Serum C1q- binding adiponectin in maintenance hemodialysis patients
Serum C1q- binding adiponectin in maintenance hemodialysis patients
Ken Kishida 0 1
Naohiro Kishida 0
Masaaki Arima 0
Hideaki Nakatsuji 1
Tohru Funahashi 1
Iichiro Shimomura 1
Trial registration: ClinicalTrials.gov: UMIN
0 Kishida Clinic , 5-6-3, Honmachi, Toyonaka, Osaka 560-0021 , Japan
1 Department of Metabolic Medicine, Graduate School of Medicine, Osaka University , 2-2 B-5, Yamada-oka, Suita, Osaka 565-0871 , Japan
Background: Patients on maintenance hemodialysis (HD) have much higher levels of adiponectin (Total-APN). Adiponectin and C1q form a protein complex in human blood, and serum C1q-binding adiponectin (C1q-APN) can be measured. We recently reported that C1q-APN/Total-APN ratio rather than Total-APN correlated with atherosclerosis in diabetics. However, the characteristics of C1q-APN in HD patients remain unclear. The preset study investigated the characteristics of the adiponectin parameters including C1q-APN and also to clarify the relationship between various serum adiponectin parameters and atherosclerotic cardiovascular diseases (ACVD) in HD patients. Methods: The single cross-sectional study subjects were 117 Japanese patients (males/females = 61/56) on regular HD. Blood Total-APN, high molecular weight-adiponectin (HMW-APN), C1q-APN and C1q concentrations were measured by enzyme-linked immunosorbent assays. ACVD were defined as stroke, coronary and peripheral artery diseases, thoracic and abdominal aneurysms. Results: Stepwise regression analysis identified high-density lipoprotein-cholesterol (HDL-C) as the only significant and independent determinant of C1q-APN in males, and duration of HD as the only significant and independent determinant of C1q-APN in females. Stepwise regression analysis identified uric acid, low-density lipoproteincholesterol and triglyceride as significant and independent determinants of C1q-APN/Total-APN ratio in males, and leukocyte count and HDL-C as significant and independent determinants of C1q-APN/Total-APN ratio in females. Multiple logistic regression analysis identified inorganic phosphorus and C1q-APN or C1q-APN/C1q ratio as significant determinants of ACVD.
Adiponectin; C1q; C1q-binding adiponectin; Hemodialysis
Adiponectin is an adipose-specific circulating protein
, and circulating total-adiponectin levels (Total-APN)
are lower in males than in females but not different
between pre- and postmenopausal females . Adiponectin
has protective properties against diabetes and
atherosclerotic cardiovascular disease (ACVD) . ACVD is
the major cause of morbidity and mortality in
maintenance hemodialysis (HD) patients. Zoccali and our group
demonstrated the presence of consistently high levels of
Total-APN in HD patients, and that low Total-APN
levels were associated with increased risk for ACVD
events in HD patients over a follow-up period of 31
months . We recently reported that adiponectin binds
with C1q in human blood, and also described the
development of a system to measure human serum
C1qbinding adiponectin (C1q-APN) . Although
circulating Total-APN level is considered a biomarker of the
metabolic syndrome , serum C1q-APN/Total-APN
ratio rather than Total-APN is a novel marker of the
metabolic syndrome in male subjects . Serum
C1qAPN/Total-APN correlated with polyvascular diseases
and coronary artery disease in type 2 diabetics [7,8].
These data suggest that it is important to consider not
only the absolute amount of adiponectin but also the
levels of relative adiponectin forms in blood. However,
the characteristics of C1q-APN, C1q-APN/Total-APN
and C1q-APN/C1q in HD patients remain unclear.
The biochemical and haematological parameters
should be also important factors in mortality outcomes
in HD. The aim of the present study was to determine
the relationship between biochemical and
haematological parameters, clinical features, and various
adiponectin parameters including C1q-APN, and to
clarify the relationship between various serum adiponectin
parameters and ACVD, in HD patients.
