Nephrol Dial Transplant (2010) 25: 2846–2850

doi: 10.1093/ndt/gfq336
Advance Access publication 29 June 2010

Editorial Reviews

Target haemoglobin to aim for with erythropoiesis-stimulating agents: a

position statement by ERBP following publication of the Trial to Reduce
Cardiovascular Events with Aranesp® Therapy (TREAT) Study

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Francesco Locatelli1, Pedro Aljama2, Bernard Canaud3, Adrian Covic4, Angel De Francisco5,
Iain C. Macdougall6, Andrzej Wiecek7, Raymond Vanholder8 and On behalf of the Anaemia Working
Group of European Renal Best Practice (ERBP)
1
Department of Nephrology, Dialysis and Renal Transplant, “Alessandro Manzoni” Hospital, Lecco, Italy, 2Department of Nephrology,
University Hospital Reina Sofía, Cordoba, Spain, 3Nephrology, Dialysis and Intensive Care Department. Lapeyronie University
Hospital, Montpellier, France, 4University “Gr. T. Popa” Iasi and Hospital “C. I. Parhon” Iasi, Romania, 5Department of Nephrology
Hospital Universitario Valdecilla, Santander, Spain, 6Department of Renal Medicine, King’s College Hospital, London, UK,
7
Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland and
8
Nephrology Section, Department of Internal Medicine, University Hospital, Ghent, Belgium
Correspondence and offprint requests to: Francesco Locatelli; E-mail: nefrologia@ospedale.lecco.it

Abstract These recommendations are not intended to represent a

The European Renal Best Practice (ERBP), which are is-
sued by ERA–EDTA, are suggestions for clinical practice
in areas in which evidence is lacking or weak, together with
position statements on recently published randomized con-
trolled trials, or on existing guidelines and recommenda-
tions. In 2009, the Anaemia Working Group of ERBP
published its first position statement about the haemoglobin
target to aim for with erythropoietin-stimulating agents
(ESA) and on issues that were not covered by K-DOQI in
2006–07. This second position paper of the group follows
the publication of the Trial to Reduce Cardiovascular Events
with Aranesp® Therapy (TREAT) Study. This multi-centre,
placebo-controlled trial compared cardiovascular and renal
outcomes in 4038 patients with type 2 diabetes, chronic
kidney disease not on dialysis, and anaemia who were ran-
domized to complete anaemia correction (haemoglobin tar-
get of 13 g/dL using darbepoetin alfa) or placebo (with a
haemoglobin rescue value of 9 g/dL).
Following the findings of the TREAT study, the Anaemia
Working Group of ERBP maintains its view that ‘Hb values
of 11–12 g/dL should be generally sought in the CKD
population without intentionally exceeding 13 g/dL’ and
that the doses of ESA therapy to achieve the target haemo-
globin should also be considered. More caution is sug-
gested when treating anaemia with ESA therapy in
patients with type 2 diabetes not undergoing dialysis (and
probably in diabetics at all CKD stages). In those with
ischaemic heart disease or with a previous history of stroke,
possible benefits should be weighed up against an in-
creased risk of stroke recurrence, when deciding which
Hb level to aim for.
new guideline as they are not the result of a systematic
review of the evidence.
Keyword: anemia; chronic kidney disease; diabetes; erythropoiesis
stimulating agents; stroke
Introduction (aim and scope)
Some years ago, the nephrological community planned a
single set of international guidelines under the aegis of
Kidney Disease Improving Global Outcomes (KDIGO)
[1]. Consequently, the ERA–EDTA agreed to issue after-
wards only suggestions for clinical practice in areas in
which evidence is lacking or weak, together with position
statements on recently published randomized controlled
trials (RCTs), or on existing guidelines and recommenda-
tions issued by other bodies or previous European Best
Practice Guidelines (EBPG) [2]. Following the publication
of KDOQI guidelines about anaemia in 2006/2007 [3,4],
the Anaemia Working Group of European Renal Best
Practice (ERBP) published its first position statement
[5], giving its opinion on the ‘hot’ topic of haemoglobin
(Hb) targets and on recently raised issues that were not
covered by KDOQI in 2006 [3].
The aim of this second position statement on anaemia is
to give guidance on the interpretation of the recently pub-
lished Trial to Reduce Cardiovascular Events with Aranesp®
Therapy (TREAT) Study [6], and its possible relevance to
recommended treatments and Hb targets to be used when
treating chronic kidney disease (CKD) patients with
erythropoiesis-stimulating agents (ESA) therapy, while

