Original Articles

Coronary Calcification in Patients with Chronic Kidney

Disease and Coronary Artery Disease
Satoko Nakamura, Hatsue Ishibashi-Ueda, Sinichiro Niizuma, Fumiki Yoshihara,
Takeshi Horio, and Yuhei Kawano
Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, Department of
Pathology, National Cardiovascular Center, Osaka, Japan

Background and objectives: A close linkage between chronic kidney disease (CKD) and cardiovascular disease (CVD) has
been demonstrated. Coronary artery calcification (CAC) is considered to be the causal link connecting them. The aim of the
study is to determine the relationship between level of kidney function and the prevalence of CAC.
Design, setting, participants, & measurements: Autopsy subjects known to have coronary artery disease and a wide range
of kidney function were studied. Patients without CKD were classified into five groups depending on estimated GFR (eGFR)
and proteinuria: eGFR >60 ml/min/1.73 m2 without proteinuria; CKD1/2: eGFR >60 ml/min/1.73 m2 with proteinuria; CKD3:
60 ml/min/1.73 m2 >eGFR >30 ml/min/1.73 m2; CKD4/5: eGFR <30 ml/min/1.73 m2; and CKD5D: on hemodialysis. Intimal and
medial calcification of the coronary arteries was evaluated. Risk factors for CVD and uremia were identified as relevant to
CAC using logistic regression analysis.
Results: Intimal calcification of plaques was present in all groups, but was most frequent and severe in the CKD5D group
and less so in the CKD4/5 and CKD3 groups. Risk factors included luminal stenosis, age, smoking, diabetes, calcium-
phosphorus product, inflammation, and kidney function. Medial calcification was seen in a small number of CKD4/5 and
CKD5D groups. Risk factors were use of calcium-containing phosphate binders, hemodialysis treatment, and duration.
Conclusions: It was concluded that CAC was present in the intimal plaque of both nonrenal and renal patients. Renal
function and traditional risks were linked to initimal calcification. Medial calcification occurred only in CKD patients.
Clin J Am Soc Nephrol 4: 1892–1900, 2009. doi: 10.2215/CJN.04320709

C
ardiovascular disease (CVD) is the main cause of mor-
bidity and mortality in patients with end-stage renal
disease (ESRD) (1,2) or chronic kidney disease (CKD)
(3–7). The mechanisms underlying this increased cardiovascu-
lar risk are not clearly understood. In the general population,
traditional risk factors for CVD have been well characterized
(8), and these are also present in CKD (3– 6,9). The mechanisms
involved in the connection between CKD and CVD are proba-
bly numerous (3– 6). Vascular calcification, such as coronary
artery calcification (CAC) (10,11), is considered to be the causal
link between them.
Vascular calcification is common in physiologic and patho-
logic conditions such as aging, diabetes, dyslipidemia, genetic
diseases, and diseases with disturbances of calcium metabolism
(12–14). In CKD patients, vascular calcification is even more
common, developing early and contributing to the markedly
increased cardiovascular risk. Pathomorphologically, athero-
sclerosis (plaque-forming degenerative changes of the aorta
and of large elastic arteries) and arteriosclerosis (concentric
Received July 1, 2009. Accepted September 1, 2009.
Published online ahead of print. Publication date available at www.cjasn.org.
Correspondence: Dr. Satoko Nakamura, Division of Hypertension and Nephrol-
ogy, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-
dai, Suita, Osaka 565-8565, Japan. Phone: ⫹81-6-6833-5012; Fax: ⫹81-6-6872-7486;
E-mail: snakamur@hsp.ncvc.go.jp
medial thickening and hyalinosis of muscular arteries) can be
distinguished. Increased knowledge about the mechanisms of
calcification together with improved imaging techniques have
provided evidence that vascular calcification should be divided
into two distinct entities according to the specific site of calci-
fication within the vascular wall: plaque calcification, involving
patchy calcification of the intima in the vicinity of lipid or
cholesterol deposits, and calcification of the media in the ab-
sence of such lipid or cholesterol deposits, known as Möncke-
berg-type atherosclerosis (12–14). These two types of calcifica-
tion may vary in terms of the type of vessel affected, the
location along the arterial tree (proximal versus distal), clinical
presentation, and treatment and prognosis (12–14). In the gen-
eral population and in patients with CKD, electron-beam com-
puted tomography (EBCT) has proven CAC as a potent predic-
tor of cardiac events (15–18). Both the prevalence and intensity
of CAC are increased in patients with CKD (19 –27). Several
studies have been undertaken to investigate whether calcifica-
tion occurs in the intima or media of the coronaries and
whether the morphologic details of calcified plaques differ
between renal and nonrenal patients (12–14,24). Causal ele-
ments for either type of CAC have not been definitively deter-
mined (12–14).
Autopsy studies are limited in terms of patient selection, but
have a major advantage in terms of being able to distinguish
intimal from medial calcification. Therefore, our primary goal is

Copyright © 2009 by the American Society of Nephrology ISSN: 1555-9041/412–1892

Clin J Am Soc Nephrol 4: 1892–1900, 2009 Coronary Calcification and CKD 1893

Table 1. Patients’ clinical and biochemical characteristicsa

Patients Patients Patients Patients Patients
Patient Characteristics without with with with with
CKD CKD1/2 CKD3 CKD4/5 CKD5D