The study (Victor-J study; #UMIN 000004318) subjects
were 117 Japanese patients (n; males/females = 61/56) on
standardized HD for at least 1 year (500800 mL/min
dialysate flow; 250300 mL/min blood flow; 3.5-4 hours
dialysis per session; 3 sessions per week), who visited the
Kishida Clinic in February 2010. Patients treated with
pioglitazone, which is known to increase serum
adiponectin levels , and/or patients with clinical
evidence of heart failure (defined as dyspnea in addition to
two of the following conditions: increased jugular
pressure, bi-basal crackles on auscultation, pulmonary
venous hypertension, or interstitial edema on the chest
xray, requiring hospitalization or extra ultrafiltration)
were excluded from the study. The Medical Ethics
Committee of Osaka University approved the study. Each
participant gave a written informed consent.
Anthropometry and laboratory tests
Anthropometric variables [height and weight] were
measured in the standing position and body mass index
(BMI) was calculated [=weight (kg) / height (m)2]. Waist
circumference (WC) at the umbilical level was measured
with a non-stretchable tape in late expiration while a
standing (in cm). Systolic and diastolic blood pressures
(SBP, DBP) were measured with a standard mercury
sphygmomanometer on the right or left arm in the
supine position after at least 5-minute rest.
Venous blood samples were collected before dialysis
session for measurements of serum biochemical
parameters, red blood cell counts (RBC), hemoglobin
(Hb), hematocrit (Ht), white blood cell counts (WBC),
creatinine (Cr), blood urea nitrogen (BUN), albumin
(Alb), calcium (Ca), inorganic phosphorus (IP),
potassium (K), magnesium (Mg), uric acid (UA), intact
parathyroid hormone (intact-PTH), 2-microglobulin
(2MG), blood glucose (BS), total-cholesterol
triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C),
and C-reactive protein (CRP). Low-density
lipoproteincholesterol (LDL-C) was calculated using the Friedewald
formula. Adjusted-Ca (mg/dL) = measured serum total
Ca (mg/dL) measured serum Alb (mg/dL) + 4.0.
Intact-PTH was measured by immunoradiometric assay.
For the purpose of the present study, serum samples
that were obtained at baseline from each participant
were stored promptly at 20C. After thawing the
samples, serum levels of Total-APN and high molecular
weight-adiponectin (HMW-APN) were measured by
enzyme-linked immunosorbent assay (ELISA) (Human
adiponectin ELISA kit, Human HMW-adiponectin
ELISA kit, Otsuka Pharmaceutical Co. Tokushima,
Japan) [1,10]. C1q-APN and C1q were measured by our
handmade ELISA, as reported previously by our
group . The intra- and inter-coefficients of
variation for C1q-APN ELISA are below 4.6% and 6.7%,
Hypertension (HT) was defined as SBP 140 mmHg
and/or DBP 90 mmHg, or use of antihypertensive
medication; (calcium channel antagonist / angiotensin
converting enzyme inhibitor or angiotensin receptor
blocker / blockade / diuretics / blockade =20/11/3/1/5).
Diabetes mellitus (DM) was defined as either fasting BS
>126 mg/dL, random BS >200 mg/dL, or use of insulin (n
= 11) or antidiabetic medication (GI = 5). Dyslipidemia
(DL) represented high LDL-C of >120 mg/dL,
hypertriglyceridemia [fasting or postprandial TG of 3150
or 200 mg/dL, respectively], and/or low HDL-C of
Measurements of baPWV, and ABI
Arterial stiffness was assessed by measuring
brachialankle pulse wave velocity (baPWV) and ankle-brachial
index (ABI) using an automatic waveform analyzer
(Form/ABI; Omron-Colin Co., Komaki, Japan).
Definition of ACVD
Documented coronary artery disease (CAD) consisted of
one or more of the following criteria: history of stable or
unstable angina with documented CAD, history of
previous myocardial infarction, percutaneous coronary
intervention or coronary artery bypass graft surgery.
Documented cerebrovascular disease (CVD) consisted
of a hospital or neurologist report with the diagnosis
of transient ischemic attack or ischemic stroke.
