ORIGINAL ARTICLE
DOI:10.5301/JN.2011.8446
Cardiac valve calcification is a marker of
vascular disease in prevalent hemodialysis
patients
Antonio Bellasi 1, Emiliana Ferramosca 1,
Carlo Ratti 2, Geoffrey Block 3, Paolo Raggi 4
Abstract
Background: Vascular and valvular calcifications are
a common finding in chronic kidney disease (CKD)
patients and are associated with increased morbidity
and mortality. We investigated the hypothesis that cal-
cification of the cardiac valves is a marker of coronary
artery calcification (CAC) and thoracic aorta calcifica-
tion (AoC) in hemodialysis (CKD-5) patients.
Methods: This was a cross-sectional study of 145
maintenance CKD stage 5 (CKD-5) patients. All pa-
tients underwent electron beam tomography for
quantification of CAC and AoC score via the Ag-
atston score. The presence of calcification of the
cardiac valves was assessed by standard bi-dimen-
sional echocardiography.
Results: Eighty-four of the study patients (58%) had
echocardiographic evidence of valvular calcifica-
tion. A significant and graded association between
valvular calcification and CAC as well as AoC was
detected. Patients with 1 or 2 calcified valves had
a significantly greater likelihood of having a CAC
score >1,000 (odds ratio [OR] = 5.94; 95% confi-
dence interval [95% CI], 1.91-18.44; p=0.002; and
OR=3.27; 95%CI, 1.36-7.88; p=0.007, respectively).
Similarly, the presence of 1 or 2 calcified valves was
associated with an eightfold and threefold increased
probability of an AoC score greater than the third
quartile, respectively.
Conclusions: This cross-sectional analysis shows
that calcification of the cardiac valves is closely as-
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 0000; 00 ( 00 ) : 000-000
1
Division of Nephrology, Malpighi Hospital, University of
Bologna, Bologna - Italy
2
Division of Cardiology, St. Maria Bianca Hospital,
Mirandola - Italy
3
Denver Nephrology, Denver, Colorado - USA
4
Division of Cardiology, Emory University, Atlanta, Georgia -
USA
sociated with vascular calcification, an established
marker of risk in prevalent hemodialysis patients.
Key words: Atherosclerosis, Chronic kidney disease,
Coronary artery calcification, Coronary artery disease,
Valvular calcification
Introduction
Extensive soft-tissue calcification is a common finding in
chronic kidney disease stage 5 (CKD-5) (1, 2). The increased
prevalence of risk factors for atherosclerosis (3), derange-
ments in mineral metabolism (4), as well as loss of inhibi-
tors (5-7) of calcifications are believed to contribute to the
deposition and progression of cardiovascular calcification
in uremia. Indeed, calcification of the coronary arteries
and cardiac valves has been reported with a significantly
higher prevalence than in age- and sex-matched individu-
als without evidence of renal disease (1, 2, 8). Additionally,
substantial evidence has been accumulated demonstrating
the negative prognostic impact of both valvular and vascular
calcification in CKD-5 (8-11).
Coronary artery calcification (CAC) and thoracic aorta cal-
cification (AoC) can be accurately assessed noninvasively
by means of electron beam tomography and multidetector
computed tomography (CT). However, echocardiography is
a less expensive, widely available and non-radiation-based
tool that could prove useful in predicting the severity of vas-
cular calcification in CKD-5 patients.
1
Raggi et al: Valvular and vascular calcification in CKD-5
Calcification of the aortic and mitral valve on echocar-
diography has been linked to coronary atherosclerosis
in the general population (12, 13) and carotid intima-me-
dia thickness (an indirect marker of atherosclerosis) (14)
among patients undergoing continuous ambulatory peri-
toneal dialysis (15), suggesting that vascular and valvular
calcification might share common pathogenetic mecha-
nisms.
In the present study we tested the hypothesis that cardiac
valve calcification detected by echocardiography is associ-
ated with coronary and thoracic aorta calcification in preva-
lent hemodialysis (CKD-5) patients.