Number of subjects 15 15 48 16 23
Age (years) 63 ⫾ 13 69 ⫾ 10 70 ⫾ 11c 73 ⫾ 9c 66 ⫾ 12
Gender (% male) 80 73 63 81 78
eGFR (ml/min/1.73m2) 111 ⫾ 22 72 ⫾ 10b 48 ⫾ 11c,e 15 ⫾ 6c,e,g —
Body mass index (kg/m2) 22 ⫾ 5 22 ⫾ 3 21 ⫾ 3 21 ⫾ 2 21 ⫾ 4
Comorbid conditions (% yes)
Hypertension 47 60 77 100b,d 91b,d
Diabetes 13 67b 46b 63b 52b
Dyslipidemia 33 47 40 19 38
Smoking 53 60 52 63 78
Coronary artery disease (single vessel disease) 20 20 23 6 26
Coronary artery disease (double vessel 20 13 25 19 35
disease)
Coronary artery disease (triple vessel disease) 60 67 52 75 39
Cerebrovascular disease 40 53 38 56 18
Peripheral vascular disease 7 13 15 25 27
Aortic aneurysm 27 20 21 25 27
Laboratory parameters
Total protein (g/dl) 6.6 ⫾ 0.7 6.2 ⫾ 1.1 6.4 ⫾ 0.9 6.0 ⫾ 0.7c 6.5 ⫾ 0.8h
Serum albumin (g/dl) 3.8 ⫾ 0.6 3.5 ⫾ 0.8 3.7 ⫾ 0.5 3.4 ⫾ 0.5c 3.4 ⫾ 0.6c
Hematocrit (%) 41 ⫾ 5 38 ⫾ 5 36 ⫾ 7c 32 ⫾ 7b,d,f 31 ⫾ 6b,e,g
Serum phosphorus (mg/dl) 3.4 ⫾ 0.9 2.7 ⫾ 0.9 3.4 ⫾ 1.1c 3.9 ⫾ 0.9e 4.8 ⫾ 1.6b,e,g,h
Serum calcium (mg/dl) 9.3 ⫾ 0.4 9.1 ⫾ 0.6 9.2 ⫾ 1.0 9.1 ⫾ 0.5 9.9 ⫾ 1.6f
Calcium-phosphorus product (mg2/dl2) 32 ⫾ 9 24 ⫾ 9 31 ⫾ 11d 36 ⫾ 8e 47 ⫾ 17b,e,g,h
Total cholesterol (mg/dl) 161 ⫾ 40 186 ⫾ 30 166 ⫾ 49 210 ⫾ 57b 177 ⫾ 46h
Glucose (mg/dl) 142 ⫾ 58 156 ⫾ 63 156 ⫾ 87 160 ⫾ 67 136 ⫾ 63
CRP (mg/dl) 1.0 ⫾ 1.3 0.4 ⫾ 0.2 1.6 ⫾ 2.2 2.6 ⫾ 2.8b,d 3.7 ⫾ 4.8b,d,f
Medications (% yes)
Calcium-containing phosphate binders 0 0 0 6 43c,e,g,i
Aluminum-containing phosphate binders 0 0 0 0 9b,d,f,h
Calcium channel blockers 53 80 67 81 52
Angiotensin-converting enzyme inhibitors 20 27 23 13 39
hb blockers 7 13 15 25 39
Statins 13 7 10 19 17
Vitamin D 0 7 4 0 17
Warfarin 7 33 23 19 22
a
Data refer to the mean ⫾ SD.
Versus without CKD: bP ⬍0.05, cP ⬍0.01. versus CKD1/2: dP ⬍0.05, eP ⬍0.01.
Versus CKD3: fP ⬍0.05, gP ⬍0.01. Versus CKD4/5: hP ⬍0.05, iP ⬍0.01.
CKD, chronic kidney disease; eGFR, estimated GFR; CRP, C-reactive protein.

