Nephrol Dial Transplant (2011) 26: 3537–3543

doi: 10.1093/ndt/gfr081
Advance Access publication 4 March 2011

Vascular health, systemic inflammation and progressive reduction in

kidney function; clinical determinants and impact on cardiovascular
outcomes

Mahmut Ilker Yilmaz1, Peter Stenvinkel2, Alper Sonmez3, Mutlu Saglam4, Halil Yaman5, Selim Kilic6,
Tayfun Eyileten1, Kayser Caglar1, Yusuf Oguz1, Abdulgaffar Vural1, Mustafa C
xakar7, Battal Altun7,

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1
Mujdat Yenicesu and Juan Jesus Carrero2,8,9
1
Department of Nephrology, Gülhane School of Medicine, Ankara, Turkey, 2Division of Renal Medicine, Karolinska Institutet,
Sweden, 3Department of Endocrinology, Gülhane School of Medicine, Ankara, Turkey, 4Department of Radiology, Gülhane School of
Medicine, Ankara, Turkey, 5Department of Biochemistry, Gülhane School of Medicine, Ankara, Turkey, 6Department of
Epidemiology, Gülhane School of Medicine, Ankara, Turkey, 7Department of Internal Medicine, Gülhane School of Medicine, Ankara,
Turkey, 8Centre for Molecular Medicine, Karolinska Institutet, Sweden and 9Centre for Gender Medicine, Karolinska Institutet, Sweden
Correspondence and offprint requests to: Juan Jesus Carrero; E-mail: Juan.Jesus.Carrero@ki.se

Summary of key findings of the article
Introduction. Systemic inflammation, endothelial
dysfunction and arterial thickening contribute to the
elevated cardiovascular risk of dialysis patients. How-
ever, the course of these derangements and their
relative contribution to the cardiovascular risk of nondia-
lysed chronic kidney disease (CKD) are scarcely
investigated.
Methods. Flow-mediated dilatation (FMD) and intima-
media thickness (IMT) were assessed in 304 nondialysed
CKD patients Stages 1–5 (mean age 46 6 12 years, 158
men), together with routine biochemical measurements,
C-reactive protein (CRP) and insulin resistance. Patients
were then followed for time-to-event analysis of cardiovas-
cular outcomes (fatal and nonfatal).
Results. CRP and IMT increased, while FMD decreased in
parallel with estimated glomerular filtration rate (eGFR)
decline (P < 0.001 for all). CRP and intact parathormone,
as well as eGFR, appeared as strong determinants of FMD
and IMT in multivariate analyses. After a median follow-up
of 41 (range 6–46) months, 30 fatal and 59 nonfatal car-
diovascular events occurred. In univariate analysis, FMD,
IMT and CRP were significant predictors of outcome. In a
multivariate Cox model excluding IMT, both FMD [hazard
ratios 0.52 (95% confidence intervals 0.37–0.73) per %]
and CRP [1.07 (1.03–1.11) per mg/L] predicted cardiovas-
cular outcomes independently of confounders. In a model
excluding FMD, only CRP (and not IMT) was a significant
predictor.
Conclusions. Endothelial dysfunction, arterial thickening
and inflammation occur in parallel with the decline in
eGFR, contributing to the increased cardiovascular risk of
nondialysed CKD. Our results support the use of FMD over
IMT measurements to monitor nondialysed CKD patients
at risk.