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For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Nephrol Dial Transplant (2010): Editorial Reviews
awaiting the publication of KDIGO anaemia guidelines
(probably sometime in the first half of 2011).
This paper is not intended to represent a new guideline
as it is not the result of a systematic review of the evidence.
Current guidelines
The last revision of EBPG relating to the management of
anaemia in patients with CKD was published in 2004 [7].
This document contains the following recommendations
on the appropriate haemoglobin targets for anaemia
treatment:
(i) ‘Guideline II: 1) In general, patients with chronic kidney
disease (CKD) should maintain a target Hb concentra-
tion of >11 g/dL. 2) Exact target Hb concentrations
>11 g/dL should be defined for individual patients,
taking gender, age, ethnicity, activity and co-morbid
conditions into account. In HD patients, pre-dialysis
Hb concentrations above 14 g/dL are not desirable due
to the risks associated with the effects arising from post-
dialysis haemoconcentration (Evidence level C).’
(ii) ‘Guideline III. The optimal target Hb concentration
may vary in patients with significant co-morbidity:
(a) Hb concentrations >12 g/dL are not recommended
for patients with severe cardiovascular disease (class
III and above of the New York Heart Association
Classification of Congestive Heart Failure) unless
continuing severe symptoms (e.g. angina) dictate
otherwise (Evidence level A).
(b) Until data become available, it seems prudent to rec-
ommend a cautious approach to raising Hb concen-
trations to levels >12 g/dL in patients with diabetes,
especially with concurrent peripheral vascular dis-
ease (Evidence level C).
(c) Patients with chronic hypoxaemic pulmonary disease
may benefit from a higher Hb target (Evidence
level C).’
After the publication of the Correction of Hemoglobin
and Outcomes in Renal Insufficiency (CHOIR) [8] and
the Cardiovascular Reduction Early Anemia Treatment
Epoetin beta (CREATE) [9] trials, the NKF-KDOQI work-
ing group in 2007 reformulated its recommendations by
stating that the Hb target in patients receiving ESAs should
generally be 11–12 g/dL, and not intentionally >13 g/dL
because ‘the possibility of causing harm weighs more
heavily than the potential of improving the quality of life
and decreasing transfusions’.
In 2009, the ERBP Group substantially agreed with the
recommendation of KDOQI Hb target update [4] and took
the following position about the Hb target range:
‘In the opinion of the ERBP Work Group, it appears
reasonable to maintain the lower limit of the target,
although the actual evidence for choosing this value
is also very limited. On the basis of new evidence,
Hb values of 11–12 g/dL should be generally sought
2847
in the CKD population without intentionally exceed-
ing 13 g/dL’ [5].
This position was in line with that of KDIGO about this
matter published in 2008 [10].
The rationale for this was that available evidence
showed possible harm or, at best, no effect when aiming
for higher Hb targets, without any clear benefit on quality
of life. The ERBP group acknowledged that it is difficult
to keep patients within a narrow target window mainly be-
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cause of Hb variability. A better understanding of the me-
chanisms leading to increased thrombosis and death while
attempting to reach higher Hb values in patients with co-
morbidities or those who are hyporesponsive to ESA was
considered of importance.
The TREAT Study
The TREAT Study is the largest study performed to date,
testing the hypothesis whether a complete anaemia correc-
tion, using darbepoetin alfa, may improve outcome and
quality of life in patients with type 2 diabetes and CKD.
Its results were published in November 2009 [6]. This mul-
ticentre, placebo-controlled trial compared cardiovascular
(death, non-fatal myocardial infarction, congestive heart
failure, stroke or hospitalization for myocardial ischaemia)
and renal (end-stage renal disease and death) outcomes in
4038 patients with type 2 diabetes, chronic kidney disease
not on dialysis, and anaemia. TREAT was an event-driven
trial, designed with the notion that treatment of anaemia in
the early phase of CKD might produce the best results. A
large separation between achieved Hb levels in the two
