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Received for publication: 4.6.09; Accepted in revised form: 25.9.09
Received for publication: 23.1.09; Accepted in revised form: 6.10.09
Nephrol Dial Transplant (2010) 25: 901–906
doi: 10.1093/ndt/gfp587
Advance Access publication 30 November 2009
Visfatin is increased in chronic kidney disease patients with poor
appetite and correlates negatively with fasting serum amino acids and
triglyceride levels
Juan J. Carrero1,2, Anna Witasp2, Peter Stenvinkel1, Abdul R. Qureshi1, Olof Heimbürger1,
Peter Bárány1, Mohamed E. Suliman3, Björn Anderstam1, Bengt Lindholm1, Louise Nordfors2,
Martin Schalling2 and Jonas Axelsson1
1
Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, 2Department of
Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden and 3King Fahad Medical
City, Riyadh, Kingdom of Saudi Arabia
Correspondence and offprint requests to: Juan Jesús Carrero; E-mail: [email protected]
Abstract
Objective. Anorexia is a common complication of chronic
kidney disease (CKD), while novel animal and human data
suggest a role for visfatin in regulating feeding behavior.
We hypothesized that increased visfatin levels in CKD patients may be involved in the regulation of appetite and nutrient homeostasis.
Methods. This is a cross-sectional study where circulating visfatin levels were analysed in 246 incident CKD
stage 5 patients starting dialysis therapy. The associations
between visfatin (enzyme-linked immunosorbent assay,
ELISA) and anthropometric and biochemical nutritional
status, self-reported appetite, fasting serum amino acids
(high-performance liquid chromatography) and circulating
cytokine levels (ELISAs) were assessed. We also performed genotyping (Pyrosequencing®) of two polymorphisms (rs1319501 and rs9770242) in the visfatin
gene.
Results. Serum visfatin concentrations were not associated with either body mass index or serum leptin.
Across groups with worsening appetite, median visfatin
levels were incrementally higher (P<0.05). With increasing visfatin tertiles, patients proved to be more often anorectic (P<0.05) and to have incrementally lower serum
albumin, cholesterol and triglycerides as well as lower
essential and non-essential serum amino acids (P<0.05
for all). A polymorphism in the visfatin gene was associated with increased circulating visfatin levels and, at
the same time, a higher prevalence of poor appetite
(P<0.05 for both).
Conclusion. Our study suggests novel links between visfatin and anorexia in CKD patients. Based on recent studies,
we speculate that high visfatin in CKD patients may constitute a counter-regulatory response to central visfatin resistance in uremia. Future studies should examine a
putative role of visfatin as a regulator of nutrient homeostasis in uremia.
Keywords: amino acids; anorexia; NAMPT; single-nucleotide
polymorphism
Introduction
Patients with chronic kidney disease (CKD) are prone to
protein-energy wasting (PEW), which is associated with
a poor prognosis [1,2]. The loss of the desire to eat—an-
© The Author 2009. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]
902
orexia—is one of the most common symptoms of uraemic
PEW, and is progressively associated with worse renal
function, higher hospitalization rates and worse outcomes
[3,4]. Visfatin, recently described as a novel adipokine [5],
is also known as nicotinamide phosphoribosyltransferase
(NAMPT) that is a ubiquitously expressed intracellular
protein linked to cellular energy homeostasis, and is the
rate-limiting step for cell synthesis of nicotinamide adenine dinucleotide [6]. Extracellular visfatin was recently
suggested to be upregulated in times of low-nutrient availability [7], regulating appetite in both animal and human
studies [8,9] and promoting cell survival during starvation
[6]. Indeed, as opposed to serum visfatin levels, visfatin
concentrations in human cerebrospinal fluid (CSF) decrease with rising body fat, leading to the hypothesis that
centrally acting visfatin is linked to the development of
obesity, and reduced CSF visfatin or the development of
resistance to its effects may play a role in altered body
weight regulation [10]. Further support for this hypothesis
comes from reports linking rare polymorphisms of the visfatin gene to protection from obesity [11,12].
In uraemia, we have recently reported that circulating
NAMPT/visfatin is a strong predictor of the endothelial
dysfunction commonly found in these patients [13–15].