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Keywords: cardiovascular; C-reactive protein; flow-mediated dilatation;
intima-media thickness
Introduction
Chronic kidney disease (CKD) is an escalating worldwide
public health problem [1]. Progression towards end-stage
renal disease (ESRD) exposes patients to increased risk of
developing premature vascular disease and cardiovascular
morbidity, thus contributing to exceedingly high mortality
rates [2]. In fact, cardiovascular disease (CVD) and death
are a more likely outcome in subjects with CKD than
progression to ESRD and subsequent initiation of renal
replacement therapy [3].
The mechanisms for the elevated CVD risk in early CKD
are complex and may, in addition to classical Framingham
risk factors, include systemic inflammation, oxidative
stress and endothelial dysfunction [4]. While the relevance
of inflammation and vascular health in the morbidity and
mortality of dialysis patients has been largely investigated
[5–10], less attention has been given to their respective
roles in early-moderate CKD. Endothelial dysfunction in-
creases in prevalence as renal function declines and is con-
sidered an obligatory prodromal phase in the
atherosclerosis that precedes cardiovascular complications
[11]. Endothelial dysfunction, as assessed by flow-medi-
ated dilatation (FMD), has been associated to progressive
kidney failure, CVD, anaemia, inflammation and oxidative
stress [12–17]. Studies on vascular health using carotid
artery intima-media thickness (IMT) in early-moderate
CKD have shown associations with declining kidney func-
tion and future CVD [18–22]. However, existing evidence
is limited by community-based studies or studies with
3538
reduced sample size, selected individuals or restricted to
moderate CKD stages only.
The prevalence of systemic inflammation also rises across
progressive CKD and is believed to promote atherogenesis
[23, 24]. Relatively few studies have addressed the clinical
associates and the prognostic use of C-reactive protein (CRP)
measurements in earlier CKD stages [25–27]. Importantly, no
studies have addressed the relative contribution of inflamma-
tion and vascular derangements in patients with mild-moder-
ate CKD. Such study seems pertinent since these putative risk
factors to CVD are believed interconnected and causally re-
lated through the atherosclerotic–cardiovascular process [28].
Hence, the aim of this study was to assess in nondialysed
CKD the clinical determinants of systemic inflammation, en-
dothelial function and vascular health, on one hand, and to
study the implications of such alterations on cardiovascular
outcomes (both fatal and nonfatal) on the other. We did so in
a large cohort of CKD patients uniformly distributed and
balanced across the different disease stages.
Methods
Patients and study design
The ethical committee of Gulhane School of Medicine (Etlik-Ankara,
Turkey) approved the study, and informed consent was obtained from
each subject. Between January 2005 and July 2009, 908 patients <70
years of age were referred to the Renal Unit of the Gulhane School of
Medicine Medical Center, Ankara, Turkey, for the first time because of
suspected or manifest renal failure. All patients were diagnosed as having
CKD according to their estimated glomerular filtration rate (eGFR) and the
presence of kidney injury as defined by National Kidney Foundation K/
DQOI Guidelines. By protocol, and in order to minimize any confounding
effects of conditions that may influence ED, 454 patients who were taking
drugs that may influence endothelial function at baseline were excluded,
including angiotensin-converting enzyme inhibitors (ACEIs; n ¼ 166),
angiotensin receptor blockers (ARBs; n ¼ 132), statins (n ¼ 93), eryth-
ropoietin (n ¼ 22) or supplemental vitamin pills (n ¼ 41). Otherwise, other
exclusion criteria including acute infections and unwillingness to partic-
ipate in the study were applied (n ¼ 26). One hundred and twenty-four
eligible patients dropped out for the following reasons: lost to follow-up or
transferred to other dialysis units (n ¼ 68), viral hepatitis (n ¼ 9), vasculitis
(n ¼ 5) and withdrew consent (n ¼ 42). In total, 304 patients with a mean
age of 46  12 years were included in the study.
The diagnoses of CKD are given in Table 1. Hypertension was defined
as systolic blood pressure (SBP)
140 mmHg or diastolic blood pressure
(DBP)
90 mmHg on repeated measurements, or the use of antihyperten-
sive drugs. Fifty-nine of the patients were on other antihypertensive ther-
apy (37 patients were treated with calcium channel antagonists, 8 with
beta-blocker agents, 8 with alpha blockers and 5 with loop diuretics). At
time of evaluation, 73 of the patients were on antidiabetic therapy (50 pa-
tients were treated with oral antidiabetics and 23 with insulin). Once base-
line determinations were performed, drugs were prescribed when necessary
upon physician’s judgment and following common practice. As such, as
soon as diabetic nephropathy was diagnosed, all patients with oral antidia-
betics were changed to insulin. Fifty-five of the patients (18%) had a history
of CVD as defined by medical history and/or clinical findings at time of
enrollment. Of these 55 patients, 7 had suffered from cerebrovascular dis-
ease (stroke), 37 from CVD (acute myocardial infarction, angina pectoris or
had undergone coronary artery bypass surgery), 9 had a history of peripheral
ischaemic atherosclerotic vascular disease and 2 patients had a history of an