groups, together with a large sample size, was planned
in order to provide adequate statistical power.
After a median follow-up of 29.1 months, the primary
cardiovascular composite end point occurred at a similar
rate in the two groups (hazard ratio for darbepoetin alfa
vs. placebo, 1.05; 95% CI, 0.94–1.17; P=0.41). Similar
findings were obtained with the other primary end point
(death or end-stage renal disease). Analysis of single com-
ponents of the composite end point showed an increased
risk of fatal or non-fatal stroke in the patients with a pre-
vious history of stroke, assigned to darbepoetin alfa and a
Hb target of 13 g/dL. Safety data also indicated a higher
frequency of death from malignancy (in patients with a
previous history), and venous and arterial thromboembol-
ic events in this group. Conversely, cardiac revasculariza-
tion procedures were performed less frequently in the
darbepoetin alfa than in the placebo group. Effects on
quality of life were modest favouring complete anaemia
correction.
Interpretation and evidence level
Intention-to-treat analyses of primary composite end
points showed a neutral effect of complete anaemia correc-
tion (Hb = 13 g/dL) with darbepoetin alfa compared to pla-
cebo (evidence of level A, high grade). Half of the patients
2848
in the control group, however, received active treatment,
albeit at a very low dose, at some point during follow-up
because of Hb levels <9 g/dL, and were treated more often
with intravenous iron and blood transfusions. Their Hb
levels increased from a baseline value of 10.4 g/dL to an
end-trial value of 11.2 g/dL (median value 10.6 g/dL) mak-
ing the true definition of a placebo group questionable [11].
Data from secondary analyses of the TREAT Study
(moderate or low grade of evidence) cause concern and
reinforce the recommendation of previous EBPG guide-
lines [7] that caution is needed when correcting anaemia
in patients with diabetes. On the other hand, the mean dose
of darbepoetin alfa was ∼175 μg/month in the experimental
group, a dose which is several times higher than that of the
same patient population in Europe, and about twice the
mean dose in haemodialysis patients in Europe. This sug-
gests that the risk factor could be more linked to ESA resist-
ance than the achieved Hb concentration per se, as has also
been suggested by a secondary analysis of the CHOIR
Study [12].
The interpretation of the TREAT Study is further com-
plicated by the results of another recent secondary analysis
of the CHOIR Trial [13]: in an unadjusted model, patients
with diabetes did not have a greater hazard associated with
the higher Hb target. No increased risk associated with the
higher Hb target was found also among patients with heart
failure.
Even if numbers are small, the unexpected finding of
increased death rate from malignancies in patients with a
previous history of cancer who were randomized to darbe-
poetin alfa and a complete anaemia correction (low grade
of evidence) are consistent with concerns raised about the
use of ESA about increased tumour growth and death in
the setting of oncology in some types of cancer (especially
when used off-label) [14].
Conclusions and guidance
Haemoglobin target
The TREAT Study provides high-quality scientific evidence
to inform guidelines groups, regulatory authorities and the
nephrological community about how to manage CKD an-
aemia. It is relevant specifically in relation to guiding the
optimum use of ESA therapy in the CKD population, and
is not relevant for patients not receiving ESA therapy, or
who are being only treated with oral or IV iron. Thus, the
data from this study are not relevant for CKD patients
who have a spontaneously high haemoglobin of 13 g/dL
or greater without supplemental ESA therapy (e.g. those
with polycystic kidney disease), or those whose anaemia
is being managed with iron alone.
The TREAT Study was conducted in CKD patients with
type 2 diabetes, and the debate now is whether the data can
only inform anaemia management in this specific patient
population. Some scientific purists might argue that evi-
dence from the TREAT Study is applicable only to patients
with type 2 diabetes and CKD stages III to IV. Others will
argue that, although the TREAT Study was conducted in
type 2 diabetics, the results on strokes and malignancies