to determine whether, among autopsy subjects known to have
CAD, there exists a direct relationship between level of kidney
function and the prevalence of intimal or medial calcification.
Materials and Methods
Study Population
During the 6-yr period between 1991 and 1997, 699 subjects were
autopsied at the National Cardiovascular Center, Osaka, Japan (28).
Given our goal of examining the coronary arteries, we limited autopsy
cases to those with significant coronary artery disease (CAD), resulting
in 123 remaining cases. To permit a pathologic study of the coronary
arteries, we excluded six cases in which serum creatinine had not been
measured. Thus, a final total of 117 autopsy subjects were reviewed
histopathologicaly and immunohistochemicaly.
CAD included myocardial infarction and stable and unstable angina
pectoris. Myocardial infarction was diagnosed using either electrocar-
diograms or echocardiograms, and angina pectoris was diagnosed
based on both symptoms and electrocardiograms. Cerebral vascular
disease was diagnosed using clinical history and computerized tomog-
raphy findings. Peripheral vascular disease was diagnosed based on
symptoms, an ankle/brachial pressure index of less than 0.9, or prior
lower limb revascularization procedures. Thoracic or abdominal aortic
1894 Clinical Journal of the American Society of Nephrology
Table 2. The degree of luminal stenosis of coronary arterya
Patients without Patients with Patients with Patients with Patients with
CKD
Right coronary artery, proximal (%) 50 ⫾ 10
Right coronary artery, distal (%) 53 ⫾ 12
Left main coronary artery (%) 48 ⫾ 8
Left anterior descending coronary artery, 63 ⫾ 25
proximal (%)
Left anterior descending coronary artery, 95 ⫾ 7
distal (%)
Left circumflex coronary artery, proximal (%) 77 ⫾ 3
Left circumflex coronary artery, distal (%) 50 ⫾ 14
a
Data refer to the mean ⫾ SD
Versus CKD1/2: bP ⬍0.05.
versus CKD3: cP ⬍0.05. Versus CKD4/5: dP ⬍0.05.
Figure 1. Coronary artery pathologic findings (A) A representative
left anterior descending coronary artery proximal segment of
CKD5D case with acute myocardial infarction. Large calcification
of intimal atheromatous plaque (surrounded by arrow) (HE). (B)
Distal segment of the same case as (A). Severe stenosis with
calcified hard plaque (HE). (C) Osteopontin-positive calcified
plaque (crop area from A) (immunohistochemistry, DAB). (D)
RCA proximal segment of case without CKD. Large necrotic core
with minute foci of calcification (HE). (E) Distal segment of the
same case as (D) shows no stenosis (HE). (F) Significant CD68-
positive macrophages accumulation in atheromatous plaque with
lymphocyte (arrow) infiltration (crop area from D) (immunohis-
tochemistry, DAB).
aneurysm was diagnosed using clinical history and computed tomog-
raphy. Smoking habits were recorded in two categories: current or
former smokers, and nonsmokers. We possessed extensive laboratory
data on all the study subjects, including serum creatinine, cholesterol,
glucose, and urinalysis results. To create our dataset we chose the most
representative data from the 3 mo before death. All laboratory values
and medical information was obtained by chart review.
To define the presence of CKD, we applied the Modification of Diet
in Renal Disease (MDRD) Study equation for evaluating Japanese CKD
patients (29 –31); eGFR (ml/min/1.73m2) ⫽ 0.741 ⫻ 175 ⫻ (serum
creatinine, mg/dl)⫺1.154 ⫻ (age, years)⫺0.203 ⫻ (0.742 for women).
One-hundred seventeen study subjects were classified into five
Clin J Am Soc Nephrol 4: 1892–1900, 2009
CKD1/2 CKD3 CKD4/5 CKD5D
62 ⫾ 28 71 ⫾ 27 69 ⫾ 23 69 ⫾ 28
58 ⫾ 34 57 ⫾ 26 76 ⫾ 21c 56 ⫾ 30d
58 ⫾ 24 56 ⫾ 22 57 ⫾ 20 52 ⫾ 21
71 ⫾ 23 71 ⫾ 24 77 ⫾ 18 73 ⫾ 21
65 ⫾ 34 65 ⫾ 28 76 ⫾ 15 65 ⫾ 21
67 ⫾ 22 68 ⫾ 25 80 ⫾ 19b 64 ⫾ 27d
58 ⫾ 28 60 ⫾ 28 74 ⫾ 20b,c 55 ⫾ 36d
groups based on eGFR and proteinuria, as follows: without CKD: eGFR
over 60 ml/min/1.73 m2 without proteinuria; CKD1/2: eGFR over 60
ml/min/1.73 m2 with proteinuria; CKD3: eGFR below 60 ml/min/1.73
m2 but above 30 ml/min/1.73 m2; CKD4/5: eGFR below 30 ml/min/
1.73 m2; and CKD5D: patients on maintenance hemodialysis therapy.
In the CKD5D group, the renal diseases that caused ESRD included
nine cases of chronic glomerulonephritis, 11 cases of diabetic nephrop-
athy, and three cases of nephrosclerosis. The mean duration (⫾ SD) of
hemodialysis therapy was 43 ⫾ 60 mo.
Causes of death among all subjects were coronary heart disease in
67% of cases, cerebrovascular disease in 9%, aortic aneurysm in 9%,
infection in 10%, and other causes in the remaining 5%.
Pathologic Examination of Coronary Arteries
In accordance with the regulations of our pathology department, the
all autopsy examination was performed within 3 h after patient’s death.
The coronary arteries were perfusion-fixed for 2 h with neutral buffered
formalin at 100 mmHg and then studied by subserial sectioning at 4
mm intervals. These sections were sliced 5 ␮m thick on glass slides and
stained. We studied all sections with or without significant stenosis of
the proximal and distal right coronary artery (RCA), left main coronary
artery, proximal and distal left anterior descending (LAD) coronary
artery, and proximal and distal left circumflex (LCX) coronary artery.
Apparent stenosis of a coronary artery with more than 75% narrowing
of the luminal area was considered significant.
We used the American Heart Association histologic classification of
atherosclerosis (32) to identify type V lesions that manifested as calci-
fied plaques. Histologic calcification of the intima and media was
detected using Hematoxylin and eosin (HE) staining and osteopontin
immunostaining. To determine the extent of calcification, coronary
artery sections were evaluated using a 5-point scale: grade 0, no calci-
fication; grade 1, calcification ⬍25% in cross-sectional area; grade 2,
calcification ⬎25% and ⬍50% in cross-sectional area; grade 3, calcifica-
tion ⬎50% and ⬍75% in cross-sectional area; grade 4, calcification
⬎75% in cross-sectional area. To detect inflammation, immunostaining
for CD68-positive macrophages was performed.
Statistical Analyses
Values are represented as means ⫾ SD with a p-value of ⬍0.05 as
significance. To compare the variables, one-way ANOVA and chi-
squared tests were used. The association between risk factors and
calcification of coronary arteries was determined by logistic regression
Clin J Am Soc Nephrol 4: 1892–1900, 2009 Coronary Calcification and CKD 1895