However, to our knowledge, no studies have yet investigated the putatively metabolic role of visfatin in CKD. In this
hypothesis-generating study, we tested the possible involvement of visfatin in the regulation of appetite and nutrient
homeostasis in patients with CKD. We thus measured circulating visfatin and two polymorphisms of the visfatin
gene in 246 incident CKD stage 5 patients starting dialysis therapy and related the data to subjective and objective
markers of nutrient intake.
J.J. Carrero et al.
Nutritional status
Self-reported appetite is a part of the subjective global assessment questionnaire (SGA) [17], which was recorded at the time of inclusion, concurrent with the drawing of blood samples. We have previously
demonstrated the validity of this self-reported appetite assessment [18]
where all patients were asked to grade their appetite themselves according
to the following scale: 1=good, 2=sometimes bad, 3=often bad and 4=
always bad. In the following analyses, categories 3 and 4 were grouped
together as ‘poor appetite’ for simplification purposes. In some cases, dichotomization into presence or absence (categories 2–4) of appetite loss
was also performed. Body mass index (BMI) was calculated as weight (in
kilograms)/height [2]. Handgrip strength was measured using a Harpenden handgrip dynamometer (Yamar, Jackson, MI, USA) in both the dominant and non-dominant arms. Each measurement was repeated three
times in each arm, and the highest value for each arm was noted. For
our analysis, we used the highest result obtained.
Biochemical measurements
After an overnight fast, venous blood samples were drawn and stored at
−70°C for biochemical analyses. Evaluation of serum visfatin levels was
performed by using a C-terminal (human) enzyme-linked immunosorbent
assay (ELISA) kit from Phoenix Pharmaceuticals Inc. (Belmont, CA,
USA) with a reported sensitivity of 1.89ng/mL. Following the protocol
provided by the manufacturer, the intra-assay variability was <5% and interassay variability was <14%. Plasma amino acid concentrations were
measured with the use of reversed-phase high-performance liquid chromatography and fluorometric detection, as described elsewhere [19].
The routine procedures used in the Clinical Chemistry Laboratory at Huddinge University Hospital were used to measure serum concentrations of
albumin (bromcresol purple), high-sensitivity CRP (hs-CRP, by nephelometry), serum cholesterol and triacylglycerols (Roche Diagnostics
GmbH). The serum concentration of interleukin-6 (IL-6) was measured
with a photometric ELISA (Boehringer Mannheim, Mannheim, Germany). Measurements of soluble vascular cell adhesion molecule-1 and
long pentraxin-3 were also performed with commercial kits (R&D Systems Europe Ltd, Abington, UK and Perseus Proteomics, Tokyo, Japan,
respectively). GFR was estimated as the mean of urea and creatinine
clearance obtained from a 24-h urine collection.
Visfatin genotyping
Methods
Patients
The patients in the present study were included in an ongoing prospective cohort study including incident patients who are beginning dialysis
replacement therapy at the Renal Clinic of the Karolinska University
Hospital Huddinge, Stockholm, Sweden [16]. In the present study, post
hoc analyses of 246 CKD stage 5 patients (151 men) with a median age
of 56years (IQ range: 44–64years) and a median glomerular filtration
rate (GFR) of 6.3mL/min (IQ range: 4.9–7.9mL/min) were conducted.
Exclusion criteria were age >70years, liver dysfunction, clinical signs of
intercurrent infection and unwillingness to participate in the study.
Causes of CKD were chronic glomerulonephritis in 65 patients, diabetic
nephropathy in 77 patients, polycystic kidney disease in 26 patients,
nephrosclerosis in six patients and other or unknown in 72 patients.
In accordance with current therapy recommendations, most of the
patients initially taking oral antiglycaemic agents or on restricted diets
had been switched to insulin therapy at the time of inclusion in the
study. The majority of patients were on antihypertensive medications
(angiotensin-converting enzyme [ACE] inhibitors and/or angiotensin II
receptor antagonists, n=123; beta-blockers, n=143; calcium channel
blockers, n=99) and other commonly used drugs in CKD, such as phosphate and potassium binders, diuretics, erythropoiesis-stimulating
agents, iron substitution and vitamin B, C and D supplementation.
Forty-eight patients (19%) were on lipid-lowering medication (HMGCoA reductase inhibitors). Fifty-seven (23%) patients were taking essential amino acid supplements at the time of inclusion. The protocol was
approved by the Ethics Committee of the Karolinska Institutet at the
Karolinska University Hospital Huddinge, Stockholm, Sweden, and informed consent was obtained from each patient.
