease, hyperlipidemia, mineral 
and bone disorders, and anemia. Anemia is 
characterized by a decrease in red blood cells 
and, consequently, hemoglobin (Hb), and typical 
symptoms and signs include paleness, fatigue, 
and breathlessness. 
 
At least two factors determine the lag between 
CKD onset and development of anemia. First, 
EPO, the hormone that promotes red blood cell 
production, is produced in smaller quantities in 
CKD patients than in non-CKD patients. Second, 
hepcidin, a hormone that suppresses dietary iron 
absorption when levels are elevated, is elevated 
in greater concentrations in CKD patients. Iron is 
one constituent of hemoglobin; it serves as a 
critical component in the oxygen transport 
process. Anemia in patients with CKD is a 
known contributor to a lower quality of life and 
increased risk of clinical outcomes that are 
unfavorable [7]. 
 

1.3 Chronic Kidney Disease (CKD) 
 
Chronic kidney disease is a degenerative and 
incurable illness with high morbidity and mortality 
rates and also the most common cause of 

morbidity in adults, especially those with 
diabetes and hypertension. As such, 
nonpharmacological interventions, for instance, 
dietary and lifestyle changes, and renal disease-
specific pharmacological treatments, targeting 
chronic kidney disease can help preserve renal 
function that otherwise may otherwise improve 
the outcomes. 
 
A plant-based diet low in protein and salt may 
reduce glomerular hyperfiltration and halt or slow 
the progression of renal deterioration and even 
contribute to alterations in acid-base balance 
and in the gut microbiome that are favorable. 
 
Alteration in intrarenal hemodynamics through 
pharmacological therapies (e.g., renin-
angiotensin-aldosterone pathway regulators and 
SGLT2 [SLC5A2] inhibitors) may preserve renal 
function through a reduction in intraglomerular 
pressure that is independent of control of BP and 
glycemia; other pharmacological therapies are 
novel active moieties: nonpharmacologic 
steroidal mineralocorticoid receptor antagonists 
which may protect the kidney through anti-
inflammatory or anti-fibrotic mechanisms [8]. 
 
Some glomerular and cystic kidney diseases 
may benefit from disease-specific treatment. 
Considering the sheer number of comorbidities, 
the morbidity and mortality associated with them, 
and the role of non-traditional risk factors in 
CKD, managing the cardiovascular risk of CKD, 
minimizing infection risk, and preventing acute 
renal failure are some important interventions for 
these patients. If renal replacement therapy is 
unavoidable, then stepwise switching to dialysis 
may be considered. It has also been suggested 
that this may preserve residual renal function for 
longer. KSP and SC share similarities but are 
different from one another. More research is 
needed, along with the development of new 
treatment strategies in dietary and 
pharmacological interventions, to achieve 
optimal kidney-sparing treatment in these 
patients, increasing their life expectancy, and 
achieving better HRQOLID anemia is a frequent 
complication present in CKD. Both absolute and 
functional ID are encountered in CKD patients 
[9]. 
 
Absolute iron deficiency is defined as 
substantially depleted or depleted iron stores. 
Functional iron deficiency refers to sufficient 
storage but insufficient availability of iron to be 
absorbed into erythroid precursors, primarily 
because of increased hepcidin levels. Anemia in 



 
 
 
 

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patients with CKD has been tied to increased 
morbidity and mortality. The association of 
mortality with anemia may be related to the 
severity of anemia. All patients with CKD should 
be assessed for anemia when first evaluated. 
The concept of iron deficiency in CKD is much 
less similar to that in patients with normal renal 
function. In the case of CKD patients, absolute 
iron deficiency is characterized by TSAT ≤20% 
and a serum ferritin concentration ≤100 ng/ml in 
predialysis and peritoneal dialysis patients and 
≤200 ng/ml in hemodialysis patients [11]. 
 
 Iron-restricted erythropoiesis, or functional iron 
deficiency, is characterized by TSAT ≤20% and 
elevated ferritin. Iron supplementation is 
provided to all CKD patients who have anemia. 
Furthermore, the overwhelming majority of 
patients do not attain optimal responses to 
ESAs. To overcome these barriers, HIF-PHIs 
have been created as oral agents in the 
treatment of anemia in CKD.They mimic the 
body's exposure to moderate hypoxia, thereby 
stimulating endogenous erythropoietin 
production. Some of these agents are already 
approved for clinical use in specific countries. 
Clinical trial data show noninferiority compared 
with ESAs and superiority to placebo for the 
correction of anemia. 
 