Table 3. Coronary artery intimal plaque calcification

The Percentage of Patients with Intimal Calcification (%)

Patients Patients with Patients Patients with Patients with

without CKD CKD1/2 with CKD3 CKD4/5 CKD5D

Right coronary artery, proximal 20 47 58a 56a 78a

Right coronary artery, distal 7 27 29 44b 78b,c,d
Left main coronary artery 33 53 50 50 96b
Left anterior descending coronary artery, 40 40 73b,c 69b,c 87b,c
proximal
Left anterior descending coronary artery, 7 27 23 25 91b,c,d,e
distal
Left circumflex coronary artery, proximal 53 40 58 88a,c 83a,c
Left circumflex coronary artery, distal 27 13 33 44a,c 61a,c,d
Versus without CKD: aP ⬍0.05, bP ⬍0.01. Versus CKD1/2: cP ⬍0.05.
Versus CKD3: dP ⬍0.05. Versus CKD4/5: eP ⬍0.05.

Table 4. Coronary artery intimal calcification scorea

Patients Patients Patients Patients Patients
without with with with with
CKD CKD1/2 CKD3 CKD4/5 CKD5D

Right coronary artery, proximal 0.4 ⫾ 0.4 0.8 ⫾ 1.0 1.0 ⫾ 0.9b 1.0 ⫾ 1.0b 2.1 ⫾ 1.6c,e,f,g
Right coronary artery, distal 0.1 ⫾ 0.3 0.4 ⫾ 0.7 0.4 ⫾ 0.6 0.8 ⫾ 0.8b 1.8 ⫾ 1.4c,e,f,g
Left main coronary artery 0.7 ⫾ 1.0 0.6 ⫾ 0.6 0.9 ⫾ 0.9 1.0 ⫾ 1.0 2.2 ⫾ 1.0c,e,f,h
Left anterior descending coronary artery, 0.7 ⫾ 1.0 0.6 ⫾ 0.8 1.5 ⫾ 1.1e 1.6 ⫾ 1.1b,d 2.9 ⫾ 1.1c,e,f,g
proximal
Left anterior descending coronary artery, 0.1 ⫾ 0.3 0.8 ⫾ 1.1 0.6 ⫾ 0.9 0.7 ⫾ 1.0 1.9 ⫾ 1.0c,e,f,g
distal
Left circumflex coronary artery, 0.6 ⫾ 0.6 0.7 ⫾ 0.8 1.1 ⫾ 0.9d 1.7 ⫾ 1.0c,d,e 2.4 ⫾ 1.4c,e,f,g
proximal
Left circumflex coronary artery, distal 0.4 ⫾ 0.9 0.5 ⫾ 0.9 0.6 ⫾ 0.8 1.1 ⫾ 1.1 1.6 ⫾ 1.5c,e,f
a
Data refer to the mean ⫾ SD
Versus without CKD: bP ⬍0.05, cP ⬍0.01. Versus CKD1/2: dP ⬍0.05, eP ⬍0.01.
Versus CKD3: fP ⬍0.01. Versus CKD4: gP ⬍0.05, hP ⬍0.01.
Coronary arterial sections were evaluated regarding extent of calcification using a 5-point scale: grade 0, no calcification;
grade 1, calcification ⬍25% of cross-sectional area; grade 2, calcification ⬎ 25% and ⬍50% of cross-sectional area; grade 3,
calcification ⬎50% and ⬍75% of cross-sectional area; grade 4, calcification ⬎75% of cross-sectional area.