Nephrol Dial Transplant (2010): Editorial Reviews
(although secondary analyses) are concordant with a large
body of other evidence, such as that obtained from the US
Normal Hematocrit Trial [15] and the CHOIR Study [12],
not to mention multiple oncology trials, all of which sug-
gest possible concerns about increased thrombogenicity
with ESA therapy when targeting higher Hb levels than
suggested by present guidelines. At the very least, greater
caution should be exerted in using high ESA doses, and
targeting Hb levels >12 g/dL, in type 2 diabetics [16,17].
Although there is no ‘grade A’ evidence to suggest that
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possible concerns about thrombotic adverse events are
dose-related, post hoc analyses from both the US Normal
Hematocrit Trial [15] and the CHOIR Study [12] suggested
that the patients who had the worse outcomes were those
who were the most resistant to treatment, and who were re-
ceiving the highest doses of ESA. Thus, while this ERBP
group still maintains a view that ‘Hb values of 11–12 g/
dL should be generally sought in the CKD population with-
out intentionally exceeding 13 g/dL [5], their opinion is that
the doses of ESA therapy to achieve this level of target
haemoglobin should also be considered. If a patient can ob-
tain a Hb of 11.5 g/dL on no or low doses of ESA therapy,
then there is less cause for concern than with a patient who is
requiring very high doses of ESA therapy to achieve this Hb.
The ERBP group also feels that it is reasonable to
suggest that:
(i) In patients with type 2 diabetes not undergoing dialy-
sis (and probably in diabetics at all CKD stages), more
caution is needed when treating anaemia with ESA
therapy. In diabetic patients with a history of stroke,
a lower target is more sensible (10–12 g/dL), balan-
cing the risk–benefit of treatment and the desired
Hb target in the individual patient. It is also of para-
mount importance to involve the patient in the deci-
sion making, and seek their personal views after a
discussion about the benefits/risks of treatment. On
this respect, the patient’s opinion should be carefully
taken into consideration [18].
(ii) The risk–benefit of increased transfusions should also
be considered carefully, especially for patients eligible
for transplantation.
(iii) In diabetic patients with ischaemic heart disease or with
a previous history of stroke, possible benefits of re-
duced need for coronary revascularization procedures
and transfusions should be weighed up against an in-
creased risk of stroke recurrence, when deciding which
Hb level to aim for, and use of the lowest possible doses
of ESA appears reasonable.
(iv) In patients with CKD and a previous history of cancer,
the risk of tumour recurrence and related death should
be considered when deciding whether or not to start
ESA treatment. Again, in these patients, the lowest
possible doses of ESA should be used.
Treatment of renal anaemia
Broadly speaking, anaemia management consists of ESA
therapy, iron supplementation and red cell transfusions.
Avoidance of the latter is particularly important in patients
Nephrol Dial Transplant (2010): Editorial Reviews
eligible for renal transplantation where exacerbation of
HLA sensitization should be avoided. Other potential ha-
zards of blood transfusions are well known. The TREAT
Study reinforces the message of anaemia guidelines sug-
gesting the importance of an integrated approach using iron
and ESA therapy. It is still a matter of debate how much iron
can safely be given to patients in order to minimize the ESA
dose and what the highest doses of IV iron and ESA are that
can safely be administered for reaching and maintaining a
Hb target range. In this respect, the definition of ESA resist-
ance (i.e. a continued need for >20 000 IU/week of recom-
binant human erythropoietin, or 300 IU/kg/week, or
equivalent [7]) could be helpful. The use of IV iron therapy
should also be balanced against the risk of compromising
veins in the light of possible future vascular access for
haemodialysis. In relation to this, the ERBP group suggests
the following:
(i) Iron administration is an important factor for the suc-
cessful treatment with any kind of ESA, in order to
use the lowest dose for reaching and maintaining
the desired Hb target.
(ii) ESA treatment should not be started in patients who