HIF prolyl hydroxylase domain inhibitors could 
offer patients with inflammation another 

advantage: enhancing iron use and mobilization 
as well as reducing LDL cholesterol levels. 
Overall, non-inferiority was also established for 
major cardiovascular events except in one 
molecule in the population of non-dialysis. Such 
a finding is rather an unexpected given that, 
based on their mechanism of action, these drugs 
have low levels of erythropoietin. More data and 
longer follow-up are needed to clarify safety 
issues and further explore the diversity of 
signaling pathways activated by HIF that may 
have positive or negative effects and distinguish 
HIF-PHIs from ESAs [12]. 
 

2. MECHANISM OF ACTION OF 
VADADUSTAT 

 

2.1 HIF-PH Inhibition 
 
“The HIF system elicits an adaptive response to 
tissue hypoxia in order to prevent cell damage 
by optimizing oxygen delivery and reducing 
tissue oxygen utilization which causes the 
production of EPO, primarily by interstitial 
perinephric cells of the kidney and by cells in the 
liver. EPO binds to its receptor on the surface of 
erythroid progenitor cells in the bone marrow, 
thus enhancing the survival, maturation, and 
proliferation of red blood cells. The activity of the 
HIF system varies according to tissue 
oxygenation”. 

 
 

Fig. 1. Hypoxia-inducible factor (HIF) system. PH—prolyl hydroxylase, pVHL—von 
Hippel−Lindau protein, HRE—hypoxia-responsive element, EPO—erythropoietin, VEGF—

vascular endothelial growth factor 



 
 
 
 

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Fig. 2. Schematic overview of the PHD/hypoxia-inducible factor (HIF) pathway 
 
“The HIF system consists of subunits α and β. 
HIF-1α accumulates and translocates to the 
nucleus of a cell where it binds to HIF-β and 
leads to the synthesis of the heterodimer HIF-
1αβ. The heterodimer HIF-1αβ leads to the 
expression of various hypoxia-inducible genes, 
such as the gene for EPO, thereby enhancing its 
rate of production. There are three isoforms of 
the subunit HIF-α: HIF-1α, HIF-2α, and HIF-3α, 
which all can dimerize with HIF-β and stimulate 
the expression of many genes other than the 
EPO gene. Thus, the dimer composed of the 
HIF-α and HIF-β subunits controls the 
expression of transferrin receptors, VEGF, and 
endothelin-1 receptors” [13]. 
 
In addition, it has been postulated that the HIF 
system is somehow involved in the control of cell 
metabolism and activity, including immune cells, 
and affects the total cholesterol and LDL 
fraction. The HIF system is nearly ubiquitous: the 
transcription factor HIF-1α is induced in virtually 
all cell types whereas HIF-2α is expressed in a 
more tissue-restricted manner. 
 
“mRNA expression of HIF-2α is mainly detected 
in the brain, heart, lung, kidney, pancreas, and 
intestine. HIF-3α tissue expression was 
observed in the heart, lungs, and kidneys. 
Normoxic tissue oxygenation leads to the 
degradation of HIF-1α through its hydroxylation 
via prolyl hydroxylase (PH) with the von Hippel-
Lindau protein (pVHL) thereby preventing 
dimerization between HIF-1α and HIF-β at a 
lower level of gene expression that encodes 
EPO. Under hypoxia, PH is inhibited and HIF-1α 
does not undergo degradation, and there is 

possibility of combination to produce the 
heterodimer HIF-1αβ, which activates the gene 
in charge of EPO synthesis. Inhibition of PH 
corresponds to the site of action for a class of 
drugs HIF-PHIs, used to treat anemia in patients 
with CKD” [14]. 
 