We analysed two validated single-nucleotide polymorphisms (SNPs) with
a minor allele frequency of ≥5%: rs1319501 (−423 A/G) and rs9770242
(−1001T/G), as described in the National Center of Biotechnology Information Database (www.ncbi.nlm.nih.gov). Genomic DNA was extracted
from a 5-mL EDTA sample of peripheral blood by using QIAamp DNA
kit (Qiagen, Valencia, CA) in 206 of the patients, while 40 patients lacked
a stored whole blood sample. Samples were stored at −20°C. Primers for
polymerase chain reaction (−423 A/G forward 5′-GGG GAG GAG GAC
GTG ATG-3′ and reverse 5′-TGC CGG GAA CTC GAA CTTA-3′; 1001
T/G forward 5′-CGG GAA GGA AAA GCG AACG-3′ and reverse 5′CGC AAG TCT TTC TTG GAA TGGT-3′) and sequencing primers
(−423 A/G 5′-CTT AGG TAA GCG CCC-3′ and −1001 G/T 5′-TAA
CGA TGA TAA AAG TCA GT-3′) were designed according to the Pyrosequencing Assay Design Software, version 1.0 (Biotage AB, Uppsala,
Sweden), and sequencing was performed on a PSQ 96MA instrument
(Biotage AB) [20]. All oligonucleotides were purchased from Thermo
Electron Corporation (Ulm, Germany). For sample preparation, the PSQ
96 Sample Prep Tool was used. Because calculation of linkage disequilibrium between the two SNPs showed that the −423 and −1001 alleles
were completely linked (D′=1; r2 =0.98), only the results for the −1001 T/
G variant will be shown. Both SNPs fulfilled the assumptions of the Hardy–Weinberg equilibrium in the patient cohort.
Statistical analyses
Normally distributed variables were expressed as means±SDs (unless otherwise noted), and non-normally distributed variables were expressed as
medians and interquartile ranges (IQR). Statistical significance was set at
the level of P<0.05. Comparisons between two groups were assessed with
the Student’s unpaired t-test, Mann–Whitney test or χ2 test as appropriate.
Differences among more than two groups were analysed by the Kruskal–
Visfatin levels and appetite loss in CKD
903
Table 1. Spearman rank correlation coefficients between visfatin and
relevant parameters in 246 CKD stage 5 patients
Parameters
Model 1 (n=246)
Model 2 (n=170)
Age
S-Albumin
BMI
Leptin
NEAAs
EAAs
Cholesterol
Triglycerides
0.14*
−0.17***
−0.02
−0.05
−0.25***
−0.14*
−0.23***
−0.18***
0.15*
−0.12
−0.07
−0.03
−0.25***
−0.14*
−0.25***
−0.18***
*P<0.05; **P<0.01; ***P<0.001. Model 1 considers all patients, whereas model 2 is performed after exclusion of diabetics (n=76). Abbreviations: BMI, body mass index; NEAAs, non-essential amino acids:
EAAs, essential amino acids.
Wallis test. Spearman’s rank correlation (ρ) was used to determine correlations of visfatin with other variables. Fifty-seven (23%) patients were
taking amino acid supplements (receiving a mix of essential amino acids)
at the time of inclusion, but we did not consider this as a confounder since
previous literature reported that the association between visfatin and nutrient intake may be bi-directional [8,9]. Statistical analyses were performed using statistical software JMP, version 7.0.1 (SAS Institute, Cary,
NC). Evaluation of Hardy–Weinberg equilibrium was performed for the
two polymorphisms by using the DeFinetti procedure (http://ihg.gsf.de).
Results
Median serum visfatin concentrations were 31.5 ng/mL
(IQR 23.3–41.8). No differences were observed between
men and women (31.5 [22.3–43.5] vs 32.2 [25.0–42.7]
ng/mL, respectively). However, visfatin levels tended to
be higher in 76 diabetics than in patients without diabetes
(34.1 [27.0–45.0] vs 30.4 [21.2–42.4]ng/mL; P=0.06) and
in 91 patients with previous clinical history of cardiovascular disease (CVD) as compared to those without clinical
signs of CVD (35.5 [24.9–48.4] vs 30.1 [22.4–40.6]ng/
mL; P=0.03). Plasma visfatin levels did not differ between
patients taking or not taking beta-blockers, calcium chan-
nel blockers, ACE inhibitors, statins or amino acid supplements (not shown).
