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ORIGINAL RESEARCH
Relationship Between Adiposityand Cardiovascular Risk Factors in PrevalentHemodialysis PatientsGeorge A. Kaysen, MD, PhD, FASN,*†‡ Peter Kotanko,*§ Fansan Zhu, MS,*
Shubho R. Sarkar, MD, FASN,*{ Steven B. Heymsfield, MD,! Martin K. Kuhlmann, MD,*
Tjien Dwyer,† Len Usvyat, MCP,* Peter Havel, DVM, PhD,# and
Nathan W. Levin, MD, FASN*
Objective: Increased body mass index (BMI) is associated with reduced all-cause and cardiovascular (CV)
mortality in hemodialysis (HD) patients, whereas CV risk increases with BMI in the general population. In the general
population, obesity is associated with inflammation, decreased high-density lipoprotein (HDL) cholesterol, increased
low-density lipoprotein (LDL) cholesterol, and triglycerides (TGs), all risk factors for CV disease. Low-density lipopro-
tein cholesterol does not predict CV risk in HD, whereas increased C-reactive protein and interleukin-6 (IL-6), low
HDL and apolipoprotein (apo) AI, and increased fasting TGs do predict risk. Renal failure is associated with dyslipi-
demia and inflammation in normal-weight patients. We hypothesized that the effects of obesity may be obscured by
renal failure in HD.
Methods: We explored the relationship between adipose tissue pools and distribution, i.e., subcutaneous adipose
tissue (SAT) and visceral adipose tissue (VAT) (measured by magnetic resonance imaging) and measures of inflam-
mation (C-reactive protein, IL-6, ceruloplasmin, and a1 acid glycoprotein), HDL and LDL cholesterol, total TGs, apo
AI, apo B, apo CII (an activator of lipoprotein lipase), apo CIII (an inhibitor of lipoprotein lipase), and the adipokines,
leptin and adiponectin, in 48 patients with prevalent HD.
Results and Conclusions: Total TG concentrations were positively correlated with VAT controlled for age, sex,
and weight. Both apo CII and apo CIII were correlated only with VAT. Adiponectin was inversely correlated with
VAT, and leptin was positively associated with SAT. C-reactive protein and a1 acid glycoprotein were weakly asso-
ciated with SAT, whereas ceruloplasmin was strongly associated with VAT according to multiple regression analysis.
In contrast, apo B, LDL, apo AI, HDL, and IL-6 were not correlated with any measure of body composition, potentially
mitigating the effects of obesity in HD
� 2009 by the National Kidney Foundation, Inc.
ALTHOUGH THE RELATIVE risk of mor-tality is high among dialysis patients, one fac-
tor that predicts survival is a higher body massindex (BMI).1–3 Body mass index is imprecise as
*Renal Research Institute, New York, New York.
†Division of Nephrology, Department of Medicine and Depart-
ment of Biochemistry and Molecular Medicine, University of Califor-
nia at Davis, Davis, California.
‡Research Service, Veterans Administration Northern California
Health Care System, Mather, California.
§Krankenhaus der Barmherzigen Brueder, Graz, Austria.
{Department of Medicine, Weil Cornell Medical Center, New
York, New York.!Department of Internal Medicine, New York Obesity Research
Center, St. Luke’s Hospital, New York, New York.
Journal of Renal Nutrition, Vol 19, No 5 (September), 2009: pp 357–36
a measure of body composition, and does not dis-tinguish between muscle and fat mass. Neverthe-less, the lack of an increase in mortality amonga population with a very high BMI (.35 kg/m2)
#Department of Molecular Biosciences, School of Veterinary
Medicine, and Department of Nutrition, University of California
at Davis, Davis, California.
Address reprint requests to George A. Kaysen, MD, PhD,
FASN, Division of Nephrology, Department of Medicine, University
of California at Davis, One Shields Ave., Genome and Biomedical
Sciences Facility 451 Health Sciences Dr., Davis, CA 95616.
E-mail: [email protected]� 2009 by the National Kidney Foundation, Inc.