2.2 The PHD/HIF Oxygen-Sensing 
Pathway 

 

“HIF-α is rapidly degraded under normoxic 
conditions through the hydroxylation of certain 
proline residues. Hydroxylated HIF-α is tagged 
for proteasomal degradation by the von Hippel-
Lindau (VHL) tumor HIFs are basic pleiotropic 
helix-loop-helix transcription factors that belong 
to the PAS (PER/aryl hydrocarbon receptor 
nuclear translocator [ARNT]/single minded) 
family of transcription factors. They consist of 
two subunits, an oxygen-sensitive α-subunit and 
a constitutively expressed β-subunit, which is 
often referred to as the ARNT. The HIF-α subunit 
is continuously synthesized but is rapidly 
degraded in the presence of molecular oxygen. 
Three HIF-α-subunits have been identified, HIF-
1α, HIF-2α (also known as EPAS1), and HIF-3α. 
Under hypoxic conditions, HIF-α no longer gets 
degraded, but translocates to the nucleus, forms 
a heterodimer with HIF-β, and activates gene 
transcription.HIF-1 and HIF-2, the most 
intensively studied HIF transcription factors, 
control a very wide range of hypoxia responses, 
such as angiogenesis, anaerobic glucose 
metabolism, mitochondrial biogenesis, and many 
others, thus ensuring oxygen delivery and 
adaptation of cells to hypoxia [15]. The list of 
genes directly HIF-regulated is vast and several 



 
 
 
 

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hundred high stringency HIF binding sites have 
been identified in the genome. Although HIF-1 
and HIF-2 share many transcriptional targets, 
some genes are not co-regulated. For example, 
the glucose metabolism through glycolysis is 
under the control of HIF-1, whereas EPO 
production and some iron genes are under the 
regulation of HIF- suppressor protein, which acts 
as the substrate recognition”  

 
“Under hypoxic conditions, HIF-prolyl 
hydroxylation is decreased, HIF-α is no longer 
degraded and translocates to the nucleus where 
it heterodimerizes with HIF-β and initiates gene 
transcription. Any decrease in HIF-proline 
hydroxylation or inactivation of VHL function 
decreases HIF degradation and leads to greater 
expression of HIF target gene [16]. For example, 
patients carrying particular inactivating VHL 
mutations are susceptible to CNS 
hemangioblastomas, clear cell renal cancer, and 
pheochromocytomas, cancers that are described 
by upregulated HIF-regulated gene expression. 
In addition, particular mutations that compromise 
the ability of cells to faithfully hydroxylate HIF-α 
lead to abnormal regulation of HIF activity and 
predispose to polycythemia”.  

 
“Although the oxygen-sensitive α-subunit of HIF 
is ubiquitously expressed and continuously 
produced, it is degraded rapidly in normoxic 
conditions [17]. On the contrary, in hypoxia, the 
levels of cellular HIF-α accumulate and HIF-α 
moves to the nucleus, where it dimerizes with 
HIF-β. HIF-α degradation is orchestrated by the 
pVHL-E3-ubiquitin ligase complex, but this is 
only possible in the presence of oxygen- and 
iron-dependent PHD dioxygenases (PHD1-3) 
that hydroxylate prolyl residues of HIF-α. 
Decarboxylation of 2-oxoglurate (2OG produces 
hydroxylated HIF-α, succinate and CO2. 
Inhibition of PHD or von Hippel-Lindau leads to 
increased transcription of HIF-regulated genes 
such as VEGF, EPO, PGK1, LDH, and other 
genes implicated in hypoxia response regulation, 
including cellular metabolism, mitochondrial 
function, inflammation, vascular function, 
oxidative stress, and other responses. Here is 
the structure of a HIF-PHD inhibitor (PHI), which 
has been found to hold promise in potently 
inducing endogenous EPO in dialysis patients 
[18]. HIF-α is hydroxylated in an oxygen-
dependent reaction by PHD1, PHD2, and PHD3” 
[18]. 

