Better treatment of anaemia and improved quality of life in patients with chronic kidney disease
Submitting InstitutionKing's College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Clinical Sciences
Summary of the impact
King's College London (KCL) research has made a major contribution to
improving the quality of life for patients who have anaemia linked with
chronic kidney disease. Studies undertaken by KCL researchers established
that intravenous iron supplementation was required in anaemic patients
with advanced kidney disease, in whom oral iron therapy was ineffective,
and defined the best regimes for administration of intravenous iron.
Subsequent KCL work on drugs that stimulate production of red blood cells
(erythropoiesis) defined the target levels of haemoglobin to aim for in
chronic kidney disease patients. Most recently, KCL researchers made the
key discovery that the novel drug peginesatide for the first time enables
the rescue of patients who develop a rare and potentially fatal reaction
against erythropoietin (which is the commonest treatment for anaemia in
chronic kidney disease). These KCL research studies have had a significant
impact by making a major contribution to national and international
clinical guidelines, including UK NICE guidelines and the 2012 National
Kidney Foundation KDIGO Clinical Practice Guideline for Anemia in Chronic
Anaemia in chronic kidney disease: Chronic kidney disease is
invariably accompanied by anaemia, as the kidneys are the source of
erythropoietin, which stimulates red blood cell production in the bone
marrow. Anaemia increases breathlessness and tiredness in these patients,
increases their risk of infections and heart disease, and substantially
worsens quality of life. It is therefore crucial to develop effective
treatments to deal with this problem.
KCL research to improve treatment of anaemia in chronic kidney
disease: The KCL team led by Professor Iain Macdougall has
consistently tackled this problem over the last 20 years through multiple
clinical trials and other studies to find the best way to treat anaemia.
The overall focus of KCL research has been to define the best mode of iron
supplementation and to use novel drugs (eythropoietin-stimulating agents)
to stimulate red blood cell formation. An additional major achievement is
research showing the effectiveness of the drug peginesatide to treat pure
red cell aplasia, a rare and potentially fatal reaction that can develop
Clinical trials establishing role of intravenous iron therapy: A
randomised controlled trial led by the KCL group provided evidence that
iron taken orally is not effective in advanced chronic kidney disease, and
that intravenous iron supplementation is required in this patient group
(1). All the main anaemia guidelines refer to this seminal research. The
safety of administering intravenous iron sucrose as a 2-minute push was
also investigated in a subsequent study (2), and this practice has since
been adopted in numerous kidney units worldwide. In addition, the largest
study ever conducted in this field has established that the use of ferric
carboxymaltose, a specific type of iron sucrose, reduces the need for
erythropoiesis-stimulating agents or blood transfusion in patients who
have chronic kidney disease that does not require dialysis and who suffer
from iron deficiency anaemia (3). This study was conceived, designed and
led by Professor Macdougall.
Clinical trials studying target haemoglobin level: It has been
unclear how high a haemoglobin level should be aimed for in chronic kidney
patients being treated for anaemia. KCL researchers contributed to several
large randomised controlled trials showing that normalising the
haemoglobin concentration in patients with chronic kidney disease
potentially causes harm. Perhaps the most important study was the CREATE
study published in the New England Journal of Medicine (4), for
which Professor Macdougall was on the steering committee and involved in
the design and running of the study. KCL researchers also contributed to a
large Europe-wide study on the relation between variability in haemoglobin
concentration and patient deaths (5), which showed that mortality is not
predicted by modest fluctuations in haemoglobin levels. These studies have
significantly influenced clinical guidelines for target haemoglobin levels
in patients with chronic kidney disease.
Comparing alternative epoietins: KCL researchers have studied new
epoietin drugs which mimic natural erythropoietin. Professor Macdougall
was on the steering committee and was involved in the design, conduct and
publication of the PATRONUS study, a large European multicentre randomised
controlled trial that examined the efficiency of two such drugs in
controlling anaemia if given at extended intervals compared to previous
practice. This study showed that pegylated epoetin beta was more effective
than darbepoetin alfa (6). This evidence contributes to better anaemia
management and improved convenience for patients and is incorporated into
Pentoxifylline, which reduces blood viscosity and hence improves blood
flow, was shown by the KCL group to affect the haemoglobin response in
dialysis patients who did not respond to erythropoietin, and also to
reduce inflammatory response (7). This finding became the basis for a
large Australasian Kidney Network-funded study called the HERO trial,
which is a randomised double-blind placebo-controlled study currently
being conducted in centres throughout Australia (8).