aortic aneurysm. Smoking habits were recorded as follows: whereas 134
patients were former or current smokers, 170 were nonsmokers. Patients
were classified with respect to eGFR levels from Stages 1–5 as determined
by K/DOQI, which was calculated according to the simplified version of the
Modification of Diet in Renal Disease formula as defined by [glomerular
filtration rate (GFR) ¼ 186 3 Pcr1.154 3 age0.203 3 1.212 (if black) 3
0.742 (if female)]. Additionally, patients were followed for time-to-event
analysis of cardiovascular outcomes, until cardiovascular event or death,
whichever came first.
M.I. Yilmaz et al.
Laboratory measurements
All samples were obtained from patients and controls in the morning
after 12 h of fasting for measurement of serum albumin, total serum
cholesterol, triglyceride (TG), high-density lipoprotein (HDL) and
low-density lipoprotein (LDL) cholesterol. Total plasma cholesterol,
TG and HDL cholesterol were measured by enzymatic colorimetric
method with Olympus AU 600 auto analyser using reagents from
Olympus Diagnostics GmbH (Hamburg, Germany). LDL cholesterol
was calculated by the Friedewald’s formula. Serum total calcium was
measured by the cresolphtalein complexone method using Menagent
Calcium 60sec kits (Menarini Diagnostics, Florence, Italy). Serum
phosphorus was measured by the ammonia molybdate complex method
using Menagent Phosphofix kits (Menarini Diagnostics). Intact para-
thormone (iPTH) was measured by immunoradiometric, using kits
(Immulite Intact PTH) from Diagnostic Product Corporation (Los
Angeles, CA) with a sensitivity of 1 pg/mL. For the measurement
of high-sensitivity C-reactive protein (hsCRP), serum samples were
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diluted with a ratio of 1/101 with the diluents solution. Calibrators,
kit controls and serum samples were all added on each microwell
with an incubation period of 30 min. After three washing intervals,
100 lL enzyme conjugate (peroxidase-labeled anti-CRP) was added
on each microwell for additional 15 min incubation in room temper-
ature in the dark. The reaction was stopped with a stop solution and
photometric measurement was performed at the 450 nm wavelength. The
amount of serum samples was calculated as mg/L with a graphic that was
made by noting the absorbance levels of the calibrators. The interassay
Coefficient of variation (CVs), at hsCRP concentrations of 0.47, 10.5 and
54.9 mg/L, were 6.4, 3.7 and 2.9%, respectively. The intraassay CVs at
1.24, 3.28 and 8.36 mg/L were 0.82, 1.20 and 0.84% for the hsCRP assay.
Lower limits of detection and quantification were 0.02 and 0.15 mg/L for the
hsCRP assay, respectively. The maximum measurable concentration was
110 mg/L.
Vascular assessment
Arterial blood pressure was measured by a physician in the morning three
consecutive times after a 15-min resting period and mean values were
calculated for systolic and diastolic pressure in all patients.
Endothelium-dependent vasodilatation (FMD) and endothelium-in-
dependent vasodilatation [nitroglycerine-mediated dilatation (NMD)] of
the brachial artery were assessed noninvasively, using high-resolution
ultrasound. Measurements were made by a single observer using an
ATL 5000 ultrasound system (Advanced Technology Laboratories
Inc., Bothell, WA) with a 12-MHz prob. The subjects remained at rest
in the supine position for at least 15 min before the examination started.
The subject’s arm was comfortably immobilized in the extended posi-
tion to allow consistent recording of the brachial artery 2–4 cm above
the antecubital fossa. Three adjacent measurements of end-diastolic
brachial artery diameter were made from single 2-D frames. All ultra-
sound images were recorded on S-VHS videotape for subsequent
blinded analysis. A pneumatic tourniquet was inflated to 200 mmHg
with obliteration of the radial pulse. After 5 min, the cuff was deflated.
Flow measurements were made 60 s post-deflation. After a further 15-
min, measurements were repeated and again 3 min after administration
of sublingual glyceryl trinitrate 400 lg po. The maximum FMD and
NMD dilatation diameters were calculated as the average of the three
consecutive maximum diameter measurements. The FMD and NMD
were then calculated as the percent change in diameter compared with
baseline resting diameters.
IMT was assessed in all subjects. Briefly, a high-resolution B-mode
ultrasound of the common carotid arteries with scanning of the longitudi-
nal axis until the bifurcation and of the transversal axis was performed
using an instrument generating a wide band ultrasonic pulse with a middle
frequency of 12 MHz (ATL 5000; Advanced Technology Laboratories
Inc.). For each carotid artery, two longitudinal measurements were ob-
tained by rotating the vessels at 180 increments along their axis. All
patients and controls were blindly examined by one experienced operator
(the intra-operator variability was 4%). IMT was measured at 1 cm prox-
imal to the bifurcation on each side. IMT and FMD measurements were
performed ideally in the same day or within 7 days from blood extraction
and biochemical assessment.
Statistical analysis
All the statistical analyses were performed by using SPSS 11.0 (SPSS
Inc., Chicago, IL) statistical package. Nonnormally distributed
Vascular health, inflammation and kidney failure 3539
Table 1. Demographic and clinical characteristics of the study groups, and recorded events during follow-up