Subjects and methods
Study population
A total of 145 consecutive subjects on maintenance hemo-
dialysis (more than third month; 4-hour sessions, 3 times
weekly) were recruited from 2 clinical research sites (New
Orleans, LA, USA; Denver, CO, USA). Men and women over
18 years of age on maintenance hemodialysis, able to pro-
vide an informed consent prior to entering the study were
included. Pregnant or lactating women or women planning
to become pregnant in the 6 months following entry into the
study were excluded. The study protocol was approved by
the ethics committee of Tulane University, School of Medi-
cine, New Orleans, LA.
Electron beam tomography
All imaging procedures were performed on a C-150 scanner
(GE-Imatron, South San Francisco, CA, USA) with a 100-ms
scanning time and a single-slice thickness of 3 mm. De-
tails on the method have been published elsewhere (16).
Briefly, a total of 36 to 40 tomographic slices were obtained
for each subject during a single breath-holding period from
the level of the carina to the diaphragm. This allowed the
inclusion of the full length of the coronary artery tree as
well as a portion of the ascending and descending thoracic
aorta with the exclusion of the aortic arch. Tomographic
slices were ECG-gated and obtained at 60%-80% of the
R-R interval.
Scans were considered of acceptable research quality only
if the images were free from motion, respiratory or arrhyth-
mic artefacts. CAC and AoC scores were computed using
the Agatston score as previously described (17). All scans
were analyzed independently by 2 experienced investiga-
tors (P.R. and A.B.).
2 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428
Echocardiography
A standard 2-dimensional transthoracic echocardiogram
was performed at the time of CAC assessment. All echocar-
diograms were performed according to the recommenda-
tions of the American Society of Echocardiography and
were analyzed by a single experienced cardiologist (P.R.)
who was blinded to all clinical details of the study patients
(18, 19). Cardiac valve calcification was considered present
when bright echoes of more than 1-mm thickness where
seen on 1 or more cusps of the aortic valve, mitral valve and
mitral valve annulus (20).
Laboratory measurements
Blood specimen were drawn in the morning of the midweek
dialysis day, after an overnight fast of at least 12 hours.
Serum albumin, calcium, phosphorus, intact parathyroid
hormone (PTH), alkaline phosphatase, C-reactive protein,
fetuin-A, troponin I and uric acid were measured. Whole
blood was used to measure hemoglobin, and ethylenedi-
aminetetraacetic acid (EDTA)-plasma to measure glucose
and lipids profile (total cholesterol, high-density lipoprotein
[HDL] cholesterol, low-density lipoprotein [LDL] cholesterol
and triglycerides). Women of childbearing potential were
required to have a pregnancy test prior to enrollment, to
exclude pregnancy. All samples were shipped to and ana-
lyzed in a central laboratory (Quest Diagnostics, Los Ange-
les, CA, USA).
Statistical analysis
Continuous variables are expressed as means +standard
deviation (SD) or median and interquartile range (IQR), de-
pending on the normality or nonnormality of data distribu-
tion. Dichotomous variables are expressed as numbers and
percentages. Between-group comparisons were tested
using a 2-tail Student’s t-test for continuous data and chi-
square test for dichotomous data. The ANOVA test was
used to determine differences in CAC score (CACS) and
AoC score between patients without or with echocardio-
graphic evidence of 1 or 2 calcified valves. Logistic regres-
sion was used to calculate the odds ratios (ORs) of having
a CACS greater than 100, 400 and 1,000 in the presence
of valvular calcification. These cutoff points are associated
with a significant increase in morbidity and mortality in the
general population and in CKD-5 patients (9, 21, 22). Simi-
larly, logistic regression was applied to calculate the OR of
having a calcium score greater than the first, second and
third quartile of AoC score in the study sample. All models