analysis. Degree of luminal stenosis (%), smoking, diabetes, age (years),
serum calcium level (mg/dl), serum phosphate level (mg/dl), calcium-
phosphorus product (mg2/dl2), use of calcium-containing phosphate
binders, hemodialysis, kidney function (eGFR, ml/min/1.73 m2), C-re-
active protein (CRP) (mg/dl), and use of vitamin D and warfarin were
included in univariate models. All statistical analyses were performed
with Stat View version 5.0 (SAS Institute Inc).
The authors had full access to the data and take responsibility for its
integrity. All authors have read and agree on the manuscript as written.
Results
Patient Characteristics
Table 1 shows the baseline characteristics. The mean age was
higher in the CKD3 and CKD4/5 groups. Hypertension was
evident in the CKD4/5 and CKD5D groups. Diabetes was
infrequent in the patients without CKD. Incidence of smoking,
CAD, CVD, peripheral vascular disease, and aortic aneurysm
were not different among the groups. Serum albumin concen-
tration was lower in the CKD4/5 and CKD5D groups. CRP
data were higher in the CKD4/5 and CKD5D groups. The
prescription of phosphate binders was more frequent in
CKD5D groups. The use of statins, vitamin D, and warfarin,
which may affect vascular calcification, was not different.
Histopathology of Coronary Arteries
Table 2 shows the degree of luminal stenosis of coronary
arteries, and the stenosis was severe in CKD4/5 group. Figure
1 shows representative sections of coronary arteries. In the
CKD5D group, severe stenosis in the proximal segment was
composed of an atheromatous plaque containing a large area of
intimal calcification (Figure 1A), and distal segment showed
also severe stenosis with calcified plaque (Figure 1B). In a
patient without CKD we observed a large necrotic core with
1896 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 1892–1900, 2009

Table 5. Univariate risk factors for the presence of intimal plaque calcification in coronary arteries based on
logistic regression analysis
Right Coronary Artery, Proximal Right Coronary Artery, Distal
Risk Factors
RR (95% CI) P value RR (95% CI) P value

Luminal stenosis (%) 1.03 (1.01 to 1.05) ⬍0.001 1.02 (1.01 to 1.04) ⬍0.05
Smoking 2.67 (1.15 to 6.19) ⬍0.05 1.22 (0.50 to 2.98) 0.66
Diabetes 1.64 (0.74 to 3.60) 0.22 2.70 (1.14 to 6.36) ⬍0.05
Age (years) 1.02 (0.98 to 1.06) 0.41 1.07 (1.02 to 1.12) ⬍0.01
Serum calcium (mg/dl) 1.30 (0.84 to 2.00) 0.24 2.44 (1.22 to 4.89) ⬍0.05
Serum phosphorus (mg/dl) 0.88 (0.64 to 1.20) 0.42 1.09 (0.78 to 1.51) 0.63
Calcium-phosphorus product (mg2/dl2) 1.00 (0.97 to 1.03) 0.99 1.02 (0.99 to 1.06) 0.24
Calcium-containing phosphate binder 3.04 (0.61 to 15.10) 0.17 6.32 (1.26 to 31.75) ⬍0.05
Hemodialysis 2.81 (0.95 to 8.32) 0.07 4.70 (1.51 to 14.66) ⬍0.01
eGFR (ml/min/1.73 m2) 0.99 (0.98 to 1.01) 0.26 0.97 (0.95 to 0.99) ⬍0.0005
CRP (mg/dl) 1.10 (0.94 to 1.29) 0.23 1.14 (1.01 to 1.30) ⬍0.05
Vitamin D 0.25 (0.05 to 1.33) 0.11 1.32 (0.18 to 9.85) 0.78
Warfarin 1.60 (0.60 to 4.05) 0.36 1.81 (0.64 to 5.14) 0.26

Left Anterior Descending

Left Main Coronary Artery Coronary Artery, Proximal
Risk Factors
RR (95% CI) P value RR (95% CI) P value

Luminal stenosis (%) 1.01 (0.99 to 1.04) 0.18 1.03 (1.01 to 1.05) ⬍0.01
Smoking 0.87 (0.35 to 2.17) 0.76 1.44 (0.54 to 3.84) 0.46
Diabetes 1.32 (0.57 to 3.07) 0.52 2.08 (0.79 to 5.49) 0.14
Age (years) 1.03 (0.99 to 1.08) 0.12 1.06 (1.01 to 1.11) ⬍0.05
Serum calcium (mg/dl) 0.81 (0.52 to 1.26) 0.35 1.28 (0.79 to 2.01) 0.32
Serum phosphorus (mg/dl) 0.98 (0.69 to 1.37) 0.89 1.12 (0.76 to 1.64) 0.58
Calcium-phosphorus product (mg2/dl2) 0.99 (0.96 to 1.02) 0.56 1.01 (0.97 to 1.05) 0.55
Calcium-containing phosphate binders 10.04 (0.40 to 87.52) 0.98 9.80 (0.30 to 82.40) 0.98
Hemodialysis 14.2 (1.8 to 111.5) ⬍0.05 7.53 (0.95 to 59.6) 0.06
eGFR (ml/min/1.73 m2) 0.97 (0.95 to 0.99) ⬍0.0005 0.99 (0.97 to 1.00) 0.09
CRP (mg/dl) 1.64 (1.04 to 2.60) ⬍0.05 1.32 (0.93 to 1.88) 0.12
Vitamin D 1.02 (0.18 to 5.86) 0.99 0.61 (0.11 to 3.56) 0.58
Warfarin 2.84 (0.87 to 9.22) 0.08 4.00 (0.86 to 18.57) 0.07