90 Stage 1 60–89 Stage 2 30–59 Stage 3 15–29 Stage 4 <15 Stage 5
eGFR (mL/min/1.73m2) (n ¼ 61) (n ¼ 62) (n ¼ 62) (n ¼ 59) (n ¼ 60)

Age (years) 50 (26–69) 54 (28–67) 49 (26–69) 52 (29–69) 47 (26–69)

Sex (M/F) 33/28 34/28 31/31 31/28 29/31
Body mass index (kg/m2) 26.4 6 2.1 26.7 6 3.1 25.4 6 2.6 25.8 6 2.8 26.3 6 2.7
History of CVD (n)
Cardiovascular episode 6 2 9 9 11
Stroke 3 1 1 1 2
Peripheral vascular disease 2 3 1 0 2
Aortic aneurysm 1 1 0 0 0
Etiology of CKD (n)
Diabetes mellitus 12 16 14 16 15
Glomerulonephritis 14 13 10 9 12
Hypertension 10 12 13 11 13

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Polycystic kidney disease 4 5 2 2 4
Reflux nephropathy 1 2 3 1 3
Unknown 20 24 20 20 23
Smoking, current (n) 28 29 28 23 26
Noncardiovascular deaths (n) 0 0 1 1 1
Cardiovascular deaths (n) 2 6 8 5 9
Nonfatal cardiovascular events (n) 10 18 17 22 22