were adjusted for age, sex, dialysis vintage and history of
cardiovascular disease (CVD).
Finally, sensitivity and specificity as well as negative and
positive predictive value of cardiac valve calcification to
predict CAC and AoC were calculated. All analyses were
completed using R version 2.9.2 (2009-08-24; R Foundation
for Statistical Computing at http://cran.r-project.org/).
Results
Study population characteristics
We enrolled 145 prevalent hemodialysis patients (mean di-
alysis vintage 4 ± 3.9 years); their mean age was 54 ± 14
years, and 49% were men. Patients’ clinical characteristics
are shown in Table I.
There was a greater prevalence of whites[AUTHORS: please
advise: correct edit? (The AMA Manual of Style, 10th edn., p.
415, points out that “Caucasian” is technically incorrect and
“should be avoided”; it suggests the use of the term “white”
instead.] in the group with cardiac valve calcification (29.5%
vs. 47.6%; p=0.013) compared with a greater prevalence of
African-Americans in the group without evidence of valvular
calcification (62.3% vs. 46.4%; p=0.03), and patients with
valvular calcification were on average 5 years older than
those without (56.9 vs. 51.2 years; p=0.01).
Cardiovascular calcification in relation to valvular
calcification
Eighty-four of the 145 study patients (58%)[AUTHORS:
please advise: correct edit? (84/145 = 0.5793)] had echocar-
diographic evidence of valvular calcification. Of the study
patients, 19 (13%)[AUTHORS: please advise: correct edit?
(19 / “of these” 84 = 0.2262)] had isolated calcification of
the aortic valve, 28 (19%) isolated calcification of the mitral
valve and 37 (25%) had calcification of both valves.
The mean ± SD CACS and AoC score in our population
were 909 ± 1,675 (median 202; IQR 18-882) and 2,857 ±
6,295 (median 602, IQR 60-2,452) (Tab. II). Twenty-four
patients (16.5%) had no detectable CAC, and 11 (7.6%)
had no AoC. In contrast, 58 (40%) had severe CAC
defined as a CACS >400. The presence and number of
calcified cardiac valves was associated with a high cal-
cium burden both in the coronary artery tree and the aorta
(Tab. III, Fig. 1).
As shown in Table III the association between cardiac valve
calcification and presence and extent of CAC and AoC was
graded. For example, subjects with 1 calcified valve were
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 0000; 00 ( 00 ) : 000-000
1.74 (95% CI, 0.76-3.97) times more likely to have a CACS
>100; 2.59 (95% CI, 1.15-5.83) time more likely to have a
CACS >400 and 5.94 (95% CI, 1.91-18.44) times more likely
to have a CACS >1,000. These associations were only mar-
ginally attenuated by adjusting for different covariates (data
not shown).
The sensitivity, specificity, negative and positive predictive
value of valvular calcification seen on a standard 2-dimen-
sional transthoracic echocardiogram to predict CAC and
AoC are shown in Table IV.
Discussion
This study provides evidence that calcification of the cardiac
valves and arterial wall are closely associated in hemodialy-
sis (CKD-5) patients. Although less frequent than vascular
calcification, calcification of the cardiac valves is found in
CKD-5 patients with a prevalence several fold higher than
in the general population (1). The presence of inflammatory
cells, lipoproteins and bone matrix proteins in the calcified
regions of the cardiac valves (23), along with the association
with common risk factors (1, 24), suggests that valvular and
vascular calcifications are syndromes dependent on com-
mon pathogenetic mechanisms (25). New pathways poten-
tially responsible for accelerated cardiovascular calcification
in advanced CKD involve factors such Kloto and FGF-23 as
well as fetuin-A; whether these factors are merely elements
of a complex pathway or directly causal remains to be dem-
onstrated (26, 27). Additionally, drugs such as warfarin (28,
29), sevelamer (30) and cinacalcet (31) may impact both
vascular and valvular calcification progression by interfering
with important steps along this complex pathway.
Although CT cannot dissociate intimal (i.e., atherosclerotic)
from medial (i.e., dystrophic) vascular calcification, it has
been reported that vascular calcification in CKD-5 occurs
predominantly in the intima (32). Therefore, it would appear
appropriate to consider valvular calcification a hallmark of
vascular disease.
Valvular calcifications have been linked to a poor progno-
sis in CKD-5 patients on continuous ambulatory perito-
neal dialysis (CAPD) (8). In a series of 192 CAPD patients,
Wang et al (8) found a stepwise increase in all-cause and
cardiovascular mortality associated with the number of
calcified valves. In that study the all-cause and cardio-
vascular death rates were similar among patients with
valvular calcifications and atherosclerotic vascular dis-
ease, suggesting once again that valvular calcification is
probably a surrogate marker of vascular disease. In this
regard, the same group (15) showed that CKD-5 patients
with calcified valves have a significant increase in carotid
3
Raggi et al: Valvular and vascular calcification in CKD-5

