Biomedical Research 32 (2) 83-90, 2011

Left ventricular hypertrophy is associated with inflammation in sodium loaded

subtotal nephrectomized rats

Yoshiyuki Moriguchi1, Kenji Yogo1, Ken Aizawa1, Ken-ichi Serizawa1, Yoshihito Tashiro1, Keigo Yorozu1,
Nobuhiko Ishizuka1, Sadahiro Iwabuchi2, Hidemitsu Kitamura2, and Takashi Nishimura2, 3
1
Product Research Department, Chugai Pharmaceutical Co., LTD., 2 Division of Immunoregulation, Research Section of Disease Con-
trol, Institute for Genetic Medicine, Hokkaido University, and 3 Division of ROYCE Health Bioscience, Institute for Genetic Medicine,
Hokkaido University
(Received 13 October 2010; and accepted 13 December 2010)

ABSTRACT
The pathological influences of inflammation on left ventricular hypertrophy (LVH) were studied in
subtotal nephrectomized (SNx) rats after 0.3% NaCl loading for 5 weeks. We found that mild hy-
pertension, increased plasma levels of creatinine, inorganic phosphate, asymmetric dimethylargi-
nine (ADMA), and parathyroid hormone (PTH) were observed in the present SNx rats without
LVH. In the present study, the NaCl-loaded SNx (SNx + NaCl) rats were characterized by signifi-
cant LVH and hypertension with aggravated values of all the parameters. We further confirmed
that glomerular sclerosis, tubulointerstitial fibrosis, and inflammatory cell infiltration into the tubu-
lointerstitial area, observed in the SNx rats, were more severely caused in the SNx + NaCl rats. In
addition, plasma interleukin-6 (IL-6) levels in the SNx + NaCl rats were significantly increased
compared to those in the SNx rats. These findings indicated that NaCl-loaded SNx rats developed
LVH and hypertension, which were accompanied with increased plasma levels of PTH, creatinine,
inorganic phosphorus, ADMA, and IL-6. Thus, these results suggest that inflammation as well as
endothelial dysfunction would be correlated with LVH as non-traditional risk factors at the early
stage in the present renal failure model.