Univariate correlates for circulating visfatin and relevant parameters are included in Table 1, model 1. Visfatin
was positively correlated with age, and no association was
found with fat mass (both BMI and leptin). Negative associations were found for plasma amino acids (both essential and non-essential), blood lipids (cholesterol and
triglycerides) and albumin. Visfatin shared statistically
significant negative associations with several non-essential (asparagine, glutamine, glycine, citrulline, arginine, alanine, ornithine) and essential amino acids (histidine,
tyrosine, methionine, tryptophan, phenylalanine), being
the strongest for arginine (ρ=−0.31; P<0.0001) and histidine (ρ=−0.27; P<0.0001). We also performed the same
correlations excluding diabetic patients (Table 1, model
2), which did not alter the results significantly.
Patients were also divided according to tertiles of visfatin, and the clinical characteristics of each group are
shown in Table 2. Briefly, higher visfatin was associated
with an increased prevalence of diabetes and a greater proportion of patients reporting loss of appetite as well as
lower circulating albumin, cholesterol and triglyceride
concentrations. Data presented in Table 3 show that, with
increasing visfatin tertiles, there was a significant decrease
in most serum non-essential (NEAAs) and essential
(EAAs) amino acid concentrations, resulting in a significant decrease in total serum amino acid levels.
Visfatin levels proved to be higher in patients reporting
poor appetite (Figure 1). No difference in age, sex, GFR,
diabetes or BMI was found across the appetite categories
(data not shown). Across worsening appetite, patients were
more often wasted (SGA>1; P<0.0001) and with a bigger
proportion of patients with a history of CVD (P<0.01). Interestingly, the −1001 T/G (rs9770242) SNP in the upstream region of the visfatin gene was associated with
significantly different visfatin levels (Figure 2A). Patients
carrying one or two T-alleles displayed higher serum visfatin concentrations, and a greater proportion of the pa-
Table 2. Main characteristics, according to tertiles of visfatin, in 246 CKD stage 5 patients
Age (years)
Male gender (%)
GFR (mL/min)
Cardiovascular disease (%)
Diabetes mellitus (%)
Body mass index (kg/m2)
S-Leptin (ng/mL)
Protein-energy wasting (SGA>1, %)
Handgrip strength (kg)
Self-reported loss of appetite (%)
S-Albumin
S-Triglycerides (mmol/L)
S-total cholesterol (mmol/L)
Low
Visfatin ≤26.1ng/mL
Medium
Visfatin=26.1–39.2ng/mL
High
Visfatin ≥39.2ng/mL
n=82
n=82
n=82
P value
51 (43–63)
66
6.5 (5.1–7.9)
29
18
24.3±4.3
13.0 (5.4–25.0)
33
32.4±12.1
42
34.2±6.3
2.4±1.5
5.6±1.5
56 (48–64)
60
6.6 (5.0–7.8)
40
41
24.6±4.0
10.1 (4.5–23.2)
38
29.1±10.4
55
33.0±5.1
2.1±1.2
5.3±1.5
57 (47–65)
58
6.2 (4.5–8.2)
41
34
24.4±4.8
9.6 (4.8–32.0)
43
28.1±11.6
63
31.0±7.2
1.8±1.0
4.8±1.3
ns
ns
ns
ns
<0.001
ns
ns
0.08
ns
<0.05
<0.01
<0.05
<0.001
Mean±SD, median (interquartile range) or percentage. Self reports of appetite categories were dichotomized, grouping together any report of appetite
loss (categories 2–4, see Methods).an=65/68/71.
904
J.J. Carrero et al.