Documented aneurysm of the thoracic aorta (TAA)
consisted of aortic diameter >4.5 cm, and documented
aneurysm of the abdominal aorta (AAA) represented
aortic diameter >4.5 cm, an infra-renal aortic diameter
>3.0 cm, or a history of TAA and/or AAA repair.
Documented peripheral vascular disease (PAD)
represented one or both criteria: current intermittent
claudication with an anklebrachial index of < 0.9 or a history
of intermittent claudication together with previous and
related intervention, such as angioplasty, stenting,
atherectomy, peripheral arterial bypass graft, or other
vascular intervention, including amputation. Patients
Table 1 Baseline characteristics of hemodialysis patients
with negative results by either of the above definitions
were considered ACVD-free.
Data are presented as meanSEM. Data of two groups
were compared by the Students t-test. Differences in
frequencies were examined by the 2 test. Relationships
Body weight (BW), kg
Body mass index (BMI), kg/m2
Waist circumference (WC), cm
Systolic blood pressure (SBP), mmHg
Diastolic blood pressure (DBP), mmHg
Duration of hemodialysis (HD), years
Primary disease (CGN/Diabetic/Others)
Diabetes mellitus (DM)
Red blood cell count (RBC) x104, /mL
Hemoglobin (Hb), mg/dL
Hematocrit (Ht), %
White blood cell count (WBC), /mL
Creatinine (Cr), mg/dL
Blood urea nitrogen (BUN), mg/dL
Albumin (Alb), g/dL
Adjusted-calcium (Ca), mg/dL
Inorganic phosphorus (IP), mg/mL
Potassium (K), mEq/L
Magnesium (Mg), mg/dL
Uric acid (UA), mg/dL
Intact parathyroid hormone (intact-PTH), pg/mL
2-microglobulin (2MG), mg/L
Blood glucose (BS), mg/dL
Low-density lipoprotein-cholesterol (LDL-C), mg/dL
Triglyceride (TG), mg/dL
High-density lipoprotein-cholesterol (HDL-C), mg/dL
C-reactive protein (CRP), mg/dL
Ankle-brachial index (ABI)
Data are mean SEM (range), or number of subjects.
ACVD; atherosclerotic cardiovascular diseases (stroke, coronary and peripheral artery diseases, thoracic and abdominal aneurysms), CVD; cerebrovascular disease,
CAD; coronary artery disease, TAA; aneurysm of the thoracic aorta, AAA; aneurysm of the abdominal aorta, PAD; peripheral vascular disease, CGN;
between two continuous variables were analyzed using
scatter plots and Pearsons correlation coefficient. The
correlations between clinical features and adiponectin
parameters were first analyzed by simple regression
analysis and then by stepwise regression analysis. The
correlations between clinical features and ACVD were
first analyzed by simple regression analysis and then by
logistic regression analysis. In all cases, p values <0.05
and F value >4 were considered statistically significant.
All analyses were performed with the JMP Statistical
Discovery Software 9.0 (SAS Institute, Cary, NC) or the
Statistical Package for Social Sciences (version 11.0.1 J;
SPSS, Chicago, IL).
Characteristics of male and female HD patients
Table 1 summarizes the characteristics of male and
female HD patients enrolled in this study. The prevalence
of ACVD was significantly higher in males than females
(57.4% versus 28.6%, p = 0.0299). Serum levels of
TotalAPN, HMW-APN and C1q-APN were significantly
lower in males than in females (16.5 1.1 versus 23.3
1.3 g/mL, p = 0.0001, 14.5 1.2 versus 21.5 1.5 g/
mL, p = 0.0005, 106.1 4.4 versus 136.3 4.7 units/mL,
p < 0.0001, Figure 1). There was no significant difference
in serum C1q level between males and females (59.7
1.2 versus 58.3 1.3 g/mL, p = 0.4277, Figure 1). Serum
HMW-APN/Total-APN and C1q-APN/C1q ratios were
significantly lower in males than in females (0.82 0.02
versus 0.89 0.02, p = 0.0272, 1.81 0.08 versus 2.37
0.08, p < 0.0001, Figure 2). There was no significant
difference in serum C1q-APN/Total-APN ratio between
males and females (8.02 0.55 6.81 0.48, p = 0.1015,
Serum HMW-APN levels correlated significantly and
positively with serum Total-APN level both in males
and females (Figure 3A). Serum C1q-APN levels
correlated significantly and positively but weakly with
serum Total-APN level both in males and females
(Figure 3B). Serum C1q-APN levels also correlated
significantly and positively with serum HMW-APN level
both in males and females (r = 0.70, p < 0.0001; r = 0.57,
p < 0.0001, respectively, data not shown).