are iron-deficient.
(iii) Iron replacement should be used first in any CKD
patient who is proven or likely to be iron-deficient,
and only once the iron stores are replete should ESA
therapy be initiated.
(iv) In CKD patients, ESA treatment should be considered
when Hb levels are consistently (i.e. measured twice at
least 2 weeks apart) below 11 g/dL (possibly < 10 g/dL
in patients with type 2 diabetes and with a history of
strokes), and all other causes of anaemia have been
excluded; the threshold for treatment should be
decided according to patient characteristics and symp-
toms, and the desired Hb target.
(v) ESA treatment should be started at a low dose, to
avoid overshooting to high Hb levels; dose adjust-
ments should be made smoothly in the following
months in order to avoid too rapid increases in Hb
levels (Hb increases of >2 g/dL per month should
be avoided if possible).
(vi) The use of high ESA doses in patients who are hy-
poresponsive to treatment should be carefully evalu-
ated; increased cardiovascular risk should be weighed
against the possible benefits of anaemia correction. It
seems wise to avoid progressively increasing the
ESA dose in those patients who do not respond to
treatment as expected or in whom it is obvious that
worsening of anaemia is linked to non-renal factors.
(vii) The risk–benefit of red cell transfusions should be
considered carefully, especially for patients eligible for
transplantation.
Acknowledgements. F.L., A.C., A.W. and R.V. are members of the ERBP
Advisory Board. Other members of the ERBP Advisory Board are D.
Abramovicz, J. Cannata-Andia, P. Cochat, K. U. Eckardt, D. Fouque, O.
Heimburger, K. J. Jäger, S. Jenkins, E. Lindley, G. London, A. MacLeod,
A. Marti-Munros, G. Spasovski, J. Tattersall, W. van Biesen, C. Wanner
2849
and C. Zoccali. This document has been approved by the Advisory Board
of ERBP and by the ERA–EDTA Council.
Disclaimer. The present text is based upon the information available to
the work group at the moment of the preparation of this publication. It
has been designed to provide information and assist decision making,
but is not intended to define a standard of care or to improve an exclu-
sive course of diagnosis, prevention or treatment. It is not the product of
an evidence-based review, and should not be considered as an evidence-
based guideline. Individual decision making is essential in the approach
to any disease, including CKD anaemia. Variations in practice are inev-
itable when physicians take into account individual patient needs, avail-
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able resources, and limitations specific for a geographic area, country,
institution or type of practice. In addition, evidence may change over
time as new information becomes available, so that practice may be
modified subsequently. Every practitioner using this text is responsible
for its application to any particular clinical situation. The work group
members involved in the development of the present text have disclosed
all actual and potential conflicts of interest that may arise as a result of
an outside relationship or a personal, professional or business interest.
Conflict of interest statement. F.L is a member of an advisory board of Af-
fymax, Amgen-Dompé, Merck, Janssen–Cilag and Roche, and of a safety
committee of Sandoz. P.A. has received research grants and been a member
of Advisory Boards of Amgen, Roche, Takeda and Janssen-Cilag. B.C. has
received honoraria for lectures for Amgen, Roche, Janssen-Cilag, Vifor,
Fresenius and Bellco. A. C. is on the speaker bureau for Amgen and Roche.
A.D.F. has received consulting fees from Amgen, Fresenius and Roche, and
lecture fees from Amgen, Abbott,Shire, Vifor and Roche. I.C.M. has re-
ceived lecture fees and honoraria from Amgen, Ortho Biotech, and Roche,
and consultancy fees from Amgen, Ortho Biotech, Roche, Affymax, Hos-
pira, and Sandoz. A.W. has received travel grants and honoraria for lectures
from Janssen-Cilag, Roche and Amgen, and serves as an Advisory Board
Member for Affymax and Hospira. The unit of R.V. has received unrestrict-
ed research grants from Amgen and Hoffmann La Roche. R.V. has received
honoraria for presentations from Amgen.
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Nephrol Dial Transplant (2010) 25: 2850–2865