1051-2276/09/1905-0002$36.00/0
doi:10.1053/j.jrn.2009.04.002
4 357
KAYSEN ET AL358
strongly supports the hypothesis that adiposity insome way protects dialysis patients from mortality,or that risk factors normally associated with adi-posity may not be associated with adiposity amongdialysis patients. Indices associated with lean bodymass, such as total body water, approximated by thevolume of distribution of urea, independently pre-dict survival.4,5 Similarly, total body potassium,a measure of intracellular volume, predicts survivalin a variety of chronic diseases.6–8 Although thepositive association between lean body mass andsurvival can be explained by better-preserved nu-tritional reserves or lower comorbidities, the basisfor improved survival among obese patients isnot obvious, although a similar survival advantageis evident in patients with other chronic diseases.9
Several cardiovascular risk factors are linkedmetabolically to body composition among subjectswith normal kidney function.10 Low-density lipo-protein (LDL) cholesterol levels and triglyceride(TG) levels are positively associated with adiposity,whereas high-density lipoprotein (HDL) choles-terol is inversely associated with adiposity amongsubjects with normal kidney function.11 Inflamma-tion, as assessedby plasma C-reactive protein (CRP)or interleukin-6 (IL-6) concentrations, is also animportant cardiovascular risk factor, both in dialysispatients and in subjects with normal kidney func-tion.12–14 C-reactive protein and IL-6 levels arethought to be associated with adiposity in subjectswith normal kidney function as a result of inflam-mation within or caused by increased visceral adi-pose mass.15,16 A third set of risk factors associatedwith adiposity both in the population with normalkidney function and in patients with kidney failureconsists of the adipokines, leptin and adiponectin.
Although some risk factors that predict cardio-vascular disease among populations without kid-ney failure are no longer predictive in dialysispatients, such as hypertension and LDL choles-terol,17 other risk factors preserve their predictivevalues, such as CRP, IL-6,12,13,18 and low levels ofHDL cholesterol.17,19
Elevated TGs are also associated with mortalityamong dialysis patients.19 Although TG levels areassociated with adiposity among subjects with nor-mal kidney function, TG levels are also increasedin dialysis patients by factors that may not be linkedto body composition, such as increased levels oflipoprotein lipase inhibitors such as apolipoproteinCIII (apo CIII),20,21 which is also linked to insulinresistance and increased body adiposity.
A third cluster of risk factors associated withbody composition modulating cardiovascular riskconsists of the adipokines.22,23 Leptin is secretedby adipocytes, and is increased in dialysis patientsbeyond what would be anticipated by total fatmass, primarily because of a reduced renal clear-ance of leptin,24,25 although the relationship toadiposity persists within populations of patientswith renal failure.24,25 Leptin is associated withinsulin resistance, and increased circulating leptinwas directly associated with vascular disease.26–29
Circulating concentrations of a second adipokine,adiponectin, are inversely proportion to fat mass,30
and specifically, are inversely related to the impor-tant visceral adipose tissue mass.31,32 Adiponectin,like HDL, was reported to be inversely associatedwith vascular disease in subjects with normal renalfunction.33 The relationship between adiponectinlevels and cardiovascular risk in patients withkidney disease is controversial. High levels wereassociated with increased cardiovascular risk insome studies of dialysis patients,23 and in patientswith stage 3 and 4 chronic kidney disease,34
whereas high levels were reported to be protectivein other studies.22
In the present study, we measured body adiposetissue compartments and lean body mass, usingmagnetic resonance imaging (MRI), in a cohortof HD patients, to investigate the relationshipbetween adiposity and a number of risk factorsfor cardiovascular disease.
Methods
Institutional Review Board approval wasobtained, and all subjects gave written, informedconsent before participation. Forty-eight preva-lent HD patients (20 women and 28 men, aged.18 years) were chosen, to encompass a widerange of BMIs and ages. Thirty-seven patientswere African American, 3 were nonblack His-panic, 3 were white, 2 were Asian, and 3 were‘‘other.’’ Sixteen patients had diabetes mellitus.For an analysis of the effects of race, patients werecoded as black or nonblack because of the smallnumbers in the other groups. All but one subjecthad been on maintenance HD for at least 3 monthsbefore the study. One subject had been on dialysisfor 2 months. They were studied on the day ofa regularly scheduled HD session, approximately3 hours before initiation of a dialysis treatment.