Compared with general population, a large propor-
tion of patients with chronic kidney disease (CKD)
die from cardiovascular disease (9). The mecha-
nisms underlying the higher risk of cardiovascular
events in CKD patients are not fully understood,
though they are thought to be associated with the
high incidence of both traditional and non-tradition-
al risk factors for cardiovascular disease. A large
percentage of patients with CKD have traditional
cardiovascular risk factors such as hypertension, left
ventricular hypertrophy (LVH), dyslipidemia and di-
Address correspondence to: Takashi Nishimura, Ph.D.
Division of Immunoregulation, Research Section of Dis-
ease Control, Institute for Genetic Medicine Hokkaido
University, Sapporo 060-0815, Japan
Tel & Fax: +81-11-706-7546
E-mail: tak24@igm.hokudai.ac.jp
abetes (12). Although the prevalence of traditional
risk factors in patients with CKD is high, the sever-
ity of cardiovascular disease does not necessarily
correspond to these risk factors (18), which suggests
the relation of non-traditional cardiac risk factors to
patients with CKD. It has been demonstrated that
the prevalence of non-traditional cardiac risk factors
such as hyperparathyroidism, endothelial dysfunc-
tion, albuminuria, inflammation and anemia in-
creased as kidney function declines (2, 19). It was
also reported that parathyroid hormone (PTH) con-
tributed to the LVH observed in chronic renal fail-
ure, which would play roles in vascular calcification
and the development of cardiac fibrosis via activa-
tion of fibroblasts (1).
Recently, the consequences of inflammation, a
non-traditional risk factor, have gained attention in
nephrology. Chronic inflammation is characterized
84
by the persistent effect of a causative stimulus,
which leads to destruction of cells and tissues. Pre-
vious paper demonstrated that plasma levels of in-
flammatory factors such as C-reactive protein (CRP)
and interleukin-6 (IL-6) were elevated in patients
with CKD (17), but the relative importance of these
factors in predicting cardiovascular outcomes re-
mained unresolved. Although CRP reflects systemic
inflammation and predicts cardiovascular risk, there
is no direct supporting data for CRP to promote vas-
cular disease. On the other hand, it has been report-
ed that IL-6 might directly act as a promoter of
atherosclerosis and wasting disorders by providing
oxidative stress and endothelial dysfunction (24).
Endothelial dysfunction is also a non-traditional
risk factor in patients with CKD which causes re-
duced bioavailability of nitric oxide (NO). Recent
papers indicated that the accumulation of asymmet-
ric dimethylarginine (ADMA), an endogenous inhib-
itor of NO synthase (NOS), became not only a
biomarker of endothelial dysfunction but also a new
potential risk factor for LVH in patients with or
without CKD (14, 26). It was also demonstrated that
ADMA was a potential proinflammatory factor to
induce the monocytic adhesion to endothelial cells
and the release of chemokines in vitro (4). However,
the precise mechanism of proinflammatory action of
ADMA on monocytes has not been fully understood
in the kidney.
In the present study, we established NaCl-loaded
SNx rats as an early stage CKD model with LVH
and evaluated the involvements of non-traditional
risk factors, namely inflammation and endothelial
dysfunction in addition to the traditional risk factors.
MATRIALS AND METHODS
Animal models. Male Wistar rats (6 weeks old; Ja-
pan SLC Inc, Shizuoka, Japan) were fed ordinary
laboratory chow (CE-2; CREA Japan, Tokyo, Japan)
and allowed free access to water under a constant
light and dark cycle of 12 h. After 1 week of adap-
tation, animals were subjected to two-step surgical
partial nephrectomy under anesthesia (22.5% iso-
flurane). Laparotomy was undergone under sterile
conditions and the upper and lower side of the left
kidney was resected in the first procedure. One
week after the first operation, animals were re-
anesthetized and the right kidney was removed.
Sham-operated animals (sham) underwent laparoto-
my alone. Subtotal nephrectomized rats were divid-
ed into 2 groups and received drinking water ad
libitum containing either 0 (SNx) or 0.3% NaCl
Y. Moriguchi et al.
(SNx + NaCl) from 1 week after the second opera-
tion. All animal procedures were conducted in
accordance with Chugai Pharmaceuticals ethical
guidelines for animal care, and all experimental pro-
tocols were approved by the Animal Care Commit-
tee of the institution.
Measurement of blood pressure and blood biochemi-
cal parameters. Systolic blood pressure (SBP) was
measured every week from immediately before
NaCl loading, by the tail cuff method (BP-98A;
Softron, Tokyo, Japan) under conscious conditions.
At 5 weeks after NaCl loading, whole blood was
collected from the abdominal aorta under deep pen-
tobarbital anesthesia. Plasma levels of creatinine, in-
organic phosphorus and calcium were measured
with an autoanalyzer (Hitachi 7170; Hitachi Co.
Ltd, Tokyo, Japan). Plasma PTH levels were mea-
sured by rat intact PTH enzyme-linked immunosor-