Left Anterior Decending Coronary Left Circumflex Coronary Artery,

Artery, Distal Proximal
Risk Factors
RR (95% CI) P value RR (95% CI) P value

Luminal stenosis (%) 1.01 (0.99 to 1.03) 0.19 1.03 (1.01 to 1.05) ⬍0.01
Smoking 0.68 (0.26 to ⫺1.77) 0.43 1.35 (0.54 to 3.35) 0.52
Diabetes 1.61 (0.65 to 4.00) 0.30 2.50 (1.00 to 6.25) 0.05
Age (years) 1.04 (0.99 to 1.09) 0.07 1.03 (0.99 to 1.08) 0.16
Serum calcium (mg/dl) 1.80 (0.93 to 3.49) 0.08 1.22 (0.78 to 1.93) 0.38
Serum phosphorus (mg/dl) 1.37 (0.91 to 1.98) 0.14 1.24 (0.85 to 1.79) 0.27
Calcium-phosphorus product (mg2/dl2) 1.05 (0.99 to 1.09) 0.07 1.03 (0.99 to 1.07) 0.19
Calcium-containing phosphate binders 12.12 (1.41 to 104.05) ⬍0.05 3.60 (0.43 to 29.86) 0.24
Hemodialysis 9.53 (2.44 to 37.2) ⬍0.005 2.88 (0.78 to 10.6) 0.12
eGFR (ml/min/1.73 m2) 0.97 (0.95 to 0.99) ⬍0.005 0.97 (0.95 to 0.99) ⬍0.001
CRP (mg/dl) 1.10 (0.94 to 1.28) 0.23 1.01 (0.87 to 1.18) 0.88
Vitamin D 0.45 (0.05 to 4.51) 0.50 0.71 (0.12 to 4.14) 0.71
Warfarin 1.25 (0.45 to 3.47) 0.68 2.02 (0.62 to 6.61) 0.24
(continued)
Clin J Am Soc Nephrol 4: 1892–1900, 2009
Table 5. (Continued)
Risk Factors
Risk factors
Luminal stenosis (%)
Smoking
Diabetes
Age (years)
Serum calcium (mg/dl)
Serum phosphorus (mg/dl)
Calcium-phosphorus product (mg2/dl2)
Calcium-containing phosphate binders
Hemodialysis
eGFR (ml/min/1.73 m2)
CRP (mg/dl)
Vitamin D
Warfarin
minute foci of calcification at proximal segments (Figure 1D),
without severe stenosis of distal segments (Figure 1E). Using
immunohistochemical staining, osteopontin-positive calcified
plaque was found in the atheromatous plaque of the intima at
the proximal segment in the CKD5D group (Figure 1C), and an
accumulation of CD68-positive macrophages was seen in an
atheromatous plaque with lymphocyte infiltration (Figure 1F).
Intimal Plaque Calcification and Risk Factors
Intimal calcification was most evident in groups CKD5D,
CKD4/5, and CKD3 (Table 3).
Table 4 shows the intimal calcification score in each segment
of the coronary arteries. Calcification was higher in the CKD5D
group than in the other groups. The scores were also high in the
CKD4/5 group, in the proximal and distal RCA lesions and
proximal LCX coronary artery lesion.
Univariate analysis was performed to assess the presence of
intimal calcification (Table 5). Stenosis, hemodialysis, and kid-
ney function seemed to be linked to intimal calcification in
almost all cases. Smoking was linked to calcification of proxi-
mal lesions, while calcium-phosphorus product or phosphate
binder use was linked to calcification of distal lesions. Diabetes,
age, and inflammation seemed to be linked to calcification of
both of proximal and distal lesions. The use of vitamin D was
not linked to calcification, but warfarin administration tended
to relate the coronary calcification.
Multivariate analysis for the presence of intimal calcification
was performed based on the logistic regression analysis (Table
6). The significant variables were kidney function, luminal ste-
nosis, and age.
Medial Calcification and Risk Factors
We evaluated calcification in media of coronary arteries in all
subjects. Medial calcification was present in CKD4/5 and
CKD5D groups, in proximal lesions of four cases and distal
lesions of three cases among 39 cases. Medial calcification of
Coronary Calcification and CKD 1897
Left Circumflex Coronary Artery, Distal
RR (95% CI) P value
1.02 (1.01 to 1.04) ⬍0.05
0.63 (0.26 to 1.52) 0.30
5.10 (2.05 to 12.7) ⬍0.0005
1.02 (0.98 to 1.06) 0.29
1.27 (0.80 to 2.01) 0.30
1.29 (0.91 to 1.83) 0.15
1.03 (0.99 to 1.07) 0.13
3.25 (0.78 to 13.50) 0.06
3.84 (1.01 to 8.80) ⬍0.05
0.98 (0.96 to 0.99) ⬍0.01
1.12 (0.97 to 1.30) 0.14
1.24 (0.17 to 9.20) 0.84
1.53 (0.57 to 4.10) 0.40
both proximal and distal lesions was seen in the segments with
or without intimal calcification, and the continuous deposit of
intimal calcification into the media was not observed. The area
of medial calcification occurred ⬍25% of the total medial area
in the proximal lesions of three patients and in the distal lesions
of two patients. One patient showed medial calcification ⬎75%
of the total medial area in both proximal and distal lesions, who
had severe CAD and more than 20 yr duration of hemodialysis.
We performed univariate analysis to assess the presence of
medial calcification. The only significant variable associated with
medial calcification in proximal lesions was the use of calcium-
containing phosphate binders (RR 21.0, 95% CI 1.9 to 236.1, P
⬍0.05), while for distal lesions significant variables were hemodi-
alysis treatment (RR 5.1, 95% CI 1.2 to 39.4, P ⬍ 0.05) and hemo-
dialysis duration (RR 1.05, 95% CI 1.01 to 1.15, P ⬍ 0.05).
Discussion
We evaluated the pathologic findings of coronary arteries fo-
cusing on locality and severity of calcification in autopsy cases
known to have CAD and a wide range of kidney function. Our
results showed that: (1) calcification of coronary arteries was de-
posited intimal plaque mainly in all cases but also medial layer
among cases of CKD4/5 and CKD5D; (2) intimal plaque calcifi-
cation was more severe in patients who had received hemodialy-
sis than in those who did not; (3) intimal calcification was more
intense in patients with an eGFR below 30 ml/min/1.73 m2 than
in CKD patients with an eGFR over 60 ml/min/1.73 m2 or in
patients without CKD; (4) intimal calcification was associated with
both traditional cardiovascular and uremic risk factors; and (5)
medial calcification was present in CKD4/5 and hemodialysis cases,
with incidence increased by the presence of uremic risk factors.
Calcification may arise in all types of arteries, both large
elastic vessels and smaller muscular ones. The location and
degree of vascular calcification depend on physiologic and
pathologic conditions (12–14). Calcification develops earlier
1898 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 1892–1900, 2009