Correlation between serum adiponectin parameters and
clinical features in males
We investigated the correlations between serum
adiponectin parameters and clinical features in males
(Table 2). Total-APN and HMW-APN correlated
significantly and negatively with BMI, WC, WBC, Cr, UA, TG
and CRP, and positively with adjusted-Ca and HDL-C.
Stepwise regression analysis that included BMI, WC,
0 10 20 30 40 50 60
0 10 20 30 40 50 60 70
Figure 1 Comparisons of total adiponectin (Total-APN), high molecular weight-adiponectin (HMW-APN), C1q-binding adiponectin
(C1q-APN), and C1q between male and female HD patients. Data are meanSEM (range). Data of two groups were compared by the
WBC, Cr, UA, adjusted-Ca, TG, HDL-C, and CRP
identified UA, TG and HDL-C as significant and
independent determinants of Total-APN, and TG and HDL-C as
significant and independent determinants of
HMWAPN. C1q-APN correlated significantly and negatively
with BMI, WC, UA and TG, and positively with HDL-C.
Stepwise regression analysis that included WC, WBC,
UA, TG, and HDL-C identified HDL-C as the only
significant and independent determinant of C1q-APN. C1q
correlated significantly and negatively with age and
adjusted-Ca, and positively with BMI, WC, SBP, duration
of HD, WBC, IP, 2MG and TG. Stepwise regression
analysis that included age, WC, SBP, duration of HD,
WBC, adjusted-Ca, IP, 2MG, and TG identified
duration of HD, 2MG and TG as significant and
independent determinants of C1q.
We recently showed that serum C1q-APN/Total-APN
ratio is associated the metabolic syndrome . We next
investigated the correlations between each adiponectin
ratio and clinical features in males. The HMW-APN
/Total-APN ratio correlated significantly and negatively
with BMI, WC, Cr and TG, and positively with K and
HDL-C. Stepwise regression analysis that included WC,
WBC, Cr, TG, K, and HDL-C identified HDL-C as
the only significant and independent determinant of
HMW-APN/Total-APN ratio. C1q-APN/Total-APN
ratio correlated significantly and negatively with age,
adjusted-Ca, LDL-C and HDL-C, and positively with
BMI, WC, WBC, Cr, IP, UA, 2MG, TG and CRP.
Stepwise regression analysis that included age, WC, WBC,
Cr, adjusted-Ca, IP, UA, 2MG, TG, HDL-C, and CRP
identified Cr, UA, LDL-C and TG as significant and
independent determinants of the C1q-APN/Total-APN
ratio. The C1q-APN/C1q ratio correlated significantly
and negatively with BMI, WC, WBC, UA and TG, and
positively with adjusted-Ca and HDL-C. Stepwise
regression analysis that included WC, WBC, adjusted-Ca, UA,
TG, and HDL-C identified TG as the only significant
and independent determinant of C1q-APN/C1q.
Correlation between serum adiponectin parameters and
clinical features in females
Next, we investigated the correlations between serum
adiponectin parameters and clinical features in females
(Table 3). Total-APN correlated significantly and
negatively with WC, WBC and TG, and positively with IP
and HDL-C. HMW-APN correlated significantly and
negatively with WC, WBC and TG, and positively with
HDL-C. Stepwise regression analysis identified WBC
and HDL-C as significant and independent determinants
of both Total-APN and HMW-APN. C1q-APN
correlated significantly and positively with the duration
of HD and IP. Stepwise regression analysis identified the
duration of HD as the only significant and independent
determinant of C1q-APN. C1q correlated significantly
and negatively with UA only.