 
“PHDs represent a large family of 2OG-
dependent dioxygenases comprising over 60 

members. Since these dioxygenases catalyze 
the hydroxylation requiring the use of molecular 
oxygen, they constitute a point of intersection 
between oxygen, intermediary, and amino acid 
metabolism and a variety of cellular processes 
including HIF regulation/hypoxia responses, 
collagen synthesis, epigenetic gene regulation, 
and fatty acid metabolism. Other small 
molecules, including reactive oxygen species, 
nitric oxide, and the Krebs cycle intermediates 
succinate and fumarate, have inhibitory effects 
on PHD catalytic activity and stabilize and 
activate HIFα, leading to associated 
transcriptional programs. The latter is clinically 
relevant in patients with deficiency of fumarate 
hydratase, who are at risk of developing the 
hereditary leiomyomatosis renal cell cancer 
syndrome associated with increased HIF activity 
within affected tissues. Structural analogues of 
2OG that inhibit the access of 2OG and HIFα to 
the catalytic center of the PHD and thus 
reversibly inhibit HIFα hydroxylation are now 
under clinical development for treatment of renal 
anemia and other indications” [19]. 
 

2.3 The PHD/HIF Axis in Erythropoiesis 
and Iron Metabolism 

 
“HIF-dependent regulation of iron metabolism. 
Overview Schematic overview of HIF-regulated 
genes in iron metabolism shown in red. In the 
intestine, duodenal cytochrome b (DCYTB) 
reduces ferric iron (Fe3+) to Fe2+, which enters 
via the enterocytes. DCYTB and DMT1 are both 
bonafide HIF-2-regulated genes. There is a 
release of iron into the circulation via ferroportin 
(FPN) that is hepcidin-regulated but also HIF-
inducible. In blood, iron is transported in complex 
with transferrin (TF) to the liver, cells of the 
reticulo-endothelial system (RES), bone marrow, 
and other organs. It has been demonstrated that 
increased erythropoietic activity in the bone 
marrow produces growth differentiation factor 15 
(GDF15) and erythroferrone that suppress 
hepcidin in hepatocytes. Inflammatory cytokines 
stimulate hepcidin production in the liver and 
lead to reduced ferroportin surface expression 
and hypoferremia. The small 25-amino-acid 
peptide produced by hepatocytes, hepcidin, 
targets FPN for degradation” [20]. 
 
“Its production increases with iron and 
inflammatory cytokines, including interleukin 6. 
As hepcidin decreases the expression of FPN on 
the cell surface, high plasma hepcidin levels 
have led to reduced intestinal iron uptake and 
impaired release of iron from internal stores. 



 
 
 
 

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Fig. 3. Schematic overview of HIF-Dependent regulation of iron metabolism 
 
Plasma hepcidin levels are generally increased 
in more advanced stages of CKD and enhance 
the pathogenesis of renal anemia by causing 
functional iron-deficiency, due to increased 
hepcidin levels. This involves systemic activation 
of HIF, suppressing hepcidin production in the 
liver and thus enhancing iron uptake and 
mobilization [21]. The first studies implicated 
HIF-1 directly in the suppression of hepcidin 
transcription; however, more detailed analysis of 
mouse models with either global or liver-specific 
HIF activation suggests that suppression of 
hepcidin is EPO-mediated stimulation of 
erythropoiesis. HIF does not have a direct 
repressor role on hepcidin transcription in the 
liver. The interaction between HIF and iron 
metabolism is a bi-directional one” . 

 
“The 5′ UTR of the gene encoding HIF-2α bears 
an iron response element that interacts with 
IRPs. In analogy to the inhibition of ferritin 
translation, IRP binding to the HIF2A 5′ UTR will 
block HIF-2α translation and therefore diminish 
the level of HIF-2α protein in the cell in response 
to low intracellular iron [22]. From this 
mechanism, one would anticipate that renal EPO 
production would be only mildly suppressed in 
iron deficiency anemia compared with other 
forms of anemia that are associated with either 
maintenance or even elevation of plasma iron. 
Hypoxia and the PHD/HIF pathway play an 
important role in regulating iron metabolism; in 
addition, it promotes erythropoiesis through 
direct effects on the bone marrow, including 
stimulating the expression of the EPO receptor 

and enhancing the synthesis of hemoglobin, as 
well as modulating the maintenance and lineage 
differentiation of stem cells and their maturation”. 
 

Anemia associated with CKD results from 
relative deficiency of renal EPO production, 
combined functional and/or absolute iron 
deficiency and resistance to EPO signaling, a 
condition often seen in the context of 
inflammation. Pharmacologic activation of HIF 
signaling may offer a more holistic and 
physiologic therapeutic option for treating renal 
anemia than therapy with recombinant 
preparations of EPO [23]. 
 