variables were expressed as median (range) and normally distributed
variables were as mean  SD, as appropriate. A P-value <0.05 was
considered to be statistically significant. Between group comparisons
were assessed for nominal variables with the chi-square test and by
Kruskal–Wallis test (analysis of variance) for the rest of variables.
Spearman’s rank correlation was used to determine correlations be-
tween paired variables. Stepwise multivariate regression analysis was
used to assess the predictors for FMD and IMT levels. Survival and
time-to-event analysis of cardiovascular outcomes (using a composite
of fatal and nonfatal events) was done using Cox proportional hazards
model, including adjustment for potential confounding factors. Data are
presented in the form of hazard ratios (HR) and 95% confidence inter-
vals (CI).
Results
The demographic and clinical characteristics of the patients
are given in Table 1. No differences were observed across
the CKD stages with regard to age, gender, body mass
index, smoking status, history of CVD and the etiology
of CKD. The biochemical and vascular assessments are
given in Table 2. Blood pressure and lipid profiles did
not differ across stages, but albumin and calcium levels
were detrimentally reduced, while the iPTH and hsCRP
gradually rose. The IMT increased and the FMD decreased
in parallel with CKD stages (Figure 1).
The univariate and multivariate associates of FMD and
IMT are shown in Table 3. FMD values were independ-
ently predicted by hsCRP, NMD, SBP, comorbid diabe-
tes, iPTH and eGFR. IMT was independently predicted
by the presence diabetes mellitus, iPTH levels and eGFR.
Because diabetes may be considered an important con-
founder in association studies of endothelial function we
repeated, as a sensitivity analysis, both uni- and multi-
variate associates of FMD and IMT after exclusion of 73
diabetics. Results were the same: the multivariate inde-
pendent predictors of FMD were hsCRP, NMD, SBP,
iPTH and eGFR (adjusted r2 ¼ 0.70) and the multivariate
independent predictors of IMT were iPTH levels and eGFR
(adjusted r2 ¼ 0.54).
Cardiovascular outcomes were determined from the
day of examination onwards, with a mean follow-up pe-
riod of 41 (range 6–46) months. Thirty-three patients
died, 30 of which due to cardiovascular causes, 2 due
to malignancies and 1 due to infection. Cardiovascular
mortality (n ¼ 30) was defined as death due to coronary
heart disease (n ¼ 14), sudden death (n ¼ 7), stroke (n ¼
6) or complicated peripheral vascular disease (n ¼ 3). In
univariate Cox analysis, each unit increase of FMD [HR
0.44 (95% CI 0.32–0.60)], IMT [1.88 (1.39–2.54)] and
hsCRP [1.08 (1.05–1.12)] significantly predicted future
deaths. However, since only 33 fatal events were regis-
tered, we do not report multivariate Cox adjustment due
to likelihood of model overfitting.
In addition to the 30 cardiovascular deaths, 59 nonfatal
cardiovascular events were registered during the follow-up
as follows: stroke (n ¼ 15); myocardial infarction (n ¼ 32);
peripheral vascular disease (n ¼ 7) and aortic aneurysm
(n ¼ 5). The predictors for time-to-cardiovascular event
(n ¼ 89, including a composite of fatal and nonfatal)
were studied by univariate and multivariate COX analysis
(Table 4, Panel A). In univariate Cox, FMD, IMT and
hsCRP were significant predictors of cardiovascular out-
comes. Multivariate Cox was used to study the impact
of these variables in pairs or together, considering the ad-
justment for age, sex, eGFR, diabetes and cardiovascular
comorbidity. In a model excluding IMT measurements,
both FMD and hsCRP significantly contributed to predict-
ing outcome, independent of each other and confounders.
In a model excluding FMD, only hsCRP was able to predict
outcome. In a model containing the three measurements,
FMD and hsCRP, but not IMT, contributed to predicting
outcome. As a sensitivity analysis, multivariate Cox mod-
els were repeated after exclusion of diabetic patients, find-
ing similar results (Table 4, Panel B).
3540 M.I. Yilmaz et al.
a
Table 2. Biochemical and vascular assessment according to CKD stages

Stage 1 (
90) Stage 2 (60–89) Stage 3 (30–59) Stage 4 (15–29) Stage 5 (<15)
(n ¼ 61) (n ¼ 62) (n ¼ 62) (n ¼ 59) (n ¼ 60) Pb

eGFR (mL/min) 96 (91–107) 68 (61–89) 45 (31–58) 20 (15–29) 9 (4–14) <0.001

SBP (mmHg) 133 (113–157) 134 (115–166) 134 (110–180) 133 (111–180) 135 (113–185) 0.7
DBP (mmHg) 83 (71–94) 83 (73–93) 85 (80–95) 85 (71–95) 84 (73–95) 0.2
S-Albumin (g/dL) 4.0 (3.5–4.6) 3.9 (3.5–4.6) 4.3 (3.5–4.7) 4.0 (3.5–4.6) 3.8 (3.2–4.4) <0.001
Total Cholesterol (mg/dL) 194 (160–240) 193 (171–237) 192 (159–236) 192 (159–236) 192 (149–235) 0.1
TG (mg/dL) 137 6 14 138 6 11 141 6 14 139 6 13 136 6 18 0.3
S-Calcium (mg/dL) 8.98 6 0.46 8.73 6 0.53 8.34 6 0.49 8.09 6 0.37 8.11 6 0.35 <0.001
S-Phosphate (mg/dL) 4.14 6 0.46 4.43 6 0.90 4.55 6 0.73 5.75 6 1.36 6.84 6 1.50 <0.001
iPTH (pg/mL) 49 6 15 64 6 27 143 6 0.45 144 6 39 217 6 69 <0.001
hsCRP (mg/L) 7.0 (3.2–10.6) 10.0 (5.0–24.0) 16.5 (5.0–35.0) 23.0 (4.7–46) 27.0 (4.0–48.0) <0.001
24-h proteinuria (g/day) 1.25 (0.23–3.77) 1.58 (0.22–5.00) 1.46 (0.33–4.40) 1.84 (0.42–5.30) 1.43 (0.27–4.10) <0.001
IMT (mm) 0.59 6 0.05 0.64 6 0.07 0.71 6 0.11 0.80 6 0.09 0.85 6 0.10 <0.001

