The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Roxadustat and Anemia of Chronic Kidney Disease

Joshua Kaplan, M.D.

Until 1989, when recombinant erythropoietin
therapy was first approved, anemia of chronic
kidney disease could be treated only symptom-
atically with blood transfusions. Erythropoiesis-
stimulating agents were able to increase pa-
tients’ hemoglobin levels to between 9 and 11 g
per deciliter, resulting in improved quality of life
and decreased left ventricular hypertrophy and
mortality.1,2 Since that time, erythropoiesis-stim-
ulating agents along with oral and intravenous
iron have been the linchpin of treatment for
chronic kidney disease accompanied by profound
anemia.
With the proof that erythropoietin and iron
could markedly correct anemia, the next obvious
question was addressed some years ago: Would
full reversal of anemia of chronic kidney disease
further improve outcomes? After all, among pa-
tients without chronic kidney disease, those with
anemia and hemoglobin levels in the range of
9 to 11 g per deciliter have worse outcomes than
those without anemia. However, multiple trials
of erythropoiesis-stimulating agents showed, at
best, no improvement in outcome and, at worst,
increased risks of stroke and death.3-5 The Cor-
rection of Hemoglobin and Outcomes in Renal
Insufficiency (CHOIR) trial3 showed that patients
with chronic kidney disease had a higher risk of
a composite end point that included death and
cardiovascular events if they were treated to a
target hemoglobin level of 13.5 g per deciliter
rather than 11.3 g per deciliter, and the Trial to
Reduce Cardiovascular Events with Aranesp Ther-
apy (TREAT)5 showed that patients with diabetes
mellitus and chronic kidney disease treated with
darbepoetin alfa to a target hemoglobin level of
13 g per deciliter had a higher risk of stroke
than those who received placebo and that they
had only a minimal improvement in fatigue. Such
findings led to lowering of the goals regarding
hemoglobin level in patients undergoing dialysis
to a range of 9 to 11 g per deciliter, and patients
with anemia of chronic kidney disease who were
not undergoing dialysis were treated only to re-
duce the risk of transfusions or to treat symp-
tomatic anemia. Why did normalization of he-
moglobin levels not reverse the risks of anemia
among patients with chronic kidney disease?
One possible reason, on the basis of post hoc
analyses of the CHOIR and TREAT trials, was
that higher doses of erythropoietin-stimulating
agents were correlated with worse outcomes,
although no clear pathophysiological mecha-
nism was established.6,7
Two phase 3 trials carried out in China, the re-
sults of which are now published in the Journal,8,9
report findings regarding roxadustat, a member
of a new therapeutic class, hypoxia-inducible fac-
tor (HIF) prolyl hydroxylase inhibitors, for the
treatment of anemia of chronic kidney disease.
In these trials, roxadustat was superior to pla-
cebo in increasing hemoglobin levels in patients
with anemia who were not undergoing dialysis
and was noninferior to erythropoietin (epoetin
alfa) in increasing hemoglobin levels in patients
with anemia who were undergoing hemodialy-
sis. Although roxadustat appeared to be an effec-
tive treatment option for these patients, the trials
leave some unanswered questions.
HIF prolyl hydroxylase inhibitors treat ane-
mia of chronic kidney disease through multiple
pathways, beyond increasing erythropoietin lev-
els, by means of effects on inflammation and
iron handling, and particularly by decreasing the