3. PROGRESS IN CLINICAL RESEARCH 
 

In clinical trials of a 20-week, phase 2b 
multicenter, randomized, double-blind, placebo-
controlled study to assess the oral, once-daily 
vadadustat ability to correct anemia in patients 
with NDD-CKD. A total of 1,929 patients at NDD-
CKD stage 3a/b, 4, and 5 stages from 61 centers 
were stratified by ESA therapy use and Hb level. 
Group 1: ESA treatment naïve and Hb ≤10.5 
g/dl; group 2: previously treated with ESA and 
Hb ≤10.5 g/dl; group 3: actively treated with 
ESA, Hb ≥9.5 g/dl to ≤12.0 g/dl [24]. 
 

Patients in each group received double blinded 
randomization 2:1 for vadadustat versus 
placebo, stratified by CKD stage and the 
presence or absence of diabetes mellitus. Two 
hundred ten patients were included in the safety 
analyses: those patients who received the study 
drug were treated with either vadadustat (n = 



 
 
 
 

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138) or placebo (n = 72). For all efficacy 
analyses, the modified intent-to-treat population 
of 208 patients was used, those patients         
who had a baseline and ≥1   postbaseline 
measurement of Hb and red blood cells [24]. 
 

 The former group included 136 patients 
randomized to vadadustat and 72 to placebo. 
The per-protocol population was defined a priori 
as the primary population for use in analysis of 
the primary endpoint and consisted of all 
modified intent-to-treat patients who completed 
the study, had efficacy data through week 20, 
were ≥80% compliant with study medication, and 
did not have a major protocol deviation [25]. 
 

A total of 160 patients qualified for the per-
protocol population. of the 210 patients who 
were treated with the study medication, 81% (n = 
112) in the vadadustat group and 88% (n = 63) 
in the placebo group completed treatment 
through to week 20 of the study. In terms of 
demographic and disease-related 
characteristics, Hb, hemoglobin; ITT, intent-to-
treat population, i.e. all randomized patients who 
received ≥1 dose of study medication; TSAT, 
transferrin saturation; uACR, urine albumin-to-
creatinine ratio. Values are n (%) or mean ± SD. 
If a subject had >1 reason checked for etiology 
of CKD, all reasons were counted. The most 
important endpoint of the investigation was the 
percentage of patients reaching or maintaining a 
mean Hb ≥11.0 g/dl at the end of the last 2 
weeks of treatment or showing an increase in Hb 
≥1.2 g/dl above the per dose average [26]. 
 
Vadadustat treatment raised and maintained Hb 
levels in the patients with anemia secondary to 
CKD. In the per-protocol population, 54.9% of 
patients treated with vadadustat achieved the 
primary endpoint compared with 10.3% of 
patients treated with the placebo (P < 0.0001). 
At an estimated odds ratio, patients receiving 
vadadustat were approximately 11.5 times more 
likely than patients receiving a placebo to attain 
a successful Hb response (P = 0.0001) Success: 
Hb average of weeks 19 and 20 ≥11.0 g/dl or Hb 
average of weeks 19 and 20 ≥1.2 g/dl higher 
than predose mean. For a missing value, a 
single value was used P-value for vadadustat 
versus placebo is from a logistic regression 
analysis [27]. 
 
Vadadustat dose-robustly increased and 
maintained Hb levels in patients throughout the 
20-week study. By week 2, mean Hb levels in 
the vadadustat group had increased 

substantially from baseline; Hb levels plateaued 
between weeks 6 to 8 and were maintained 
throughout the 20 weeks of treatment Hb 
response versus time in each of the 3 study 
groups based on ESA treatment status is shown 
in Hb excursions ≥13 g/dl occurred in only 4.3% 
(6 of 138) of patients in the vadadustat group. 
Post hoc analysis of Hb values for all weeks 
between 8 and 20: for vadadustat 71.2% and for 
placebo 42.7% were between 10 and <12 g/dl; 
and for vadadustat 8.9% were between 12.0 and 
12.9 g/dl, 1% were ≥13.0 g/dl, while none for the 
placebo group were≥12.0 g/dl [28]. 
 