TABLE I
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF STUDY PATIENTS ACCORDING TO PRESENCE OR
ABSENCE OF CALCIFICATION OF ANY VALVE
No valvular
Overall Valvular
calcification p Value
(n=145) calcification (n=84)
(n=61)
Demographic characteristics
Age (mean ± SD) 54.56 ± 14.41 51.27 ± 14.7 56.95 ± 13.79 0.01
Vintage (mean + SD) 3.97 ± 3.92 3.45 ± 3.32 4.36 ± 4.3 0.15
Men, no. (%) 71 (48.9) 28 (45.9) 43 (51.2) 0.4
Women, no. (%) 74 (51.1) 33 (54.1) 41 (48.8) 0.4
Race, no. (%)
White 58 (40) 18 (29.5) 40 (47.6) 0.013
African-American 77 (53.1) 38 (62.3) 39 (46.4) 0.03
Other 10 (6.9) 5 (8.1) 5 (5.9) 0.44
Anthropometric characteristics
Systolic blood pressure (mm Hg) 145.5 ± 25.7 145.3 ± 24.9 145.6 ± 26.3 0.94
Diastolic blood pressure (mm Hg) 78.3 ± 14.5 80.6 ± 13.8 76.6 ± 14.8 0.10
BMI (calculated as kg/m2) 26.4 ± 2.0 26.8 ± 5.6 26.2 ± 5.4 0.47
Clinical characteristics
Hypertension, no. (%) 138 (95.2) 59 (96.7) 79 (94.0) 0.38
Diabetes mellitus, no. (%) 72 (49.6) 30 (49.1) 42 (50.0) 0.64
Prior cardiovascular disease history, no. (%)* 56 (38.6) 21 (34.4) 35 (41.6) 0.38
Congestive heart failure, no. (%) 31 (21.3) 8 (13.1) 23 (27.4) 0.29
Dyslipidemia, no. (%) 71 (48.9) 26 (42.6) 45 (53.6) 0.06
Tobacco use, no. (%) 32 (22.1) 13 (21.3) 19 (22.6) 0.61
Chronic obstructive pulmonary disease 7 (4.8) 2 (3.3) 5 (5.9) 0.38
Laboratory variables
Adjusted serum calcium (mg/dL)† 9.1 ± 0.7 9.2 ± 0.6 9.1 ± 0.7 0.43
Serum phosphate (mg/dL) 5.1 ± 1.5 5.1 ± 1.5 5.1 ± 1.5 0.94
Adjusted Ca×P (mg /dL )
2 2
47.0 ± 13.9 47.3 ± 14.3 46.9 ± 13.7 0.85
Intact PTH (pg/dL) 653.5 ± 731.1 720.0 ± 646.2 606.8 ± 785.8 0.34
Total cholesterol (mg/dL) 153.9 ± 37.9 155.5 ± 40.8 152.8 ± 35.9 0.68
HDL cholesterol (mg/dL) 46.5 ± 13.8 46.6 ± 14.2 46.5 ± 13.6 0.95
LDL cholesterol (mg/dL) 71.9 ± 27.7 72.0 ± 24.6 71.8 ± 29.7 0.97
Triglycerides (mg/dL) 172.7 ± 101.9 175.0 ± 114.7 171.1 ± 92.5 0.82
Serum albumin (g/dL) 3.8 ± 0.2 3.8 ± 0.3 3.7 ± 0.3 0.41
hsCRP (mg/dL) 1.9 ± 2.2 1.1 ± 3.0 1.2 ± 1.7 0.83
Fetuin-A (g/dL) 0.3 ± 0.07 0.3 ± 0.09 0.2 ± 0.06 0.55