Table 3. Plasma amino acid concentration according to tertiles of visfatin in 246 CKD patients
Low
Visfatin≤26.1ng/mL
Medium
Visfatin=26.1–39.2ng/mL
High
Visfatin≥39.2ng/mL
n=82
n=82
n=82
Non-essential amino acids (NEAAs)
Glutamic acid
49 (34–76)
Asparagine
50 (43–69)
Serine
95 (79–109)
Glutamine
573 (506–651)
Glycine
265 (152–742)
Citrulline
84 (74–102)
Arginine
94 (78–116)
Alanine
335 (259–407)
Taurine
57 (42–73)
Ornithine
80 (62–99)
42
46
92
516
242
81
91
310
49
73
Essential amino acids (EAAs)
Histidine
78 (67–93)
Threonine
108 (88–129)
Tyrosine
40 (31–47)
Lysine
150 (130–171)
Methionine
23 (20–30)
Tryptophan
21 (17–28)
Phenylalanine
53 (44–64)
Valine
149 (127–180)
Isoleucine
55 (44–63)
Leucine
71 (57–88)
Sum of NEAAs
1740 (1545–2002)
Sum of EAAs
774 (683–890)
Sum of all AAs
2519 (2242–2856)
76
105
36
149
24
21
52
158
55
66
1645
764
2420
(27–65)
(37–56)
(73–114)
(455–641)
(102–832)
(65–103)
(66–110)
(230–427)
(32–73)
(55–96)
(64–94)
(81–150)
(31–44)
(113–177)
(16–31)
(16–28)
(43–60)
(127–193)
(41–70)
(55–85)
(1372–1939)
(636–902)
(2062–2822)
40
42
86
527
247
72
73
289
48
67
61
100
34
140
20
18
47
144
55
63
1601
713
2292
Significance (P)
(27–62)
(34–52)
(68–108)
(432–619)
(117–869)
(59–94)
(61–92)
(218–377)
(37–72)
(50–87)
ns
<0.001
ns
<0.01
ns
<0.001
<0.0001
<0.05
ns
<0.05
(55–82)
(76–136)
(26–42)
(114–173)
(16–25)
(14–23)
(39–57)
(119–172)
(39–68)
(49–82)
(1305–1789)
(587–862)
(1893–2619)
<0.0001
ns
<0.01
ns
<0.01
<0.01
<0.05
ns
ns
ns
<0.001
<0.05
<0.001
Data are presented as median (interquartile range).
90
80
P=0.02
Visfatin (ng/mL)
70
60
50
40
30
20
10
0
Good
appetite
Bad
appetite
Poor
appetite
Fig. 1. Differences in plasma visfatin concentration among three selfreported appetite categories in 246 CKD patients. Good appetite, n=
113; bad appetite, n=68; poor appetite, n=65. Non-parametric Kruskal–
Wallis test was used to denote differences among the groups considered.
tients with G/T or T/T genotypes reported appetite loss
(Figure 2B).
Discussion
In a cross-sectional study of patients with advanced CKD,
we report that elevated circulating visfatin is associated
with self-reported appetite loss and decreased circulating
levels of amino acids and triacylglycerols. Furthermore,
a gene polymorphism associated with increased circulating
visfatin was also found to be related to appetite loss.
As anorexia is common in CKD, correlates of a poor
appetite are of interest. In the present study, a high circulating visfatin was associated with a decreased appetite. A
role for visfatin in appetite regulation has not been previously suggested in CKD, but it was recently reported that a
hypocaloric diet in pre-menopausal women results in an
increase of visfatin mRNA expression in adipose tissue
[21], whereas 7 days of overfeeding reduced circulating
visfatin by 20% in a cohort of healthy men [9]. Additionally, animal studies have shown that visfatin is elevated
and acts as an important regulator of cell survival in fasting rodents [6], while intracerebral visfatin injections induce feeding behavior in chicks [8]. These data have
found a human correlate with a recent paper reporting that
visfatin concentrations in human CSF decrease with rising
body fat, while circulating visfatin levels increase, leading
to the speculation that visfatin resistance or reduced intracerebral accumulation may be pathophysiologically linked
to obesity [10]. In the present study, serum visfatin concentrations were considerably higher than those reported by
Hallschmid et al. [10] in healthy and obese subjects but still
related to both objective markers of nutrient intake and to
self-reported appetite. Indeed, high circulating visfatin levels were associated with low fasting blood triacylglycerols, low total cholesterol and low systemic levels of
Visfatin levels and appetite loss in CKD
905
Visfatin (ng/mL)
90
80
A
70
P=0.009
60
50
40
30
20
10
0
% patients reporting loss of
appetite
G/G
G/T
T/T
G/T
Visfatin -1001 G/T
T/T
70
60
50
B
P= 0.04
40
30
20
10
0
G/G
Fig. 2. Differences in (A) plasma visfatin concentrations and (B) selfreported loss of appetite between the three visfatin genotype groups in
206 CKD stage 5 patients with available genotypes (rs9770242: −1000
G/T). The sample distribution among the genotypes is: G/G, n=13; G/
T, n=75; T/T, n=118. Non-parametric Kruskal–Wallis test was used to
denote differences among the groups considered. Self reports of
appetite were dichotomized into presence or absence of appetite loss
(see Methods).
serum amino acids, especially NEAAs. This latter finding
may be explained by earlier studies that have shown that
NEAAs in the circulation are higher in well-nourished
CKD stage 5 patients [22], perhaps due to a selective decrease in splanchnic NEAA uptake [23]. Our results are also similar to and complementary of the findings by Sun et
al. [9], who found that fasting visfatin concentrations were
associated with serum triacylglycerols in healthy men.