Table 6. Multivariate risk factors for the presence of intimal plaque calcification in each coronary artery segment
based on logistic regression analysis
Right Coronary Artery, Right Coronary Left Main
Proximal Artery, Distal Coronary Artery

RR (95% CI) P value RR (95% CI) P value RR (95% CI) P value

Luminal stenosis (%) 1.05 (1.02 to 1.08) ⬍0.001 1.01 (0.96 to 1.03) 0.64 02 (1.00 to 1.05) 0.06
eGFR (ml/min/1.73 0.98 (0.95 to 1.01) 0.15 0.96 (0.93 to 0.99) ⬍0.005 0.97 (0.94 to 0.99) ⬍0.05
m2)
Smoking 4.19 (1.16 to 15.07) ⬍0.05 2.07 (0.93 to 9.90) 0.36 0.55 (0.15 to 2.06) 0.38
Diabetes 2.33 (0.70 to 7.75) 0.17 1.26 (0.33 to 4.88) 0.73 0.99 (0.28 to 3.63) 0.99
Age (years) 1.05 (1.01 to 1.11) ⬍0.05 1.09 (1.01 to 1.17) ⬍0.05 1.04 (0.98 to 1.10) 0.17
Calcium-phosphorus 0.99 (0.95 to 1.05) 0.97 1.01 (0.96 to 1.07) 0.60 0.96 (0.91 to 1.01) 0.12
product (mg2/dl2)
CRP (mg/dl) 1.07 (0.90 to 1.28) 0.45 1.05 (0.88 to 1.26) 0.59 1.13 (0.87 to 1.48) 0.36

Left Anterior Left Anterior

Descending Coronary Artery, Descending Coronary Artery,
Proximal Distal

RR (95% CI) P value RR (95% CI) P value

Luminal stenosis (%) 06 (1.02 to 1.11) ⬍0.005 1.02 (0.99 to 1.05) 0.20
eGFR (ml/min/1.73 m2) 0.96 (0.93 to 0.99) ⬍0.05 0.98 (0.96 to 0.99) ⬍0.05
Smoking 0.95 (0.21 to 4.31) 0.94 0.63 (0.14 to 2.88) 0.55
Diabetes 6.92 (1.03 to 46.41) ⬍0.05 0.91 (0.24 to 3.39) 0.88
Age (years) 1.05 (0.99 to 1.11) 0.12 98 (0.92 to 1.06) 0.63
Calcium-phosphorus 1.02 (0.95 to 1.09) 0.56 1.02 (0.97 to 1.08) 0.45
product (mg2/dl2)
CRP (mg/dl) 1.07 (0.85 to 1.34) 0.59 1.03 (0.82 to 1.30) 0.80

Left Circumflex Coronary Artery, Left Circumflex Coronary Artery,

Proximal Distal

RR (95% CI) P value RR (95% CI) P value

Luminal stenosis (%) 1.04 (1.01 to 1.07) ⬍0.05 1.03 (1.00 to 1.06) 0.08
eGFR (ml/min/1.73 m2) 0.97 (0.95 to 0.99) ⬍0.05 0.99 (0.96 to 1.02) 0.37
Smoking 1.60 (0.38 to 6.67) 0.52 1.34 (0.27 to 6.56) 0.72
Diabetes 3.10 (0.67 to 13.95) 0.14 5.06 (1.05 to 24.38) ⬍0.05
Age (years) 1.02 (0.97 to 1.08) 0.41 1.01 (0.95 to 1.08) 0.79
Calcium-phosphorus 03 (0.97 to 1.10) 0.36 1.06 (0.99 to 1.13) 0.08
product (mg2/dl2)
CRP (mg/dl) 0.93 (0.77 to 1.11) 0.40 0.92 (0.70 to 1.21) 0.55