Fewer vadadustat-treated patients required ESA 
rescue therapy compared with placebo (4.4% vs 
16.7%, P = 0.045). Of the 6 vadadustat-treated 
patients who received ESA during the study, 4 
did not meet the protocol-prespecified criteria for 
ESA rescue; of the remaining 2, 1 was in the 
previously treated group, and 1 in the actively 
treated group. Out of the 12 placebo patients 
treated with ESA rescue, 2 did not meet 
protocol-specified criteria; of the remaining 10, 1 
was in the treatment naïve group, 3 were in the 
previously treated group, and 6 were in the 
actively treated group. No patient receiving 
vadadustat and 1 placebo-treated patient 
required transfusion rescue at any time during 
the trial [29]. 
 
Baseline increase in mean absolute reticulocyte 
count occurred in the vadadustat group at week 
2 (+0.022 × 10 6 /μl) compared with a slight 
decrease in the placebo group (–0.005 × 10 6 
/μl; P = 0.0001) [30]. The mean reticulocyte 
count in the vadadustat group continued to 
decrease and reached plateau during weeks 6 to 
8 at a level significantly above that of the 
placebo group, reflecting the new Hb baseline. 
Markedly lower hepcidin and ferritin levels and 
significantly higher total ironbinding capacity 
were noted in the vadadustat group, compared 
with the placebo group, at each postbaseline 
evaluation. Serum iron and transferrin saturation 
did not differ between the 2 treatment groups 
over the course of the study [31]. 
 

At the end of 20 weeks, 45.8% of patients in the 
vadadustat group were also receiving iron 
supplementation, whereas 52.8% of those in             
the placebo group were receiving iron 
supplementation at this point. Furthermore, 2.9% 
of the patients (4 of 136) receiving vadadustat, 
but none in the placebo group received i.v. 
iron.Initial drug dosage at treatment initiation 
was 450 mg once daily; mean drug dosage at 



 
 
 
 

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Week 19: 450 mg once daily [32]. For the 
majority of patients: 89%, 120 of 135 who 
received vadadustat, a stable Hb level was 
achieved and maintained with ≤2 dose 
adjustments over the 20-week treatment period, 
and no dose adjustment was required in 24% of 
patients (33 of 135) [33]. 

 
Patients who were ≥80% compliant with the 
allocated treatment had 92.8% (128/138) in the 
vadadustat group versus 94.4% (68/72) in the 
placebo group. A higher percentage of the 
vadadustat-treated patients experienced ≥1 
adverse event (AE) compared to the placebo-
treated patients (74.6% vs 73.6) [34]. The 
incidence of ≥1 drug-related AE was reported in 
25.4% of the vadadustat-treated patients (35 of 
138) and in 11.1% of placebo-treated patients (8 
of 72). In both treatment arms, most of the AEs 
reported were mild or moderate in intensity [35]. 
Commonly reported drug-related AEs in the 
vadadustat group were diarrhea (4.3%), nausea 
(4.3%), whereas most commonly reported drug-
related AE in the placebo group was diarrhoea 
(2.8%) [36]. 10 patients treated with vadadustat 
(7.2%) and three patients treated with placebo 
(4.2%) discontinued the study due to AEs.Not 
listed in the table below is one of the 14 
vadadustat-treated patients who were reported 
to have had a renal-related SAE- one of whom 
was Subject 1490001, previously study group 
treated [37]. The patient was hospitalized for 
Goodpasture syndrome worsening that occurred 
following 1 dose of study medication; other than 
hospitalization for worsening Goodpasture 
syndrome, no other renalrelated adverse events 
were reported [38]. 
 

There were no trends observed (either increases 
or decreases) in the systolic values of blood 
pressure or diastolic values of blood pressure 
over time, and the distribution in the systolic 
values of blood pressure among patients 
receiving vadadustat was comparable to that in 
patients receiving placebo [39]. Hypertension 
was an AE in 8.0% of patients treated with 
vadadustat (11 of 138) and in 2.8% of patients 
treated with placebo (2 of 72), and all patients 
had a pre-existing history of hypertension. One 
of the 11 patients on vadadustat who 
experienced an AE of hypertension during the 
study had furosemide discontinued about 1 
month prior to the event. Otherwise, no 
participant experienced withdrawal or dose 
reduction of antihypertensive drugs before 
development of the AE of hypertension; no 

participant stopped vadadustat due to 
hypertension [40]. 
 