ADIPOSITY AND CARDIOVASCULAR RISK IN PREVALENT HD 359
After an overnight fast, body weight was mea-sured to the nearest 0.1 kg (Weight Tronix, NewYork, NY), and height was measured to the nearest0.5 cm using a stadiometer (Holtain, Crosswell,UK). Whole-body MRI scans were preparedusing a 1.5-Tesla scanner (6X Horizon, GeneralElectric, Milwaukee, WI) to evaluate muscle andfat mass.35
All assays were performed on serum obtainedwhile the patient was in a fasting state. The inflam-matory markers CRP and IL-6, the long-livedacute-phase proteins ceruloplasmin and a1 acidglycoprotein, the adipokines leptin and adiponec-tin, apo AI, apo CII, apo CIII, apo B, TGs, totalcholesterol, HDL cholesterol, and LDL choles-terol were measured. C-reactive protein, cerulo-plasmin, apo AI, apo B, and a1 acid glycoproteinwere measured by rate nephelometry, using aBeckman Array (Beckman, Ramsey, MN) auto-mated nephelometer.36 We measured apo CIIand apo CIII nephelometrically, using a Hitachichemical analyzer (Hitachi Chemical Co., Tokyo,Japan). Leptin and adiponectin were measured us-ing radio immuno assay (RIA) (Millipore, St.Charles, MO). All nephelometric measurementswere performed in duplicate in each of two opticalsystems. The average of these values was used forcalculations.
Table 1. Medians and Ranges of Risk FactorsAmong Dialysis Patients
CRP (g/L) 5.0 (0.1-260)IL-6 (pg/mL) 5.5 (1-22)
a1 AG (mg/dL) 106 (46-187)
Ceruloplasmin (mg/dL) 42 (23-73)
HDL Cholesterol (mg/dL) 43 (8-79)Apo AI (mg/dL) 131 (89-239)
Triglycerides (mg/dL) 133 (36-436)
Apo CIII (mg/dL) 15.0 (2.9-35.7)Apo CII (mg/dL) 3.2 (0.45-7.66)
LDL cholesterol (mg/dL) 66 (13-142)
Remnant cholesterol (mg/dL) 3.7 (2.1-9.1)
Total cholesterol (mg/dL) 157 (83-236)Apo B (mg/dL) 60.9 (14.9-120)
Adiponectin (mg/mL) 18.4 (5.9-59.4)
Leptin (ng/mL) 9.85 (0.2-127.2)
AG, acid glycoprotein. Values are medians and rangesof risk factors in hemodialysis patients.
Statistical Analysis
Data are presented as mean, standard deviation,median, and range. The distribution of variablesfor normality was assessed using the Kolmogorov-Smirnov test.37 Variables that were non-normallydistributed were log-transformed. Multivariateanalyses used multiple linear regression analysis,with backward elimination (P , .1 for parameterretention in the model), and with biochemicalmarkers as dependent variables. The independentvariables were subcutaneous adipose tissue mass(SAT) or visceral adipose tissue mass (VAT) or totaladipose tissue mass, measured by MRI adjusted forage, sex, presence of diabetes, weight, and race. Wealso analyzed the effect of VAT on cardiovascularrisk factors, using VAT as a categorical variable.We divided the population into tertiles, and per-formed analysis of variance using Tukey’s test forsignificance. We controlled for the effects of age,race, and sex. A two-sided P ,.05 was consideredsignificant. We used JMP 5.0.1 (SAS, Cary, NC) forstatistical analyses.
Results
The median BMI was 27.3 kg/m2 (range, 19.4-46.6 kg/m2), the median age was 54.5 years (range,33-80 years), and the median weight was 78.1 kg(range, 43.1-120 kg). The median total adiposetissue mass was 24.3 kg (range, 6.2-57.9 kg), themedian subcutaneous adipose tissue mass was20.3 kg (range, 5.8-50.8 kg), the median visceraladipose tissue mass was 3.25 kg (range, 0.13-8.88 kg), and the median skeletal muscle masswas 23.3 kg (range, 12.2-36.9 kg). Vintage rangedfrom 2 months to 15.3 years, with a medianvintageof 2.8 years. Residual renal function, expressed asurea clearance, ranged from zero to 7.7 mL/min.Only 9 patients had any urine output. Amongthose 9, the median residual clearance was1.4 mL/min. Medians and ranges of risk factorare shown in Table 1.