Pure red cell aplasia: The rare condition of pure red cell aplasia
is caused when the body generates antibodies when treated with
erythropoietin. This is life-threatening, because the antibodies
neutralise the erythropoietin being given to correct the anaemia. This
worsens the impact of the lack of natural erythropoietin and frequent red
cell transfusions are needed. KCL researchers initially collaborated with
European investigators to identify the incidence and course of this
serious complication and the response to therapies such as
immunosuppression and kidney transplantation (9).
Subsequent KCL-led research studied the use of a novel peptide-based
erythropoietin-receptor agonist, peginesatide, for the treatment of
anaemia in chronic kidney disease patients who had developed pure red-cell
aplasia due to antierythropoietin antibodies. In a key paper published in
the New England Journal of Medicine (10), it was shown that
peginesatide could mimic the effects of erythropoietin without the
immunological reaction that some patients suffered in response to
erythropoietin. Patients who developed pure red cell aplasia caused by
antibodies against erythropoietin treatment could therefore be rescued
with peginesatide therapy (10). As a result of this work, peginesatide was
licensed for the treatment of red cell aplasia.
Additional large studies were also undertaken to assess the general use
of peginesatide in chronic kidney disease patients with anaemia (i.e.
those without red cell aplasia) and showed it to be effective in this
References to the research
1. Macdougall IC, Tucker B, Thompson J et al. A randomized
controlled study of iron supplementation in patients treated with
erythropoietin. Kidney Int. 1996;50:1694-99.
2. Macdougall IC, Roche A. Administration of intravenous iron
sucrose as a 2-minute push to CKD patients: a prospective evaluation of
2,297 injections. Am J Kidney Dis. 2005;46:283-89.
4. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC,
Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. Normalization of
hemoglobin level in patients with chronic kidney disease and anemia. N
Engl J Med. 2006;355:2071-84.
5. Eckardt KU, Kim J, Kronenberg F, Aljama P, Anker SD, Canaud B,
Molemans B, Stenvinkel P, Schernthaner G, Ireland E, Fouqueray B, Macdougall
IC. Hemoglobin variability does not predict mortality in European
hemodialysis patients. J Am Soc Nephrol. 2010;21:1765-75.
6. Carrera F, Lok CE, de Francisco A, Locatelli F, Mann JF, Canaud B,
Kerr PG, Macdougall IC, Besarab A, Villa G, Kazes I, Van Vlem B,
Jolly S, Beyer U, Dougherty FC; PATRONUS Investigators. Maintenance
treatment of renal anaemia in haemodialysis patients with methoxy
polyethylene glycol-epoetin beta versus darbepoetin alfa administered
monthly: a randomized comparative trial. Nephrol Dial Transplant.
7. Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC.
Pentoxifylline improves hemoglobin levels in patients with
erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol.
8. Johnson DW, Hawley CM, Rosser B et al. Oxpentifylline versus placebo
in the treatment of erythropoietin-resistant anaemia: a randomized
controlled trial. BMC Nephrol. 2008;9:8
9. Verhelst D, Rossert J, Casadevall N, Krüger A, Eckardt KU, Macdougall
IC. Treatment of erythropoietin-induced pure red cell aplasia: a
retrospective study. Lancet. 2004;363:1768-71.
10. Macdougall IC, Rossert J, Casadevall N, Stead RB, Duliege AM,
Froissart M, Eckardt KU. A peptide-based erythropoietin-receptor agonist
for pure red-cell aplasia. N Engl J Med. 2009;361:1848-55.
11. Macdougall IC, Provenzano R, Sharma A, Spinowitz BS, Schmidt
RJ, Pergola PE, Zabaneh RI, Tong-Starksen S, Mayo MR, Tang H, Polu KR,
Duliege AM, Fishbane S; PEARL Study Groups. Peginesatide for anemia in
patients with chronic kidney disease not receiving dialysis. N Engl J
12. Fishbane S, Schiller B, Locatelli F, Covic AC, Provenzano R, Wiecek
A, Levin NW, Kaplan M, Macdougall IC, Francisco C, Mayo MR, Polu
KR, Duliege AM, Besarab A; EMERALD Study Groups. Peginesatide in patients
with anemia undergoing hemodialysis. N Engl J Med.
Details of the impact
Marked improvement in the management of anaemia in chronic kidney
disease: The research described above has significantly improved the
management of anaemia in patients with chronic kidney disease worldwide,
through its contribution to national and international guidelines.