bent assay (ELISA) (Immutopics, Inc., CA, USA).
Plasma IL-6 levels were measured with a rat IL-6
immunoassay kit (Invitrogen Corp., CA, USA).
Plasma CRP levels were measured with a rat C-
reactive protein (CRP) ELISA Kit (Alpha Diagnostic
International, TX, USA).
Measurement of plasma ADMA. Plasma ADMA lev-
els were determined using an API4000QTRAP (AB
SCIEX, CA, USA) equipped with Acquity UPLC
H-Class Bio system (Waters Corp., MA, USA). An-
alytical chromatography of ADMA was performed
on a COSMOSIL column (4.6 250 mm, type
NAP, Waters; Nacalai Tesque, Kyoto, Japan). The
Q1/Q3 values of analytes were 204.2/70.6 (ADMA).
Instrument control and data processing were run by
Analyst software version 1.4 (AB SCIEX, CA,
USA). 13C6-arginine (internal standard, IS, 100 mol/
L) was added to 50 L of plasma as an internal
standard. To precipitate plasma proteins, 90 L ace-
tonitrile was added to each plasma sample. The
samples were voltex-mixed and centrifuged at
10,000 g for 10 min at 4C. Supernatants were
then collected and dried under vacuum at 60C. The
residue was reconstituted in 500 L mobile phase.
Calibration curves were plotted using the ratio of
peak areas of analyzed molecules to IS versus con-
centrations. Calibration curve was linear in the
range of 0.1 to 50 mol/L. The limit of detection
was 0.1 mol/L. The intra-assay precision and accu-
racy were in the range of 0.32.9 and 1.56.1%,
respectively. The inter-assay precision and accuracy
were in the range of 6.612.8 and 4.36.5%, re-
spectively.
IL-6 is associated with LVH in SNx
Table 1Changes in physiological and biochemical parameters in the sham, SNx, and
SNx + NaCl rats
Sham
Body weight (g) 296 3
LV/BW (mg/g) 1.85 0.04
SBP (mmHg) 142 3
Creatinine (mg/dL) 0.38 0.01
IP (mg/dL) 6.5 0.3
Ca (mg/dL) 11.2 0.2
Data are expressed as mean SEM of 5 to 6 animals. #P < 0.05 comparing SNx with sham by Stu-
dents t-test. *P < 0.05 comparing SNx + NaCl with SNx by Students t-test.
LV/BW: left ventricular mass/body weight, SBP: systolic blood pressure, IP: inorganic phosphorus.
Histological analysis. At the experimental end point,
body weight and left ventricular mass were mea-
sured. The heart and kidney were excised and fixed
in 10% neutral buffered formalin, and embedded in
paraffin according to the standard procedure. Hema-
toxylin-eosin and Azan staining were used in light
microscopic evaluation. Pathophysiological changes
were assayed in a blinded manner and evaluated by
semi-quantitative score.
Statistical analysis. Data are expressed as mean
SEM. Comparison between two groups was per-
formed by Students t-test or Wilcoxon test using
SAS version 8.2 software (SAS Institute, NC, USA).
Values with P < 0.05 were considered statistically
significant. Multivariate correlation analysis was
performed to evaluate the associations between car-
diac abnormality and the other variables using JMP
7.0.1 software (SAS Institute).
RESULTS
Traditional risk factors and left ventricular hyper-
trophy in NaCl-loaded SNx rats
In order to address the involvements of traditional
risk factors and non-traditional risk factors such as
inflammation and endothelial dysfunction, we estab-
lished NaCl-loaded SNx rats as an early stage CKD
model. There were no differences in body weight
between the SNx and SNx + NaCl rats (Table 1),
though slight growth retardation was observed in the
SNx rats compared to the sham-operated control rats
(data not shown). We found that left ventricular
mass/body weight (LV/BW) of the SNx rats was
significantly higher than that of the sham rats (P <
0.05) at five weeks after NaCl loading (Table 1).
Plasma creatinine and plasma inorganic phosphorus
of the SNx rats were also higher than those of the
sham rats (creatinine: P < 0.001; inorganic phospho-
85
SNx SNx + NaCl
257 12# 243 6
2.10 0.09# 2.92 0.09*
168 5# 239 6*
1.24 0.15# 1.95 0.16*
8.2 0.4# 10.8 0.6*
11.4 0.2 10.5 0.3*
Fig. 1Changes in systolic blood pressures of the sham,
SNx and SNx + NaCl rats. Data are expressed as mean
SEM of 5 to 8 animals. : sham, : SNx, : SNx + NaCl.
#
P < 0.05 when comparing SNx with sham by Students
t-test. *P < 0.05 when comparing SNx + NaCl with SNx by
Students t-test.
rus: P < 0.05, Table 1).
We further confirmed that all values of the pa-
rameters in the SNx + NaCl rats were significantly
higher than those of the SNx rats (LV/BW: P <
0.001; inorganic phosphorus: P < 0.05; creatinine:
P < 0.05, Table 1). Plasma calcium levels in the
SNx + NaCl rats significantly decreased compared
to those of the SNx rats (P < 0.05), though there
were no differences between the sham and the SNx
rats (Table 1). We found that SBP in the SNx + NaCl
rats was higher than that of the SNx rats, which sig-
nificantly increased dependent on the period of Na-
Cl-loading (SNx vs. sham: P < 0.01; SNx + NaCl vs.
SNx: P < 0.001) (Fig. 1, Table 1).
Non-traditional risk factors in the NaCl-loaded SNx
rats
We also investigated the non-traditional cardiac risk
factors in the present models and then found that
plasma ADMA and PTH levels in the SNx rats were
86 Y. Moriguchi et al.