BMI = body mass index; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; LDL = low-density lipo-
protein; PTH = parathyroid hormone.
*History of cardiovascular disease includes: peripheral vascular disease, angina pectoris, myocardial infarction, percutaneous
angioplasty with or without stent placement and coronary artery bypass surgery.
†
Adjusted serum calcium: total calcium − 0.8 × (4.0 − serum albumin), where serum albumin is in g/dL.

4 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428

 JNEPHROL 0000; 00 ( 00 ) : 000-000

TABLE II
CORONARY ARTERY CALCIUM (CAC) AND THORACIC AORTA CALCIUM (AoC) SCORES ACCORDING TO PRES-
ENCE OR ABSENCE OF VALVULAR CALCIFICATION

    CAC Score AoC Score

Overall Mean (SD) 909 (1,675) 2,931 (6,365)
Median [IQR] 212 [18-882] 626 [52-2,535]
No valvular calcification Mean (SD) 369 (779) 757 (1,715)
Median [IQR] 82 [0-397] 109 [20.8-577]
1 calcified valve Mean (SD) 1,315 (2,250) 3,899 (6,146)
Median [IQR] 143 [36-1,322] 1,616 [401-4,213]
2 calcified valves Mean (SD) 1,284 (1,697) 5,121 (9,770)
Median [IQR] 465 [37-1,588] 1,975 [352-5,390]
p Trend  0.003 0.002
Mitral valve calcification Mean (SD) 1,102 (1,648) 3,937 (1,648)
Median [IQR] 321 [25-1,428] 1,805 [292-4,052]
p Value* 0.18 0.003
Aortic valve calcification Mean (SD) 1,463 (2,118) 5,258 (8,806)
Median [IQR] 621 [45-1,547] 1,975 [425-6,453]
p Value† p<0.001 p<0.001

IQR = interquartile range.

*Comparison of presence vs. absence of mitral valve calcification.
†
Comparison of presence vs. absence of aortic valve calcification.

artery intima-media thickness and frequently show calci-
fication of the carotid arteries.
This study had several limitations. First, the relatively small
sample size allowed controlling only for a limited number
of confounders. Second, the cross-sectional nature of the
study does not allow causal inferences or assessments of
the prognostic impact on survival of valvular calcification.
Third, the most obvious limitation is the lack of a histological
verification of the location and composition of calcification
in the valves and vessels of these patients.
Nonetheless, taken together with previous findings (24,
27, 28), our study supports the notion that valvular calci-
fication is a marker of systemic vascular disease in CKD-
5 patients. This has several potentially important impli-
cations. First, it supports the use of echocardiography
as a screening method for cardiovascular calcification
in CKD patients, as recently suggested by the KDIGO
experts (33). This is especially important in view of the
fact that CT delivers a considerable dose of radiation, is
expensive and is not wildly available, limiting its applica-
bility. Second, since valvular and vascular calcifications
appear to share similar pathogenetic mechanisms, the
identification of cardiac valve calcification should lead to
earlier and active intervention to attenuate progression
of vascular calcification. Preliminary studies showing en-
couraging results in this direction have been published
(30, 31) but await more definitive results.
Future studies should focus on the prognostic signifi-
cance of valvular calcification in CKD, therapeutic strat-
egies to retard its progression and the impact of such
therapies in ameliorating the cardiovascular outcome of
CKD patients.

© 2011 Società Italiana di Nefrologia - ISSN 1121-8428 5

Raggi et al: Valvular and vascular calcification in CKD-5

Fig. 1 - Coronary artery calcium scores

(A and B) and thoracic aorta calcium
scores (C and D) according to the pres-
ence or absence of aortic valve calcifi-
cation (AVC) and mitral valve calcifica-
tion (MVC).

TABLE III
ODDS RATIOS OF HAVING A CORONARY ARTERY CALCIUM SCORE (CACS) GREATER THAN 100, 400, 1,000,
AS WELL AS A THORACIC AORTA CALCIUM SCORE (AoCS) GREATER THAN THE FIRST, SECOND AND THIRD
QUARTILE OF SCORE ACCORDING TO THE PRESENCE OF VALVULAR CALCIFICATION

Coronary p Value Thoracic aorta cal- p Value

calcification cification

CACS greater than 100 AoCS greater than the 1st quartile

Presence vs. absence of aortic valve calcification 1.62 (0.71-3.70) 0.24 4.99 (1.67-14.88) 0.003