The HMW-APN/Total-APN ratio correlated
significantly and negatively with WC, WBC and TG, and
positively with K. Stepwise regression analysis that included
WC, WBC, K, and TG identified WC and K as
significant and independent determinants of the HMW-APN
/Total-APN ratio. The C1q-APN/Total-APN ratio
correlated significantly and negatively with HDL-C, and
positively with WC, WBC, adjusted-Ca and TG.
Stepwise regression analysis that included WC, WBC,
adjusted-Ca, TG, and HDL-C identified WBC and
HDLC as significant and independent determinants of the
C1q-APN/Total-APN ratio. The C1q-APN/C1q ratio
correlated significantly and negatively with WC and TG.
Stepwise regression analysis that included WC and TG
identified TG as the only significant and independent
determinant of the C1q-APN/C1q ratio.
Simple and multivariate logistic regression analyses of
Simple logistic regression analysis was used to evaluate
the relationship between ACVD and various serum
adiponectin parameters (Table 4). Sex, hypertension,
smoking status (current-smoker), IP, C1q-APN, and
C1q-APN/C1q correlated significantly with ACVD
(Model 1; no adjustment). Multiple regression analysis
identified IP and C1q-APN (Model 2) and C1q-APN
/C1q ratio (Model 3) as significant determinants of
ACVD in HD patients (Table 4).
The following were the major findings of the present
study in HD patients: 1) serum C1q-APN, Total-APN
and HMW-APN were lower in males than in females;
however, serum C1q-APN/Total-APN ratio was not
different between the two sexes, 2) stepwise regression
analysis identified HDL-C as the only significant and
independent determinant of C1q-APN in males, and
duration of HD as the only significant and independent
determinant of C1q-APN in females, 3) stepwise
regression analysis identified UA, LDL-C and TG as significant
and independent determinants of the
C1q-APN/TotalAPN ratio in males, and WBC and HDL-C as significant
and independent determinants of the
C1q-APN/TotalAPN ratio in females, and 4) multiple regression analysis
identified IP and the C1q-APN or C1q-APN/C1q ratio
as significant determinants of ACVD in HD patients,
whereas there was no relationship between the
C1qAPN/Total-APN ratio and ACVD.
Disorders of mineral metabolism, such as
hyperphosphatemia, hypercalcemia, and secondary
hyperparathyroidism, are independently associated with mortality
and morbidity of cardiovascular diseases in HD patients
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
20 30 40
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- i 0 0 0 0 0 0 0 0 .0 0 0 0 0 0
n W ra
Duration of HD
[11-14]. The present study also showed that high levels
of serum IP correlated with ACVD (Table 4). These
results suggest that diet therapy, such as low nitrogen
and phosphorus intake, are probably important for
prevention of ACVD in HD patients. Matsubara et al.
reported that increased adiponectin may contribute to
the suppressive bone marrow function . The present
study investigated the biochemical and haematological
parameters and C1q-APN paremeters. Stepwise
regression analysis identified WBC counts as a significant and
independent determinant of C1q-APN/Total-APN ratio
in females (Table 4) but not males (Table 3). More
studies are required to confirm the findings and elucidate
the biological mechanisms underlying the association
between the haematological parameters and C1q-APN.
Smoking and adiponectin are individually associated with
cardiometabolic pathologies. A systematic review reported
that there is a decreased adiponectin level in current smokers
and this reduction is reversed by quitting smoking . In
HD patients, smoking status (current-smoker) also correlated
significantly with ACVD (no adjusted, Table 4), however
there were no significant correlations between C1q-APN,
C1q-APN/Total-APN, C1q-APN/C1q and smoking status in
both male (Table 2) and female HD patients (Table 3). More
studies are required to confirm the findings.