significantly higher than those of the sham rats
(ADMA, SNx vs. sham: P < 0.01; PTH, SNx vs.
Sham: P < 0.05, Table 2). Additionally, statistically
significant increases in PTH and ADMA were ob-
served in the SNx + NaCl rats compared to those of
the SNx rats (PTH, SNx + NaCl vs. SNx: P < 0.01;
ADMA, SNx + NaCl vs. SNx: P < 0.05, Table 2).
We further evaluated plasma IL-6 and CRP as in-
flammatory markers. As a result, plasma IL-6 levels
in the SNx + NaCl rats increased significantly com-
pared to those of the SNx rats (P < 0.05), though
IL-6 showed no difference between the sham and
the SNx rats (Table 2). On the other hand, plasma
levels of CRP did not differ among the present rat
models (Table 2).
Histological analysis of the kidney
We then confirmed pathological changes in the kid-
ney of the sham, SNx, and SNx + NaCl rats. Subto-
tal nephrectomy induced significant tissue damages
such as glomerular sclerosis, tubule enlargement,
urinary casts or tubulointerstitial fibrosis (Fig. 2A

Table 2Changes in inflammatory and cardiovascular biomarkers in the sham, SNx, and
SNx + NaCl rats
Sham SNx SNx + NaCl
IL-6 (pg/mL) 8.5 0.7 7.6 0.5 11.6 1.5*
CRP (mg/mL) 495 15 512 15 478 24
PTH (pg/mL) 113 19 1902 655# 5378 508*
ADMA (mol/L) 0.66 0.03 1.27 0.13# 1.61 0.07*
Data are expressed as mean SEM of 5 to 6 animals. #P < 0.05 comparing SNx group with sham
group by Students t-test. *P < 0.05 comparing SNx + NaCl with SNx by Students t-test.
IL-6: interleukin 6, CRP: C-reactive protein, PTH: parathyroid hormone, ADMA: asymmetric di-
methylarginine.

Fig. 2Representative pathological changes in the kidneys of the sham, SNx, and SNx + NaCl rats. Glomerular sclerosis
was observed in the kidney of the SNx (B) and SNx + NaCl (C) rats compared to that of the sham (A) rats. Enlargement of
tubule, urinary casts, and inflammatory cell infiltration were observed in the kidney of the SNx (E and H) and the SNx + NaCl
(F and I) rats in contrast to that of the sham (D and G) rats. A through C are Azan-stained sections (bar = 50m). D
through I are HE-stained sections (D through F: bar = 200 m; G through I: bar = 50 m).
IL-6 is associated with LVH in SNx 87

through 2F, Table 3). We confirmed that the loading
of NaCl into the SNx rats significantly exacerbated
the glomerular sclerosis (Fig. 2B, 2C, and Table 3).
There were no remarkable histopathological changes
such as myocardial fibrosis in the left ventricle of
the heart among the rats (data not shown).
We first observed that the numbers of inflamma-
tory cells such as neutrophils and mononuclear cells
infiltrating into the kidney of the SNx rats signifi-
cantly increased compared to the sham rats. Then,
we found that the mononuclear cells infiltrated espe-
cially into the tubulointerstitial area (Fig. 2G through
2I and Table 4). Most inflammatory cells in the tu-
bulointerstitial area of the SNx and SNx + NaCl rats
were mononuclear cells comprising lymphocytes
and macrophages. Among them, neutrophil infiltra-
tion into the tubulointerstitial area of the kidney in
the SNx + NaCl rats was significantly increased
compared to the SNx rats (Fig. 2H, 2I, and Table 4).
Correlation analysis among the non-traditional risk
factors, traditional risk factors, and left ventricular
hypertrophy
We finally evaluated multivariate correlation coeffi-
cients among the traditional, non-traditional factors
and LVH in the present model, and the calculated
data were summarized in Table 5. As a result, LV/
BW was highly correlated with PTH (r = 0.946,
P < 0.0001), creatinine (r = 0.894, P < 0.0001), inor-
ganic phosphorus (r = 0.884, P < 0.0001), SBP (r =
0.851, P < 0.0001), ADMA (r = 0.838, P < 0.0001),
mononuclear cell infiltration (r = 0.765, P = 0.0006)
and IL-6 (r = 0.639, P = 0.0077). There was no cor-
relation between LV/BW and CRP (r = 0.256, P =
0.3385). The score of mononuclear cell infiltration
in the interstitial area was highly correlated with
creatinine (r = 0.900, P < 0.0001), ADMA (r = 0.899,
P < 0.0001), PTH (r = 0.827, P<0.0001), inorganic
phosphorus (r = 0.780, P = 0.0004) and SBP (r =
0.756, P = 0.0007).
DISCUSSION
In the present study, we established LVH-developed
CKD model using NaCl-loaded SNx rats and inves-
tigated the effects of the non-traditional risk fac-
torsinflammation and endothelial dysfunctionas
well as those of the traditional risk factors on the
LVH. We confirmed that LVH was correlated with
plasma level of PTH, creatinine, inorganic phospho-
rus, and SBP in the NaCl-loaded SNx rats. Previous
reports have demonstrated that non-traditional risk
factors such as vascular calcification factors (PTH,
inorganic phosphorus) and uremic toxin (creatinine)
are involved in the pathogenesis of a number of car-
diovascular abnormalities including LVH in CKD
patients (6, 19, 20). These results suggest that the
present rat model would provide the evidence for