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 The n e w e ng l a n d j o u r na l
hepcidin level (Kaplan et al. provide a review10).
Thus, treatment with HIF prolyl hydroxylase in-
hibitors differs from treatment with erythropoi-
etin and intravenous iron in two potentially
critical factors — patients receiving HIF prolyl
hydroxylase inhibitors have lower serum levels
of erythropoietin than those receiving erythro-
poietin, and HIF prolyl hydroxylase inhibitors
lead to decreased levels of hepcidin. This allows
access to existing iron stores as well as increased
absorption of oral iron, thus avoiding the use of
high doses of intravenous iron, which has been
associated with an increased inflammatory state
and increased mortality.11 These two trials, con-
ducted by Szczech and colleagues,8,9 show de-
creased hepcidin and increased hemoglobin levels
with roxadustat treatment for a total of 26 weeks,
despite decreases in transferrin saturation and
the ferritin level. The maintenance of serum iron
levels in the roxadustat group, as compared with
decreased iron levels in the erythropoietin group,
corresponds with the effect of roxadustat on
hepcidin and subsequent increase of ferroportin,
allowing increased access to enteral iron and
macrophage iron stores.
Both trials showed a higher risk of hyper­
kalemia with roxadustat than with the control
(epoietin alfa or placebo). The pathophysiologi-
cal mechanism by which HIF prolyl hydroxylase
inhibitors may cause hyperkalemia is unclear,
and hyperkalemia has not been reported as an
adverse event in phase 2 trials of other HIF prolyl
hydroxylase inhibitors, so hyperkalemia may be
an off-target effect of roxadustat rather than a
class effect. In both trials, the authors argued
that central laboratory values did not support an
increased risk of hyperkalemia with roxadustat
therapy, but given the increased incidence of
hyperkalemia that has been reported in multiple
trials of this agent, it seems prudent to exercise
caution in using this agent in patients who have
a predisposition to hyperkalemia.
Decreased levels of total cholesterol, low-
density lipoprotein cholesterol, and triglycerides
were noted in the two trials, an effect that has
been reported regarding some, but not all, of the
other HIF prolyl hydroxylase inhibitors in devel-
opment. These findings may be related to HIF-
dependent effects on acetyl coenzyme A and
3-hydroxy-3-methylglutaryl coenzyme A (HMG-
CoA) reductase. In their discussion, the authors
connect their results with the beneficial effect of
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of m e dic i n e
statins in this context, which seems question-
able, given that a change in cholesterol levels is
no longer considered to be an adequate surro-
gate marker for changes in cardiovascular risk.
As such, attributing cardiac benefits to roxadu­
stat without direct testing for this effect is un-
warranted.
Several important questions need to be an-
swered with regard to these two trials of roxa-
dustat. We should keep in mind that the find-
ings in Han Chinese patients, who may have
unique genetic factors, may render extrapolation
to other populations unwise. Furthermore, these
phase 3 trials are smaller, by a factor of 3 to 10,
and much shorter, by a factor of 3 to 4, than the
CHOIR and TREAT trials and other studies of
erythropoietin-stimulating agents. Can this agent
treat patients with erythropoietin-stimulating
agent–resistant and hyporesponsive anemia more
effectively and more safely than the current treat-
ment using erythropoietin and iron? Second, al-
though roxadustat therapy clearly increases hemo-
globin levels in patients with anemia of chronic
kidney disease who are not undergoing dialysis,
does it result in the worse outcomes that are
now already associated with treatment with
erythropoietin-stimulating agents? Until we know
the answer, should we use roxadustat to treat
such patients? Finally, can roxadustat therapy
normalize the hemoglobin level in patients with
anemia and allow them to reap the benefit of
improved oxygen delivery without the increased
risks associated with normalization of the hemo-
globin level by erythropoietin-stimulating agents?
The trial of roxadustat involving patients under-
going hemodialysis addressed the first question.
In the group that received the erythropoietin-
stimulating agent (epoetin alfa), patients with
elevated C-reactive protein levels received higher
doses of the agent yet had lower hemoglobin
levels than patients with normal C-reactive pro-
tein levels, whereas in the roxadustat group,
patients with elevated C-reactive protein levels
had hemoglobin levels similar to those in pa-
tients with normal C-reactive protein levels and
also received similar doses. Such data suggest
that roxadustat might be an appropriate choice
to treat patients undergoing hemodialysis who
have a high inflammatory state and hypore-
sponsiveness to an erythropoietin-stimulating
agent.
The last two questions are not addressed by
 Editorial
these present trials but are intriguing nonethe-
less. On the basis of the different mode of ac-
tion, there is reasonable cause to question the
existing assumption that anemia of chronic kid-
ney disease cannot be reversed fully and safely,
attributing the previously shown lack of benefit
from normalization of the hemoglobin level to
adverse effects from high doses and blood levels
of erythropoietin. Although the present trials
indicate that roxadustat effectively treated ane-
mia while reducing hepcidin levels and main-
taining lower levels of erythropoietin, adverse
events may yet appear when larger, longer trials
are completed. Accordingly, it is reasonable to
await in-progress trials (ClinicalTrials.gov num-
bers, NCT02273726 and NCT01750190) and to
proceed with additional studies reexamining the
risks and benefits of normalization of the hemo-
globin level in patients with anemia of chronic
kidney disease and carefully monitoring for as yet
unappreciated problems with HIF prolyl hydroxy-
lase inhibitors. If HIF prolyl hydroxylase inhibi-
tors fulfill their promise and facilitate normal-
ization of hemoglobin levels in patients with
chronic kidney disease and reduce cardiovascu-
lar morbidity related to anemia without the
increased risks that have been seen in trials of
erythropoietin-stimulating agents, there might
ultimately be a revolution in the treatment of
anemia of chronic kidney disease.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
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Copyright © 2019 Massachusetts Medical Society. All rights reserved.
From the Department of Medicine, Rutgers–New Jersey Medi-
cal School, Newark.
This editorial was published on July 24, 2019, at NEJM.org.
1. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant
human erythropoietin in anemic patients with end-stage renal
disease: results of a phase III multicenter clinical trial. Ann Intern
Med 1989;​111:​992-1000.
2. Möcks J. Cardiovascular mortality in haemodialysis patients
treated with epoetin beta — a retrospective study. Nephron
2000;​86:​455-62.
3. Singh AK, Szczech L, Tang KL, et al. Correction of anemia
with epoetin alfa in chronic kidney disease. N Engl J Med 2006;​
355:​2085-98.
4. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemo-
globin level in patients with chronic kidney disease and anemia.
N Engl J Med 2006;​355:​2071-84.
5. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbe-
poetin alfa in type 2 diabetes and chronic kidney disease. N Engl
J Med 2009;​361:​2019-32.
6. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis
of the CHOIR trial epoetin-α dose and achieved hemoglobin
outcomes. Kidney Int 2008;​74:​791-8.
7. Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response
and outcomes in kidney disease and type 2 diabetes. N Engl J Med
2010;​363:​1146-55.
8. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in pa-
tients with kidney disease not receiving dialysis. N Engl J Med.
DOI:​ 10.1056/NEJMoa1813599.
9. Chen N, Hao C, Liu B-C, et al. Roxadustat treatment for
anemia in patients undergoing long-term dialysis. N Engl J Med.
DOI:​ 10.1056/NEJMoa1901713.
10. Kaplan JM, Sharma N, Dikdan S. Hypoxia-inducible factor
and its role in the management of anemia in chronic kidney
disease. Int J Mol Sci 2018;​19(2):​E389.
11. Bailie GR, Larkina M, Goodkin DA, et al. Data from the Di-
alysis Outcomes and Practice Patterns Study validate an associa-
tion between high intravenous iron doses and mortality. Kidney
Int 2015;​87:​162-8.
DOI: 10.1056/NEJMe1908978
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