Inflammatory Markers
According to simple linear regression analysis,CRP was positively associated with SAT (r2 5
0.11, P 5.03), ceruloplasmin was positively associ-ated with VAT (r2 5 0.16, P 5.01) and SAT(r2 5 0.2, P , .005), and a1 acid glycoproteinwas positively associated with SAT (r2 5 0.11,P 5.03) (Table 2). After adjustment for demo-graphic variables, the associations that remainedsignificant were betweenboth a1 acid glycoproteinand log CRP and SAT, and between ceruloplasminand VAT (Table 3). Interleukin-6 was not signifi-cantly related to any measure of adiposity.
Table 2. Relationship Between Body Compositionand Cardiovascular Risk Factors in HemodialysisPatients
Relationship between acute-phase proteins and
body composition according to univariate analysis
VAT SAT
Log CRP NS P 5 .03
Log IL-6 NS NS
a1 acid glycoprotein NS P 5 .03*
Ceruloplasmin P 5 .01 P 5 .005
Relationship between adipokines and bodycomposition according to univariate analysis
VAT SAT
Log leptin ,0.0001 ,0.0001
Log adiponectin ,0.0001* 0.003
Relationship between lipids and body composition
according to univariate analysis
VAT SAT
Total cholesterol NS 0.012*Triglycerides 0.0003* 0.03
LDL NS NS
HDL NS NS
Apo CII 0.001* 0.006Apo CIII 0.002* 0.007
Apo B NS NS
Apo AI NS NS
Univariate relationships between groups of risk factors,inflammatory markers, adipokines, lipoprotein levels,
measures of adipose mass, visceral adipose tissue
(VAT), and subcutaneous adipose tissue (SAT) in hemodi-
alysis patients. All tissue compartments are in kilograms,and were measured using magnetic resonance imaging.
*Remained significant when both SAT and VAT were en-
tered into the relationship.
KAYSEN ET AL360
Lipid Markers
According to univariate analysis, TGs were cor-related with VAT (r2 5 0.27, P 5.0006) (Fig. 1and Table 2). According to multiple regressionanalysis, TGs were significantly correlated onlywith VAT after controlling for age, sex, and race(Table 3). When VATwas used as a categorical var-iable, TGs were significantly greater in tertiles 3and 2, compared with patients in the lowest tertileof VAT.
Apolipoprotein CII was correlated with VAT(r2 5 0.24, P 5.001) and SAT (r2 5 0.18, P 5.006)according to univariate analysis (Table 2). Accord-ing to multiple regression analysis, apo CII wascorrelated with VAT after adjustment for age, sex,and race (Table 3). Apolipoprotein CII was signifi-cantly greater in patients in the upper two tertiles ofVAT compared with tertile 1.
Similarly, apo CIII was correlated with VAT(r2 5 0.22, P 5.0016) (Fig. 2) and total adiposetissue mass (r2 5 0.2, P 5.003), according tounivariate analysis (Table 2). According to multipleregression analysis, apo CIII was correlated posi-tively with VAT after adjustment for age, sex, andrace (Table 3). Apolipoprotein CIII was signifi-cantly greater in patients in the upper two tertilesof VAT compared with tertile 1.
Neither HDL cholesterol, apo AI, nor LDLcholesterol was correlated with any measures ofbody composition. In contrast to other lipidmarkers, the r2 values were approximately zero,suggesting no effect of body composition onHDL or apo AI levels in these subjects.
Adipokines
Adiponectin was significantly and inversely as-sociated with SAT (r2 5 0.20, P 5.0027) andVAT (r2 5 0.37, P ,.0001). According to multipleregression analysis, adiponectin was only nega-tively associated with VAT (P , .00001), and wasnot affected by sex or any other anthropometricmeasurements (Table 3). The relationship betweenadiponectin and VAT (Fig. 3) was essentially iden-tical between men and women. Adiponectin wassignificantly greater in patients in the first tertileof VAT compared with the second tertile (P ,
.01), and was significantly greater in the first tertilethan in the second or third tertile.