Out Of these, 33 patients treated with 
vadadustat experienced ≥1 SAE (23.9%), 
compared with 11 placebo-treated patients 
(15.3%); the higher proportion of SAEs was 
mainly due to a higher proportion of renal-related 
SAEs in the vadadustat arm (10.1%) than in the 
placebo arm (2.8%) [41]. The proportion of 
patients who received a baseline requirement for 
initiation of dialysis, an inorganic marker of the 
seriousness of renal SAEs, was similar between 
the vadadustat (11 of 138, 8.0%) and placebo (7 
of 72, 9.7%) treatment groups [42]. The 
incidences of investigation-reported renal-related 
SAEs were not related to the study drug, 
according to the investigator. The clinical studies 
mentioned above have proven vadadustat as a 
worthwhile option as an induction treatment for 
patients with anemia who have chronic kidney 
disease [43]. 
 

4. CONCLUSION 
 

Anemia is an inadequacy in the number or 
quality of red blood cells (RBCs) or a reduction 
in the amount of hemoglobin, which is the 
oxygen-carrying protein in RBCs in the blood 
[44]. It is associated with poorly oxygenated 
tissues and organs within the body, resulting in a 
variety of symptoms such as fatigue and 
weakness and paleness [45]. ESAs or new HIF-
PH inhibitors like vadadustat, which act through 
mimicking hypoxia by stabilizing the hypoxia-
inducible factor pathway and activates 
erythropoiesis and EPO production, should be 
considered for achieving treatment goals [46]. 
Vadadustat is an investigational oral hypoxia-
inducible factor prolyl-hydroxylase inhibitor that 
stimulates endogenous erythropoietin formation. 
At present, erythropoiesis-stimulating agents 
(ESAs) are still the treatment mainstay for 
anaemia of chronic kidney disease (CKD) [47]. 
All ESAs function effectively to correct anemia in 
CKD by countering the EPO deficiency resulting 
from failing kidneys. In contrast, whereas ESAs 
function by antagonizing the activity of the HIF 
pathway, HIF-PHIs activate it, thereby 
stimulating the transcription of the EPO gene 
and upregulating the expression of genes 
participating in erythropoiesis and in iron 
metabolism [48]. This unusual mechanism of 
action was believed to have an excellent anemic 
correction by promoting endogenous production 
of EPO and concomitantly boosting enteric iron 



 
 
 
 

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absorption and mobilization of iron (in contrast to 
ESA). 
 
In addition, the peak serum EPO level is 
reportedly a few folds less in HIF-PHIs as 
compared to ESA treatment [49]. The vast 
majority of RCTs with HIF-PHIs established their 
non-inferiority as compared to ESAs. Vadadustat 
is a potent inhibitor of the catalytic activity of all 
three human PHD isozymes: PHD1, PHD2, and 
PHD3; all three endozymes have nanomolar 
inhibitory constant values and are similar [50]. 
Vadadustat inhibits PHD with competition 
against the cellular endogenous cofactor 2-
oxoglutarate and is not dependent on free iron 
concentration. In the human hepatocellular 
carcinoma cell line (Hep 3B) and human 
umbilical vein endothelial cells, PHD inhibition by 
vadadustat leads to time- and concentration-
dependent stabilization of HIF-1α and HIF-2α. 
This results in synthesis and secretion of EPO in 
Hep 3B cells, whereas vascular endothelial 
growth factor is not measured at detectable 
levels. A single oral dose of vadadustat in rats 
potently increases circulating levels of EPO [51]. 
 

CONSENT AND ETHICAL APPROVAL 
 
It is not applicable. 
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 
  
Author(s) hereby declares that no generative AI 
technologies such as Large Language Models 
(ChatGPT, COPILOT, etc) and text-to-image 
generators have been used during writing or 
editing of this manuscript.  
 

COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 

 
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