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NMD (%) 13.0 (11.0–13.8) 13.1(11.0–13.8) 12.9 (11.5–13.9) 13.0 (11.6–13.8) 12.0 (10.2–13.5) <0.001
FMD (%) 8.4 (7.2–9.7) 7.2 (6.0–8.3) 6.8 (5.7–8.2) 6.2 (4.1–8.2) 5.1 (4.0–7.1) <0.001
a
NMD, nitroglycerine-mediated dilatation; hsCRP, high-sensitivity C-reactive protein.
b
Differences assessed by chi-square test for categorical variables, and by Kruskal–Wallis test. Statistically significant if P <0.05. To convert total
cholesterol in mg/dL to mmol/L, multiply by 0.02586; TG in mg/dL to mmol/L, multiply by 0.01129.

Fig. 1. Box plots showing the decrease in FMD levels (Panel A) and the increases in IMT (Panel B) and CRP (Panel C) in parallel with eGFR reduction.

Discussion characterized feature of CKD, likely a consequence of both

This observational cohort study provides a comprehensive
overview of the evolution of vascular health and inflamma-
tory status in patients with progressive kidney failure. We
show that increased inflammation, arterial thickening
and impaired dilatation occur in parallel with the decline
of eGFR. Inflammation (as assessed by CRP) and iPTH
appeared as strong determinants for FMD in multivariate
analyses. Both FMD and CRP values, but not IMT, emerged
as independent predictors of future cardiovascular outcomes.
Although these findings may seem, a priori, expected, this is
the first study demonstrating this in etiologically diagnosed
CKD patients across the different stages.
A progressive reduction in kidney function is accompa-
nied by retention of uraemic solutes and purportedly are
linked with the elevated mortality risk of this patient pop-
ulation. Low-grade inflammation is an early and frequently
retention and increased production [24, 29]. Higher CRP
levels are associated with a faster rate of kidney function
loss [30, 31] and it has been proposed as an intermediate
link between renal insufficiency and the appearance of en-
dothelial dysfunction and thickening [32]. It is well estab-
lished that the endothelium synthesizes a variety of
inflammatory molecules [23, 24]. Our study supports pre-
vious studies showing that inflammation occurs hand in
hand with the decline in GFR and that in multivariate anal-
yses, CRP levels stood as an independent contributor to the
variance of FMD. These results expand previous observa-
tions in community-based studies [33], nondiabetic CKD
patients [12, 13] and studies confined to moderate CKD
stages [17]. Nonetheless, ours is probably the largest study
population of this kind including uniformly distributed etio-
logically diagnosed CKD patients across the different dis-
ease stages. This, together with the exclusion of drugs that
Vascular health, inflammation and kidney failure 3541
Table 3. Univariate and multivariate associates of FMD and IMT in nondialysis CKD patients

FMD IMT
a b,c
Parameters Univariate q Multivariate b (P) Univariatea q Multivariateb,d b (P)

FMD (%) — — 0.66 NS

IMT (mm) 0.66 NS — —
HsCRP (mg/L) 0.65 0.10 (0.03) 0.61 NS
NMD (%) 0.44 0.16 (<0.001) 0.30 NS
Age (year) NS NS NS NS
Gender (M/F) NS NS NS NS
Body mass index (kg/m2) NS — NS —
Smoking NS NS NS NS
SBP (mmHg) 0.17 0.09 (0.006) NS —
Diabetes mellitus 0.26 0.14 (<0.001) 0.17 0.11 (0.005)
Previous CVD NS NS NS NS