Leptin (after log transformation) was positivelyassociated with SAT (r2 5 0.766, P , .0001) andVAT (r2 5 0.47, P , .001) (Table 2) according tounivariate analysis, but only with SAT accordingto multivariate analysis (r2 for the model 5 0.766,P , .0001) (Table 3).
Discussion
Mortality increases with increasing BMI, aftera minimum mortality for BMIs between 23 and26, in normal subjects.38,39 Adiposity, especiallyvisceral adiposity, is associated with cardiovasculardisease,39,40 hypertension,41 and other cardiovas-cular risk factors (increased TGs, LDL cholesterol,decreased HDL cholesterol, and inflammation)10
in patients with normal kidney function. Obesity,identified as waist-to-hip ratio, is also a risk factorfor incident chronic kidney disease (CKD).42
Among patients who develop CKD, waist-to-hipratio also was a risk factor for cardiovascularevents.43 However, the mean glomerular filtration
Table 3. Multivariate Analysis of Relationship Between Body Composition and Cardiovascular Risk Factorsin Hemodialysis Patients
Dependent
Variable
Independent
Variable b
Standard
Error t
P
Value
Adjusted
r2Excluded
Variables
Log CRP Constant 20.709 0.169 24.187 .000 0.092 Race, sex, age, VAT
SAT 0.016 0.007 2.314 .026a1 acid glycoprotein Constant 85.987 9.670 8.892 .000 0.087 Race, sex, age, VAT
SAT 0.913 0.405 2.254 .029
Ceruloplasmin Constant 20.937 5.955 3.516 .001 0.300 Sex, age, SAT
VAT 3.181 0.809 3.933 .0001Race (black) 14.543 5.011 2.902 .006
Apo CII Constant 1.072 0.706 1.519 .137 .275 Age, SAT, sex
VAT 0.491 0.120 4.077 .0001
Race (black) 1.123 0.576 1.949 .059Apo CIII Constant 9.114 1.714 5.317 .0001 .219 Race, sex, SAT, age
VAT 1.571 0.450 3.491 .001
Triglycerides Constant 85.400 21.689 3.938 .000 .262 Race, SAT, sex, ageVAT 21.965 5.769 3.808 .001
Log adiponectin Constant 1.618 0.079 20.480 .000 .429 Sex, SAT, age
VAT 20.078 0.013 25.850 .0001
Race (black) 20.133 0.065 22.056 .046Log leptin Constant 20.189 0.110 21.719 .093 .766 Race, age, sex
SAT 0.047 0.006 7.388 ,.0001
VAT 0.053 0.030 1.735 .090
ADIPOSITY AND CARDIOVASCULAR RISK IN PREVALENT HD 361
rate in this cohort was 51.1 mL/min, so that theextrapolation of risk to that of the prevalent dialy-sis patient population may not be applicable.
The causal link between cardiovascular mortal-ity and adiposity is proposed, at least in part, to bea consequence of alterations in blood-lipid levelsand inflammation.15,16,44 In contrast to patientswith normal renal function, BMI is associatedwith increased survival among dialysis patients,even at BMI values .39.1 Thus, obesity in dialysispatients must contribute some beneficial effect, or
Relationship between Serum Triglycerides and
Visceral Adipose Tissue
VAT (kg)
1086420
Plasm
a T
rig
lycerid
es (m
g/d
l)
0
100
200
300
400
500r2 = 0.27 P = 0.0006
Figure 1. Relationship between serum triglyceridesand visceral adipose tissue (VAT) measured bymagnetic resonance imaging in prevalent hemodial-ysis patients.
else specific risk factors linking mortality and adi-posity must be mitigated.
We found that components of this relationship,especially the link between HDL cholesterol andapo AI, and to a lesser extent, the relationshipbetween IL-6 and CRP and elements of adiposity,were obscured among dialysis patients. By contrast,the relationship between VAT and TG-rich lipo-proteins was essentially preserved, as was the rela-tionship between adiposity and adipokine levels.
Relationship between Apo C III and
Visceral Adipose Tissue
VAT (kg)
1086420
Ap
o C
III (m
g/d
l)
0
5
10
15
20
25
30
35
40 r2 = 0.25 P = 0.0015
Figure 2. Relationship between serum apolipopro-tein (apo) CIII and visceral adipose tissue (VAT)measured by magnetic resonance imaging in prev-alent hemodialysis patients.