Presence vs. absence of mitral valve calcification 1.20 (0.52-2.74) 0.65 2.15 (0.78-5.90) 0.13

Presence vs. absence of 1 calcified valve 1.74 (0.76-3.97) 0.18 4.16 (1.56-11.07) 0.004

Presence vs. absence of 2 calcified valves 1.16 (0.45-2.96) 0.74 3.19 (0.87-11.60) 0.07

CACS greater than 400 AoCS greater than the 2nd quartile

Presence vs. absence of aortic valve calcification 3.49 (1.59-7.64) 0.001 3.49 (1.49-8.51) 0.005

Presence vs. absence of mitral valve calcification 0.98 (0.45-2.11) 0.96 4.67 (1.82-11.97) 0.001

Presence vs. absence of 1 calcified valve 2.59 (1.15-5.83) 0.02 8.20 (2.95-22.82) <0.001

Presence vs. absence of 2 calcified valves 1.52 (0.65-3.57) 0.32 3.18 (1.12-9.02) 0.02

CACS greater than 1,000 AoCS greater than the 3rd quartile

Presence vs. absence of aortic valve calcification 4.39 (1.76-10.9) 0.001 5.05 (1.94-13.12) <0.001

Presence vs. absence of mitral valve calcification 2.72 (1.17-6.32) 0.01 1.46 (0.61-3.50) 0.39

Presence vs. absence of 1 calcified valve 5.94 (1.91-18.44) 0.002 4.44 (1.56-12.60) 0.005

Presence vs. absence of 2 calcified valves 3.27 (1.36-7.88) 0.007 2.16 (0.84-5.51) 0.10

Values are odds ratios (95% confidence interval). All models were adjusted for age, sex, dialysis vintage and history of cardio-
vascular disease.

6 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428

 JNEPHROL 0000; 00 ( 00 ) : 000-000

TABLE IV
SPECIFICITY, SENSITIVITY, NEGATIVE PREDICTIVE VALUE (NPV) AND POSITIVE PREDICTIVE VALUE (PPV) OF VAL-
VULAR CALCIFICATION DETECTED ON A STANDARD BI-DIMENSIONAL TRANSTHORACIC ECHOCARDIOGRAM TO
PREDICT VARIOUS LEVELS OF CORONARY ARTERY (CAC) AND THORACIC AORTA (AoC) CALCIUM SCORES

CAC  >100 >400 >1,000

Sensitivity 0.68 (0.57-0.72) 0.74 (0.61-0.83) 0.88 (0.71-0.95)
Specificity 0.57 (0.44-0.68) 0.53 (0.42-0.63) 0.50 (0.41-0.60)
NPV 0.56 (0.43-0.67) 0.75 (0.63-0.84) 0.93 (0.84-0.97)

Presence of 1 PPV 0.69 (0.58-0.77) 0.51 (0.41-0.62) 0.33 (0.24-0.43)

calcified valve AoC 1st Quartile 2nd Quartile 3rd Quartile
Sensitivity 0.68 (0.58-0.76) 0.79 (0.68-0.87) 0.83 (0.68-0.92)
Specificity 0.78 (0.64-0.87) 0.63 (0.52-0.74) 0.50 (0.41-0.59)
NPV 0.50 (0.39-0.62) 0.75 (0.63-0.84) 0.90 (0.80-0.95)
PPV 0.88 (0.79-0.93) 0.69 (0.58-0.77) 0.35 (0.26-0.46)
CAC >100 >400 >1,000
Sensitivity 0.29 (0.21-0.40) 0.32 (0.22-0.45) 0.47 (0.31-0.63)
Specificity 0.80 (0.68-0.88) 0.79 (0.69-0.86) 0.80 (0.72-0.87)
NPV 0.44 (0.35-0.54) 0.64 (0.54-0.72) 0.84 (0.76-0.89)
PPV 0.67 (0.51-0.80) 0.51 (0.36-0.66) 0.40 (0.26-0.56)
Presence of 2
calcified valves AoC 1st Quartile 2nd Quartile 3rd Quartile
Sensitivity 0.30 (0.22-0.39) 0.35 (0.26-0.47) 0.42 (0.27-0.58)
Specificity 0.88 (0.74-0.95) 0.85 (0.75-0.91) 0.80 (0.72-0.87)
NPV 0.30 (0.21-0.38) 0.56 (0.47-0.65) 0.80 (0.72-0.86)
PPV 0.89 (0.75-0.96) 0.70 (0.54-0.82) 0.40 (0.26-0.56)