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S-albumin (g/dL) 0.14 NS NS —
24 h proteinuria (mg/day) 0.18 NS 0.13 NS
S-calcium (mg/dL) 0.48 NS 0.49 NS
S-phosphate (mg/dL) 0.60 NS 0.54 NS
iPTH (pg/mL) 0.71 0.16 (0.001) 0.64 0.16 (0.007)
eGFR (mL/min) 0.79 0.54 (<0.001) 0.75 0.62 (<0.001)
a
Denoted are statistically significant (P < 0.05) q values as assessed by Spearman Rank’s test, as well as b estimates and P-values from multivariate
regression models.
b
Variables known to influence FMD levels (age, gender, diabetes, history of CVD, smoking, IMT, hsCRP, NMD, SBP, albumin, 24 h proteinuria, Ca, P,
iPTH, eGFR) and IMT levels (age, gender, diabetes, history of CVD, smoking, FMD, hsCRP, NMD, 24 h proteinuria, Ca, P, iPTH, eGFR) were initially
included in the multivariate analyses.
c
The r2 of the multivariate models was 0.72.
d
The r2 of the multivariate models was 0.57.

Table 4. Univariate and multivariate COX analysis predicting for cardiovascular outcomes (a composite of 89 fatal and nonfatal events)a

Crude analysis Model 1 Model 2 Model 3

Panel A: in all patients (n ¼ 304)

FMD (%) 0.59 (0.49–0.70) <0.001 0.55 (0.40–0.76) <0.001 0 0.55 (0.40–0.76) <0.001
IMT (mm) 1.37 (1.16–1.61) <0.001 0 1.07 (0.82–1.39) 0.6 1.06 (0.8–1.38) 0.7
HsCRP(mg/L) 1.06 (1.04–1.08) <0.001 1.07 (1.04–1.10) <0.001 1.05 (1.03–1.08) <0.001 1.07 (1.04–1.10) <0.001
Panel B: in nondiabetic patients only (n ¼ 231)
FMD (%) 0.50 (0.39–0.65) <0.001 0.67 (0.48–0.93) 0.02 0 0.67 (0.48–0.93) 0.02
IMT (mm) 1.56 (1.21–2.01) 0.001 0 0.96 (0.65–1.40) 0.8 0.96 (0.64–1.43) 0.8
HsCRP (mg/L) 1.08 (1.05–1.11) <0.001 1.05 (1.01–1.09) 0.01 1.07 (1.04–1.10) <0.001 1.05 (1.01–1.09) 0.01
a
Represented are HR (and 95%CI) in univariate (crude) Cox model and after different adjustments. Models 1–3 show different combinations of
the variables of interest after adjustment for age (per year), sex (women as reference), SBP (per mmHg), total cholesterol (per mg/dL), eGFR
(per mL/min), diabetes (absence as reference) and medical history of cardiovascular disease (absence as reference) at baseline. In Panel B, the same
analysis is contemplated excluding diabetic patients, and therefore multivariate adjustment does not include diabetes mellitus. HsCRP, high-sensitivity
c-reactive protein.