HD patients have much higher levels of adiponectin,
compared with the general population . However, low
circulating levels of adiponectin independently predict
cardiovascular and mortality outcomes in HD patients, the
relationship being extensively confounded by various
patient-related factors [17-22]. The cross-sectional preset
study found that Total-APN did not associate with ACVD
(Table 4). Complement activation and C1q binding activity
have been described in HD patients . Inoshita et al. 
found significantly higher levels of functional complement
activity of all three pathways, i.e., the classical pathway, the
alternative pathway, and the lectin pathway, in HD patients
than healthy controls. The present study showed higher
serum C1q levels in HD male patients (59.7 1.2 g/mL,
Table 1) than the men of the general population (56.0
10.0 g/mL) . We recently reported that serum C1q-APN
/Total-APN ratio correlated with the metabolic syndrome in
men , and with polyvascular diseases and coronary artery
disease in type 2 diabetics [7,8], although there was no
significant difference in serum C1q-APN levels between
patients without and with coronary artery disease. In HD
patients, low serum C1q-APN, but not
C1q-APN/TotalAPN ratio, correlated with ACVD, independent of age-, sex-,
other ACVD risk factors (hyperphosphatemia) (Table 4), a
finding described for the first time to our knowledge.
However, the different association of adiponectin-C1q with
ACVD in between diabetic and HD patients remains
unclear. Further studies are necessary to elucidate the
pathophysiological role of C1q-APN in HD patients. Future
monitoring of the long-term effects of serum C1q-APN and
C1q on the cumulative incidence of cardiovascular events in
HD patients is required.
The present study has several limitations. First, this is a
cross-sectional study, making it difficult to establish a
causeeffect relationship. Second, all patients in this study were
Japanese and any differences from other ethnicities are
unknown. Third, there is a potential bias in single center trials.
Fourth, the number of patients was relatively small. The
study included a limited number of patients and further
studies of larger sample should be conducted in the future.
The present study demonstrated for the first time that
serum C1q-APN was lower in male HD patients than in
females, and that lower serum C1q-APN and C1q-APN
/C1q ratio, but not C1q-APN/Total-APN, correlated
with ACVD in HD patients. These results suggest that
the network of adiponectin and C1q may play a role in
the pathophysiology of ACVD in HD.
ACVD: Atherosclerotic cardiovascular disease; Alb: Albumin; 2MG:
2microglobulin; BMI: Body mass index; BUN: Blood urea nitrogen; BS: Blood
glucose; C1q-APN: C1q-binding adiponectin; Cr: Creatinine; CRP: C-reactive
protein; DBP: Diastolic blood pressure; DL: Dyslipidemia; DM: Diabetes
mellitus; ELISA: Enzyme-linked immunosorbent assay; HD: Hemodialysis;
HDLC: High density lipoprotein-cholesterol; HMW: High-molecular weight;
HMWAPN: High molecular weight-adiponectin; intact-PTH: intact parathyroid
hormone; LDL-C: Low density lipoprotein-cholesterol; RBC: Red blood cell
count; SBP: Systolic blood pressure; Total-APN: Total-adiponectin; UA: Uric
acid; WBC: White blood cell count; WC: Waist circumference.
KK, TF and IS are promotional speakers for Otsuka Pharmaceutical Co., Ltd. TF
is a member of the Department of Metabolism and Atherosclerosis, a
sponsored course endowed by Kowa Co. Ltd. The company has a scientific
officer who oversees the program. All other authors declare no competing
interests. Human serum C1q-binding adiponectin complex assay is under
patent application in Japan.
KK researched, collected, analyzed the data, participated in the concept and
design of the study, interpretation of data and reviewed/edited the
manuscript. NK and MA recruited the patients and collected the data. HN
and HK analyzed the data.TF and IS contributed to the discussion and wrote
the manuscript. All authors read and approved the final version of the
We thank all the staff at Kishida Clinic for the excellent medical care, and
Messrs Shigeo Takahashi, Suguru Akamatsu, and Tetsuya Oda for the
statistical advice and helpful discussion, and Messrs Hideaki Tanaka and
Tohru Hadama and Mrs. Miyuki Nakamura for the excellent technical
This research was supported in part by a Grant-in-Aid for Scientific Research
on Innovative Areas (Research in a proposed research area) Molecular Basis
and Disorders of Control of Appetite and Fat Accumulation (#22126008, to
T.F. and K.K.), and Osaka Universitys academia-industry collaboration policy
position on collaboration between Osaka University and Otsuka
Pharmaceutical Co., Ltd..
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