Table 3Pathological changes in the kidney of the sham, SNx, and SNx + NaCl rats
Glomerular sclerosis Enlargement of tubule Urinaly casts Interstitial fibrosis
N + ++ +++ + ++ +++ + ++ +++ + ++ +++
Sham 5 5 0 0 0 0 5 0 0 0 0 5 0 0 0 0 5 0 0 0 0
SNx 5 0 4 1 0 0# 0 0 4 1 0# 0 4 1 0 0# 0 3 1 1 0#
SNx + NaCl 6 0 0 3 3 0* 0 0 3 2 1 0 2 4 0 0 0 0 3 3 0
Date are expressed as the number of animals in each score. Score was evaluated with following criteria in a blinded manner.
: negative, : minimal, +: mild, 2+: moderate, 3+: marked.
#
P < 0.05 comparing SNx with sham by Wilcoxon test. *P < 0.05 comparing SNx + NaCl with SNx by Wilcoxon test.

Table 4Changes in inflammatory cell infiltration in the kidney of the sham, SNx, and SNx + NaCl rats
Whole kidney Interstitial area
Neutrophil and mononuclear Neutrophil Mononuclear cell
cell infiltration infiltration infiltration
N + ++ +++ + ++ +++ + ++ +++
Sham 5 5 0 0 0 0 5 0 0 0 0 5 0 0 0 0
SNx 5 0 1 3 1 0# 3 2 0 0 0 0 0 4 1 0#
SNx + NaCl 6 0 0 4 2 0 0 6 0 0 0* 0 0 2 4 0
Data are expressed as the number of animals with each score. Score was evaluated with the following criteria in a blinded manner.
: negative, : minimal, +: mild, 2+: moderate, 3+: marked.
#
P < 0.05 comparing SNx with sham by Wilcoxon test. *P < 0.05 comparing SNx + NaCl with SNx by Wilcoxon test.
88 Y. Moriguchi et al.

Table 5Multivariate correlation matrix among non-traditional risk factors, traditional risk factors, and LV/BW
LV/BW IL-6 CRP ADMA PTH MNCI SBP CRE IP
Non-traditional risk factors
IL-6 0.639a
CRP 0.256 0.352
ADMA 0.838b 0.409 0.103
PTH 0.946b 0.563 0.183 0.896b
MNCI 0.765b 0.391 0.001 0.899b 0.827b
Traditional risk factors
SBP 0.851b 0.426 0.161 0.792b 0.847b 0.756b
CRE 0.894b 0.522 0.110 0.970b 0.901b 0.900b 0.819b
IP 0.884b 0.658a 0.231 0.873b 0.856b 0.780b 0.772b 0.926b
Ca 0.670a 0.558 0.045 0.573 0.638a 0.408 0.444 0.658a 0.619
a
P < 0.01, bP < 0.001 comparing each parameters by correlation analysis.
LV/BW: left ventricular mass/body weight, CRP: C-reactive protein, IL-6: interleukin 6, ADMA: asymmetric dimethylarginine, PTH:
parathyroid hormone, MNCI: mononuclear cell infiltration, SBP: systolic blood pressure, CRE: creatinine, IP: inorganic phosphorus.