Contribution to UK NICE guidelines: The 2011 clinical guidelines
"CG114: Anaemia management in people with chronic kidney disease" (13)
published by the UK National Institute for Health and Care Excellence
(NICE) extensively incorporates the findings of KCL researchers. Seven
pieces of original KCL research contribute to the guidelines, including
the work on management of iron therapy and the use of a 2-minute push of
intravenous iron sucrose (1,2), target haemoglobin levels in patients on
erythropoietin therapy (4) and treatment of pure red cell aplasia (9).
Global impact: International clinical practice guidelines have
also assimilated the scientific evidence base for the management of renal
anaemia. The latest of these is the global KDIGO Clinical Practice
Guideline for Anemia in Chronic Kidney Disease (August 2012) (14). These
guidelines extensively incorporate the findings of KCL researchers, which
contributed 6 pieces of original research to the references cited in the
guideline. These include the work on management of iron therapy (1,2), the
work addressing normalisation of haemoglobin levels with erythropoietic
therapy (4), work on the relevance of haemoglobin variability (5),
research comparing pegylated epoetin with darbepoetin alfa (6), and
studies on the management of antibody-mediated pure red cell aplasia (9).
Iron supplementation: Iron supplementation is important in the
management of anaemia, but giving iron by oral tablet is ineffective in
dialysis patients. Professor Macdougall's randomised controlled trial
published in 1996 (1) was one of the first to show that oral
iron was ineffective in these patients. These patients benefit from
intravenous iron which corrects the iron deficiency and vastly improves
patients' quality of life. The practice of administering intravenous iron
sucrose (2) has been adopted in numerous kidney units worldwide. The
recommendations within the KDIGO Anemia guideline (14 - Chapter 2)
reinforce the benefit of this practice as evidenced by the KCL research
and the international standing of the guideline ensures its impact
worldwide. This relatively simple yet highly effective intervention has
had a major impact on patients' quality of life.
Target haemoglobin level: Although early studies suggested that
variability in haemoglobin level might be harmful, other studies,
including KCL research (4,5) suggested that this had little impact. The
CREATE study (4) provided especially strong data for the evidence base
supporting the inadvisability of aiming for haemoglobin concentrations
above 13 g/dl in kidney patients. The KDIGO Anemia guideline states "In
all adult patients, we recommend that ESAs not be used to intentionally
increase the Hb concentration above 13 g/dl (130 g/l). Evidence level 1A
(ref 14 - Chapter 3). These quote extensively from the CREATE study.
Comparing alternative epoietins: Since recombinant human
erythropoietin has become available, two longer-acting erythropoietin
analogues - darbepoetin alfa and pegylated epoetin beta - have been
investigated. International research to which KCL made a major
contribution has shown that when used once-monthly, pegylated epoetin beta
is superior to darbepoetin alfa (6). The practical benefit to
patients is in the reduced frequency of injections that is now possible
and this is also incorporated in the KDIGO Anemia guideline (ref 14 -
Pure red cell aplasia: The finding that the severe condition of
antibody-mediated pure red cell aplasia was transformed by peginesatide
(10) opened a unique treatment option for patients who had developed
antibodies against the conventional treatment, erythropoietin. It could
therefore be used to rescue patients who had developed this condition.
Before the peginesatide rescue study, there was uncertainty over the
treatment of these patients. The KCL-led research on peginesatide forms
the basis for the KDIGO global anemia guideline recommendation to consider
peginesatide as the potential treatment of choice for pure red cell
aplasia in patients with chronic kidney disease (ref 14 - Chapter 3).
The results of the studies that assessed the general use of peginesatide
in chronic kidney disease patients with anaemia (i.e. those without red
cell aplasia) (11,12) led to initial marketing authorisation for general
use of this drug by the FDA in the USA (15). However, it has subsequently
been withdrawn for this indication by the manufacturers because of cases
of severe allergic reaction (16).
Sources to corroborate the impact
- NICE Guideline 2011. CG114: Anaemia management in people with chronic
- Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group.
KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney
Int. Suppl. 2012;2:279-335.
Chapter 2: Use of iron to treat anemia in CKD references.
Recommendations on "Treatment with Iron agents" cite references 1 and 2.
Recommendations on "Cautions regarding Iron therapy" cite reference 2.
Chapter 3: Use of ESAs and other agents* to treat anemia in CKD.
Recommendations on "In initiating and maintaining ESA therapy..." and on
"ESA Maintenance Therapy" extensively cite ref 4. Recommendations on "ESA
Dosing" cite ref 5. Recommendations on "Type of ESA" cite ref 6.
Recommendation on "Pure red cell aplasia" cite references 9 and 10.
- FDA press release March 27, 2012.
- FDA press release February 23, 2013.