Financial support: No grants and funds were received for this Address for correspondence:
study. Paolo Raggi, MD
1365 Clifton Road NE, Suite AT-504
Conflict of interest statement: Drs. Paolo Raggi and Geoffrey Block Atlanta, GA 30322, USA
received research grants from Genzyme and Amgen. praggi@emory.edu

renal disease and cardiovascular disease? J Am Coll Cardiol.

References 2002;39:695-701.
2. Spiegel DM, Raggi P, Mehta R, et al. Coronary and aor-
1. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcifica- tic calcifications in patients new to dialysis. Hemodial Int.
tion in adult hemodialysis patients: a link between end-stage 2004;8:265-272.

© 2011 Società Italiana di Nefrologia - ISSN 1121-8428 7

Raggi et al: Valvular and vascular calcification in CKD-5
3. Cozzolino M, Dusso AS, Slatopolsky E. Role of calcium-
phosphate product and bone-associated proteins on vas-
cular calcification in renal failure. J Am Soc Nephrol. 2001;
12:2511-2516.
4. Schwarz U, Buzello M, Ritz E, et al. Morphology of coronary
atherosclerotic lesions in patients with end-stage renal fail-
ure. Nephrol Dial Transplant. 2000;15:218-223.
5. Ketteler M, Westenfeld R, Schlieper G, Brandenburg V.
Pathogenesis of vascular calcification in dialysis patients.
Clin Exp Nephrol. 2005;9:265-270.
6. Moe SM, Reslerova M, Ketteler M, et al. Role of calcification in-
hibitors in the pathogenesis of vascular calcification in chronic
kidney disease (CKD). Kidney Int. 2005;67:2295-2304.
7. Ketteler M, Westenfeld R, Schlieper G, Brandenburg V, Floege
J. “Missing” inhibitors of calcification: general aspects and im-
plications in renal failure. Pediatr Nephrol. 2005;20:383-388.
8. Wang AY, Wang M, Woo J, et al. Cardiac valve calcification
as an important predictor for all-cause mortality and cardio-
vascular mortality in long-term peritoneal dialysis patients: a
prospective study. J Am Soc Nephrol. 2003;14:159-168.
9. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM.
Mortality effect of coronary calcification and phosphate
binder choice in incident hemodialysis patients. Kidney Int.
2007;71:438-441.
10. Matsuoka M, Iseki K, Tamashiro M, et al. Impact of high coro-
nary artery calcification score (CACS) on survival in patients
on chronic hemodialysis. Clin Exp Nephrol. 2004;8:54-58.
11. Watanabe R, Lemos MM, Manfredi SR, et al. Impact of cardio-
vascular calcification in nondialyzed patients after 24 months
of follow-up. Clin J Am Soc Nephrol. 2010;5:189-194.
12. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. As-
sociation of aortic-valve sclerosis with cardiovascular mor-
tality and morbidity in the elderly. N Engl J Med. 1999;341:
142-147.
13. Kamenský G, Lisy L, Polak E, Piknova E, Plevova N. Mi-
tral annular calcifications and aortic plaques as predictors
of increased cardiovascular mortality. J Cardiol. 2001;37
(Suppl 1):21-26.
14. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL,
Wolfson SK Jr; Cardiovascular Health Study Collaborative
Research Group. Carotid-artery intima and media thickness
as a risk factor for myocardial infarction and stroke in older
adults. N Engl J Med. 1999;340:14-22.
15. Wang AY, Ho SS, Wang M, et al. Cardiac valvular calcifica-
tion as a marker of atherosclerosis and arterial calcifica-
tion in end-stage renal disease. Arch Intern Med. 2005;165:
327-332.
16. Achenbach S, Ropers D, Mohlenkamp S, et al. Variability of
repeated coronary artery calcium measurements by electron
beam tomography. Am J Cardiol. 2001;87:210-213, A218.
17. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte
M Jr, Detrano R. Quantification of coronary artery calcium us-