doi: 10.1093/ndt/gfq313
Advance Access publication 3 June 2010

The expanding spectrum of biological actions of vitamin D

Jorge Rojas-Rivera1,2, C. De La Piedra3, Ana Ramos1, Alberto Ortiz1,4 and Jesús Egido1,4
1
IIS-Fundación Jimenez Diaz, Division of Nephrology and Hypertension, Laboratory of Experimental Nephrology and Vascular
Pathology, Madrid, Spain, 2International Fellowship Program of International Society of Nephrology (ISN), Global Operations Center,
Rue du Luxembourg 22-24, B-1000, Brussels, Belgium, 3Biochemistry Laboratory, Fundación Jimenez Diaz, Madrid, Spain and
4
Universidad Autonoma de Madrid, Madrid, Spain
Correspondence and offprint requests to: Jorge Rojas-Rivera; E-mail: jerori2003@yahoo.com
Research support: International Society of Nephrology (ISN)—International Fellowship Program to Jorge Rojas-Rivera. ISCII grants RETIC/
REDINREN 06/0016 and PS09/00447 to Alberto Ortiz.

Keywords: cardiovascular outcomes; nephroprotection; non-calciotropic

actions; renal outcomes; vitamin D deficiency
Vitamin D

Vitamin D2 (ergocalciferol) is obtained from certain food

Introduction
The vitamin D hormonal system was classically implicated
in the regulation of calcium homeostasis and bone metabol-
ism. However, it also has extra-mineral metabolism func-
tions through activation of non-renal vitamin D receptor
(VDR) [1]. Vitamin D deficiency is an increasingly recog-
nized public health problem in the general population and in
chronic inflammatory disorders such as chronic kidney dis-
ease (CKD) [2,3]. Newly uncovered actions of the vitamin
D hormone system could underlie the impact of vitamin D
deficiency and supplementation on prognosis in CKD and
non-CKD patients.
We review emerging extra-mineral metabolism functions
of vitamin D from a translational perspective, highlighting
recent information on vitamin D deficiency, replacement
therapy, pathogenesis, and outcomes in cardiovascular,
inflammatory and renal disease.
and, principally, from vitamin supplements. Vitamin D3
(VD3, cholecalciferol) is present in food and vitamin sup-
plements, but is mainly generated by skin exposed to
ultraviolet B radiation: 7- and 8-dehydrocholesterol are
converted by photolysis to pre-VD3 and then by thermal
isomerization, to VD3. This pro-hormone is converted to
25-hydroxycholecalciferol [25(OH)D] in the liver by
25-hydroxylase (CYP2R1). Plasma levels of 25(OH)D in-
crease proportionally to vitamin D intake and are used to
determine vitamin D status [1]. The majority of circulat-
ing 25(OH)D is bound to vitamin D-binding protein
(DBP), which is filtered by the glomerulus and taken
up by proximal tubular cells via megalin-mediated endo-
cytosis. In proximal tubules, 25(OH)D is activated to
1,25-dihydroxycholecalciferol [1,25(OH)D] (calcitriol)
by 1-α-hydroxylase (CYP27B1), an activity highly regu-
lated by the Ca +2 –phosphorus–parathyroid hormone
(PTH) axis [4]. Vitamin D is slowly (5–7 days) activated
to 25(OH)D, which has a half-life of ∼15 days, while the

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For Permissions, please e-mail: journals.permissions@oxfordjournals.org