than otherwise might in the absence of severe CKD, and con-
tributes to the markedly increased cardiovascular risk observed
in this particular population (12–27).
The CAC is thought to occur in two types in the vessel wall.
There is still debate about whether these two types of calcifi-
cation are distinct entities or not (12–14). London et al. found
that typical plain x-ray aspects in CKD patients showed either
a patchy distribution, which is thought to be characteristic of
intimal calcification in association with atherosclerosis, or a
pipeline-like distribution attributed to medial calcification
(33,34). However, in many patients with ESRD these two pro-
cesses seem to develop in parallel (12). Although the entire
vascular tree may calcify, only some segments develop athero-
sclerosis, including the coronary arteries, the aorta, and the
arteries of the abdomen and lower extremities (12). In contrast,
for example, the arteries of the upper extremities, appear rela-
tively or entirely resistant to the atheromatous process (12).
Intimal and medial calcification is thought to differ with
regard to their clinical relevance. Whereas intimal calcification
appears to contribute to plaque vulnerability, possibly in a
biphasic manner, medial calcification contributes to vascular
stiffness, which increases pulse-wave velocity and decreases
diastolic BP and increases systolic BP (35). Hemodialysis pa-
tients with predominantly intimal calcification have a higher
relative risk of mortality than those with predominantly medial
calcification (34). However, presently available noninvasive im-
Clin J Am Soc Nephrol 4: 1892–1900, 2009
aging techniques cannot provide a clear-cut distinction be-
tween intimal and medial calcification. Only microscopic anal-
ysis of vessel samples from surgery or autopsy allows that
distinction of localization of calcification. Most adult patients
with CKD suffer from both intimal and medial calcification.
Given the above, we chose to analyze autopsied cases with
known CAD and a wide range of kidney function to distinguish
the presence of both intimal and medial calcification and de-
termine which risk factors contribute to each type of calcifica-
tion. We found that in patients with known CAD, CAC oc-
curred at plaque-forming degenerative intimal changes. The
degree of intimal plaque calcification correlated with the degree
of plaque-forming degenerative changes that is with the degree
of luminal stenosis. Intimal calcification was also related to
renal function. Using EBCT, Tomiyama et al. found that tradi-
tional and nontraditional risk factors correlated with calcifica-
tion in prehemodialysis patients (27). Garlannd et al. reported
that in patients with stages 3, 4, and 5 CKD without cardiovas-
cular disease, traditional cardiovascular risk factors and serum
calcium levels were associated with CAC, while no association
was shown with eGFR (25). The range of kidney function was
wider in our study than in those mentioned above (25,27),
enabling us to evaluate the association between CAC and kid-
ney function. Indeed, no association was found in several seg-
ments in our study in CKD3, CKD4/5, or CKD5D patients.
These findings showed that intimal calcification had already
started before kidney function reached CKD3, and after reach-
ing CKD3 the degree of calcification developed significantly.
The finding of Go et al. that eGFR below 45 ml/min was a risk
factor for cardiovascular mortality (36) may be associated with
the presence of intimal calcification of CKD3 patients.
We demonstrated that medial calcification occurs in CKD4/5
and CKD5D patients with known CAD, in coronary sections
with and without significant stenosis or intimal calcification.
The medial calcification was not due to the continuous depo-
sition of intimal calcification into the media. This finding was
more evident in hemodialysis patients without significant ste-
nosis or intimal calcification (unpublished data). This observa-
tion may support the hypothesis that mechanism of both types
of calcification would be different. We cannot conclude that no
association was present between medial calcification and ath-
eromatous plaque formation. Medial calcification was associ-
ated with hemodialysis therapy, but not with stenosis of arter-
ies. We identified the different risk factors for intimal and
medial calcification; for medial calcification, these included
uremic risk factors.
One limitation of our study is that we analyzed only autopsy
subjects known to have CAD, most of whom died of cardio-
vascular diseases, and did not examine any subjects without
CAD. Our autopsy study was necessarily performed using a
chart review to obtain each individual’s clinical history, poten-
tially introducing a degree of ascertainment bias. A second
source of potential bias in this study is the use of estimated
GFR. At higher GFR levels, the value may be underestimated,
an issue common to all populations.
In conclusion, we have demonstrated the presence and asso-
ciations of CAC in patients with CAD and a wide variation in
Coronary Calcification and CKD 1899
kidney function. Traditional and nontraditional risk factors
were applicable to CAC in patients with CAD and CKD. Kid-
ney function, smoking, diabetes, calcium-phosphorus metabo-
lism, and aging were risk factors for intimal calcification. Me-
dial calcification was strongly suspected to relate to uremic
risks. We should attempt to control both types of risk factors to
prevent the onset of CAC before stage 3 CKD.
Acknowledgments
The authors thank the members of the Department of Pathology,
National Cardiovascular Center, for their technical support.
Disclosures
None.
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