the effects of non-traditional risk factors on LVH
and hypertension in the initial stage of the renal
failure.
Although it is noted that inflammatory markers
such as CRP and IL-6 are elevated in patients with
CKD, the question as to which of these markers
predict cardiovascular outcomes still remains unre-
solved. Previous papers reported that increased plas-
ma levels of IL-6 in patients correlated with the
severity of heart failure, which would be predictive
of mortality in patients with or without CKD (7,
21). In addition, a recent report indicated that IL-6
infusion in normal rats caused LVH (15). The pres-
ent findings indicated that inflammation (plasma
IL-6) as well as endothelial dysfunction (ADMA)
was correlated with LVH in the early stage of the
CKD model. On the other hand, we found that plas-
ma CRP was not increased and might not be corre-
lated with LVH in the SNx + NaCl rat model. These
results were consistent with the previous clinical
data that CRP was not significantly associated with
cardiovascular outcomes after adjustment for tradi-
tional risk factors (5), suggesting that CRP and IL-6
might have different roles in the progression of
LVH.
It has been indicated that IL-6, a pleiotropic cyto-
kine, is produced by proximal tubular epithelial cells
(8) and various inflammatory cells such as mono-
cytes (3) and macrophages (10). Whereas we ob-
served a significant increase of inflammatory cell
infiltration into the tubulointerstitial area in the SNx
and SNx + NaCl rats, the precise source of increased
plasma levels of IL-6 was still unclear. Previous pa-
per suggested that urinary protein might induce pro-
duction of IL-6 and chemokines from proximal
tubular epithelial cells (11). The present study might
suggest that subtotal nephrectomy generated an in-
creased level of urinary protein, judging from the
observed glomerular sclerosis and urinary casts. Si-
multaneously, we speculated that the released che-
mokines might recruit mononuclear cells into the
tubulointerstitial area, resulting in the amplification
of the production of IL-6 and chemokines from
proximal tubular epithelial cells.
Endothelial dysfunction, another non-traditional
cardiovascular risk factor, is related to renal failure
and hypertension. It has been demonstrated that ele-
vated plasma concentration of ADMA was associat-
ed with LVH and LV dysfunction in hemodialysis
patients (27). Ueda et al. reported that increased
plasma levels of ADMA were correlated with the re-
nal damages including decreased numbers of peritu-
bular capillaries, increased tubulointerstitial fibrosis,
hypertension, and proteinuria in the SNx rats (22).
Furthermore, over-expression of the ADMA degrad-
ing enzymedimethylarginine dimethylaminohydro-
lase (DDAH-1 and DDAH-2), which were mainly
located in proximal tubules and endothelium (16)
decreased plasma levels of ADMA, prevented hy-
pertension, and blocked the progression of renal
dysfunction in the SNx rats (13). As a mechanism
of ADMA to induce renal damage, ADMA was
shown to be involved in production of IL-6 and
chemokines in renal proximal tubular cells (25)
through the activation of NAD(P)H oxidase (23).
The present results demonstrate that plasma level of
ADMA is highly correlated with the infiltration of
mononuclear cells into intersitial area, suggesting
that ADMA would play a pivotal role in recruitment
of mononuclear cells into interstitial area.
IL-6 is associated with LVH in SNx 89

In conclusion, the present study has demonstrated Fukami K, Matsuoka H, Imaizumi T and Okuda S (2007)
that NaCl-loading to SNx rats caused LVH, which Dimethylarginine dimethylaminohydrolase prevents progres-
sion of renal dysfunction by inhibiting loss of peritubular
was associated with increased plasma levels of PTH, capillaries and tubulointerstitial fibrosis in a rat model of
creatinine, inorganic phosphorus, ADMA, and IL-6 chronic kidney disease. J Am Soc Nephrol 18, 15251533.
and with hypertension. Although further studies 14. Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann G,
would be necessary to clarify the detailed mecha- Boehm BO, Winkelmann BR and Marz W (2007) Asymmet-
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cardiovascular mortality in individuals with angiographic cor-
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these findings suggest that inflammation and endo- cular Health study). Clin Chem 53, 273283.
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