Appetite is a short-term sensation that determines subsequent food intake [3,4] and, together with measures of
fasting amino acids or lipids (indirectly reflecting immediate dietary intake), should not be confused with markers of
long-term starvation. In our study, increased visfatin levels
relate with such markers of short-term intake but not with
BMI, handgrip strength or SGA, which are likely the consequence of a prolonged period of wasting/starvation leading to a state of PEW. In fact, in accordance with our
results, several well-powered observational studies have
found no apparent changes in surrogate markers of PEW,
including BMI (which is also influenced by hydration status), muscle mass and handgrip strength, across different
self-reported appetite categories in haemodialysis patients
[24,25], although in each of these studies poor appetite significantly predicted a poor outcome [24,25]. Interestingly,
patients in the present study that reported a decreased appetite also had elevated serum visfatin concentrations and car-
ried one or two copies of the T-allele of the −1001 T/G
(rs9770242) variant in the upstream region of the visfatin
gene. This polymorphism, which is in complete linkage
disequilibrium with the rs1319501 variant, has been previously associated with increased insulin sensitivity [26] and
serum visfatin concentrations [13]. In support of our findings, rare variants in the visfatin gene have also been reported to be associated with body weight [11,12].
While our data would seem to encourage further investigation into the role of visfatin in uraemic anorexia,
several important weaknesses should be discussed. First,
the cross-sectional design precludes the inference of causality, and our results are based on a relatively small cohort. Furthermore, a self-reported appetite questionnaire
such as the one we used is potentially influenced by subjective and psychological factors, but a number of recent
studies have validated this simple approach in dialysis patients [18,24,25,27], observing a consistent agreement
with more classical methods of appetite assessment, including visual analogue scales [28]. Finally, and given visfatin’s ubiquitous expression [6], it is not surprising that
the present study, like most [13–15,29] but not all [30] recent reports in dialysis patients, failed to find any association of visfatin with BMI or visceral fat. Our study also
did not show an association with leptin. Thus, it may be
inaccurate to refer to visfatin as an adipokine or even a
pseudo-adipokine.
In summary, we report novel associations between visfatin and both subjective assessment of appetite and biochemical markers reflecting nutrient intake in incident
CKD stage 5 patients. Based on recent studies in non-uremic individuals, we speculate that a high serum visfatin in
CKD patients may constitute a counter-regulatory response to central visfatin resistance or, alternatively, resistance to other unmeasured orexigenic compounds that
accumulate in uremia. Future studies should examine a putative role of visfatin as a regulator of nutrient homeostasis
in uremia.
Acknowledgements. We would like to thank the patients and personnel
involved in the creation of this cohort. We are especially indebted to our
research staff at KBC (Annika Nilsson, Ann-Kristin Emmot and Ulrika
Jenson) and KFC (Björn Anderstam, Monica Ericsson and Ann-Kristin
Bragfors-Helin). We benefited from financial support from the Karolinska
Institutet Center for Gender-based Research, KI/SLL research funds, the
Swedish Society for Medical Research, the Swedish Heart and Lung
Foundation, the Swedish Medical Research Council, Swedish Kidney Association, Loo and Hans Ostermans’ and Westman’s foundations, Scandinavian Clinical Nutrition AB and the GENECURE project (EU grant
LSHM-CT-2006-037697). Baxter Novum is the result of an unconditional
research grant from Baxter to the Karolinska Institutet.
Conflicts of interest statement. B.L. is an employee of Baxter Healthcare
Inc., while J.A. is the recipient of honoraria from Baxter and Gambro, as
well as a research grant from Sanofi-Aventis. None of the other authors
have any conflict of interest to declare.
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Received for publication: 23.1.09; Accepted in revised form: 6.10.09
Received for publication: 18.3.09; Accepted in revised form: 13.10.09