ing ultrafast computed tomography. J Am Coll Cardiol. 1990;
15:827-832.
8 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428
18. Gottdiener JS, Bednarz J, Devereux R, et al; American Soci-
ety of Echocardiography. American Society of Echocardiog-
raphy recommendations for use of echocardiography in clini-
cal trials. J Am Soc Echocardiogr. 2004;17:1086-1119.
19. Lang RM, Bierig M, Devereux RB, et al; Chamber Quantifica-
tion Writing Group; American Society of Echocardiography’s
Guidelines and Standards Committee; European Association
of Echocardiography. Recommendations for chamber quan-
tification: a report from the American Society of Echocar-
diography’s Guidelines and Standards Committee and the
Chamber Quantification Writing Group, developed in con-
junction with the European Association of Echocardiography,
a branch of the European Society of Cardiology. J Am Soc
Echocardiogr. 2005;18:1440-1463.
20. Wong M, Tei C, Shah PM. Sensitivity and specificity of two-
dimensional echocardiography in the detection of valvular
calcification. Chest. 1983;84:423-427.
21. Shaw LJ, Raggi P, Schisterman E, Berman DS, Callister
TQ. Prognostic value of cardiac risk factors and coronary
artery calcium screening for all-cause mortality. Radiology.
2003;228:826-833.
22. Shantouf RS, Budoff MJ, Ahmadi N, et al. Total and indi-
vidual coronary artery calcium scores as independent pre-
dictors of mortality in hemodialysis patients. Am J Nephrol.
2010;31:419-425.
23. Mohler ER III, Gannon F, Reynolds C, Zimmerman R, Keane
MG, Kaplan FS. Bone formation and inflammation in cardiac
valves. Circulation. 2001;103:1522-1528.
24. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft
FC. Electron beam computed tomography in the evaluation
of cardiac calcification in chronic dialysis patients. Am J Kid-
ney Dis. 1996;27:394-401.
25. Moe SM, O’Neill KD, Duan D, et al. Medial artery calcifica-
tion in ESRD patients is associated with deposition of bone
matrix proteins. Kidney Int. 2002;61:638-647.
26. Coen G, De Paolis P, Ballanti P, et al. Peripheral artery calci-
fications evaluated by histology correlate to those detected
by CT: relationships with fetuin-A and FGF-23. J Nephrol.
2011;24(3):313-21.
27. Hu MC, Kuro-o M, Moe OW. Klotho and kidney disease. J
Nephrol. 2010;23(Suppl 16):S136-144.
28. Brandenburg VM, Cozzolino M, Ketteler M. Calciphylaxis: a
still unmet challenge. J Nephrol. 2011;24:142-148.
29. Cozzolino M, Brandenburg V. Warfarin: to use or not to use
in chronic kidney disease patients? J Nephrol. 2010; 23:
648-652.
30. Raggi P, Bommer J, Chertow GM. Valvular calcification in he-
modialysis patients randomized to calcium-based phosphorus
binders or sevelamer. J Heart Valve Dis. 2004;13:134-141.
31. Raggi P, Chertow GM, Torres PU, et al. The Advance study:
a randomized study to evaluate the effects of cinacalcet plus
low-dose vitamin D on vascular calcification in patients on
hemodialysis. Nephrol Dial Transplant. 2011;26(4):1327-39.
Epub 2010 Dec 8.
 JNEPHROL 0000; 00 ( 00 ) : 000-000

32. Nakamura S, Ishibashi-Ueda H, Niizuma S, et al. Coronary
calcification in patients with chronic kidney disease and
coronary artery disease. Clin J Am Soc Nephrol. 2009;4:
1892-1900.
33. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-
MBD Work Group. KDIGO clinical practice guideline for the
diagnosis, evaluation, prevention, and treatment of chronic
kidney disease-mineral and bone disorder (CKD-MBD). Kid-
ney Int Suppl. 2009;113:S1-S130.
Accepted: April 06, 2011

© 2011 Società Italiana di Nefrologia - ISSN 1121-8428 9