may confound the interpretation of the eGFR vascular
health axis, are clear strengths of the study. At the same
time, however, due to these medical exclusions, our data
are not necessarily representative of the normal CKD
population and should be interpreted with caution. In this
sense, we bring attention to the fact that CRP or iPTH
levels in our study seem higher than in previous reports,
and patients included were overall relatively young. Be-
cause eGFR is subjected to inaccuracies in CKD classi-
fication, we included only etiologically diagnosed
patients, and eGFR was treated as a continuous variable
in all our analyses. Finally, we should also emphasize
that the cross-sectional nature of this analysis does not
allow us to infer whether the impairment of eGFR causes
increased inflammation and vascular abnormalities or
vice versa and/or if they operate in a common system
involving also other factors. These associations may well
indeed be bidirectional, in light of the recent observation
that endothelial dysfunction was a strong predictor of
subsequent eGFR decline in never treated uncomplicated
hypertensive patients [34].
Another observation of the present study pertains to the
multivariate association of iPTH in prediction of both FMD
and IMT levels. The endothelium is a recognized target
organ of PTH and may contribute to its effects on vascular
tone and blood pressure regulation [35]. Indeed, in nonrenal
patients with primary hyperparathyroidism, measures of
both FMD [36] and IMT [35] have been associated with
the extent of PTH elevation. Parathyroidectomy is able to
restore these arterial derangements [37]. In CKD patients,
3542
disorders in parathyroid function are believed to play an
important role in the high prevalence of CVD and mortal-
ity [38]. In dialysis patients, vascular calcification and
compromized reactivity and elasticity are frequently ob-
served in connection with CKD and hyperparathyroidism
and associated with increased risk of cardiovascular
complications [39]. Two small studies in haemodialysis
patients have reported associations between FMD [40]
and IMT [41] with iPTH levels. To the best of our knowl-
edge, ours is the first report confirming this important
link in nondialysis CKD stages. Although we are unable
to confirm this hypothesis in our study, the association of
iPTH and endothelial function may be the consequence of
progressive increased prevalence of vitamin D deficiency
with progressive loss of kidney function, as low 25-hydroxy
vitamin D levels importantly disturb the biological control of
PTH synthesis [42]. In support of this, Drechsler et al. [43]
recently showed that the impact of 25-hydroxy vitamin D
levels on clinical events in the NECOSAD cohort was modi-
fied by PTH status, with low vitamin D levels meaningfully
affecting outcomes only in patients with PTH levels above
the median.
Finally, an important and novel input of this study is the
analysis of the relative contribution of these interrelated
factors on prediction of cardiovascular outcomes. To the
best of our knowledge, there are no previous studies linking
FMD derangements and future cardiovascular outcomes in
nondialysis CKD patients. In our study, CRP levels, endo-
thelial function (FMD) and arterial stiffness (IMT) were all
significant predictors of cardiovascular outcomes in uni-
variate analysis. However, the predictive effect of IMT
was dependent on inflammation and basic confounders
such as age, sex, eGFR and comorbidities. Szeto et al.
[18] showed that increasing quartiles of IMT increased
the hazards of future cardiovascular events in 203 pa-
tients with CKD Stages 3 and 4 independently of CRP
levels. Our analysis, using IMT as a continuous variable,
cannot confirm this finding in an enlarged population
with CKD Stages 1–5. Desbien et al. [44] observed a
significant interaction between creatinine clearance and
IMT progression in prediction of 36 cardiovascular
events in a community study of 3364 individuals. How-
ever, results were not adjusted for important confounders
in this association like age or CRP. Although the use of
continuous variables reduces residual confounding in our
analysis, we cannot exclude the possibility of other un-
known confounders. Nevertheless, despite a thorough
phenotypical characterization and a relatively large sam-
ple size, we should not rule out the odds that larger sam-
ple sizes would modify this observation.
Taken together, our study provides solid evidence
which, from a mechanistic point of view, illustrates that
endothelial dysfunction and systemic inflammation may
contribute in parallel to the increased cardiovascular risk
of nondialysis CKD. This observation agrees with the mul-
tiple detrimental effects of systemic inflammation in CKD,
including development of protein-energy wasting, muscle
catabolism or hormonal derangements [10]. From a prog-
nostic point of view, our results support the use of FMD
over IMT measurements to monitor nondialysis CKD
patients at risk.
M.I. Yilmaz et al.
Acknowledgements. We would like to thank the patients and personnel
involved in the creation of this cohort. Also, we acknowledge support from
the Gülhane School of Medicine, the Swedish Medical Research Council,
Karolinska Institute’s Diabetes theme centre and the Loo and Hans
Osterman Foundation.
Conflict of interest statement. None declared.
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Nephrol Dial Transplant (2011) 26: 3543–3549
doi: 10.1093/ndt/gfr049
Advance Access publication 4 March 2011
Rosiglitazone does not improve vascular function in subjects with
chronic kidney disease
Doris T. Chan1,2, Gerald F. Watts1, Ashley B. Irish3 and Gursharan K. Dogra2
1
School of Medicine and Pharmacology (Royal Perth Hospital Unit), University of Western Australia, Perth, Australia, 2Department
of Nephrology, Sir Charles Gairdner Hospital, Nedlands, Australia and 3Department of Nephrology, Royal Perth Hospital, Perth,
Australia
Correspondence and offprint requests to: Doris T. Chan; E-mail: doris.chan@health.wa.gov.au
Abstract
Background. Thiazolidinediones such as rosiglitazone
(RSG) are insulin-sensitizing agents, which may improve

The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
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Received for publication: 7.12.10; Accepted in revised form: 27.1.11
inflammation and vascular function, and thus potentially
lower cardiovascular risk in patients with chronic kidney
disease (CKD). However, there is growing concern about