Relationship Between Adiponectin Levels
and VAT in Men and Women
VAT (kg)
86420
Ad
ip
on
ectin
(m
icro
gram
s/m
l)
0
10
20
30
40
50
VAT vs Adiponectin FemaleFemale r2 = 0.59
Male r2 = 0.32VAT vs Adiponectin Male
Figure 3. Relationship between serum adiponectinlevel and visceral adipose tissue (VAT) measuredby magnetic resonance imaging in prevalent hemo-dialysis patients by sex. Men are represented byopen circles, and women by open triangles.
KAYSEN ET AL362
The dyslipidemia of CKD, and specificallyof theapo B-containing lipoproteins, is characterized byreduced clearance.45 Decreased clearance of theselipoproteins is attributable, in part, to intrinsicdefects in the capacity of TG-rich lipoproteinsto act as appropriate substrates for lipolytic en-zymes,21 consistent with the presence of an intrin-sic structural change in lipoproteins making themless susceptible to lipolysis by LPL. ApolipoproteinCIII is an inhibitor of the action of LPL onTG-rich lipoproteins,46,47 and is increased in dial-ysis patients.20 Although levels of apo CIII weresignificantly greater than reported for normalsubjects,48,49 we found that apo CIII levels wereassociated with VATwithin these subjects, similarto the relationship described in patients withoutrenal failure.50 By contrast, LDL cholesterol waslow for this population as a whole, and was notsignificantly associated with adiposity.
Inflammation is common among dialysis pa-tients,51 and is well above the levels observed innondialysis populations.3,12 Inflammation is asso-ciated with the malnutrition, inflammation, andatherosclerosis syndrome,52 providing a basis forinflammation in nonobese subjects, and poten-tially obscuring an effect linked to adiposity.Among subjects with normal kidney function,the association between adiposity and eitherCRP and IL-6 is quite strong. However, themedian values are significantly lower than wereport here for dialysis patients.53 The upper tertile
of CRP among patients without kidney diseasebegins at 3 mg/L,54 a value below the medianvalue among the dialysis patients we studied. Sim-ilarly, median IL-6 values were also well above theupper quartile (.2.28 pg/mL) among the non-dialysis population.14 Axelsson et al. reported anassociation between truncal fat mass and serumIL-6 levels; however, their r2 value was 0.044.55
By contrast, we found a strong associationbetween the more long-lived acute-phase proteinceruloplasmin and VAT. Ceruloplasmin was asso-ciated with central obesity in patients not on dial-ysis.56 Serum IL-6 and CRP values are highlyvariable temporally in HD patients, far more sothan are the levels of a1 acid glycoprotein or ceru-loplasmin,57 possibly contributing to the decreasein association between these more variable pro-teins and the adipose pools. Thus, althoughinflammation and low HDL were found in thispopulation, the risk was either not linked to adi-posity at all, or only weakly linked to adiposity(CRP), primarily because of low HDL andincreased inflammation, at least as reported byshort-lived makers of inflammation, among leandialysis patients. The risk factors were presentregardless of adiposity, and present at a level associ-ated with the highest level of cardiovascular risk inpopulations without kidney failure. Other factorsthat we did not control for may have obscuredany effects of body composition.
Adiposity remained associated with TGs andwith the cardiovascular risk factor apo CIII, andvisceral adiposity was inversely associated with adi-ponectin. In contrast to patients without kidneyfailure, adiponectin was directly associated withmortality in dialysis patients by some investiga-tors,23 and was indeterminate according tosome,58 whereas a protective effect was noted byothers.22 It is possible that adiponectin is not inthe causal pathway linking body composition tooutcome, and that it simply reflects adiposity,thus explaining the apparent salutary effect ofhigh adiponectin in the population of patientswithout renal failure, with a possible deleteriouseffect observed by some investigators amongpopulations of patients with kidney failure.23
We previously established, in a much largergroup of patients (approximately 26,000), thatthe relationship between HDL cholesterol andBMI was lost as estimated glomerular filtrationrate (eGFR) declined.59 The main limitation ofthe present study is that it is small. However, we
ADIPOSITY AND CARDIOVASCULAR RISK IN PREVALENT HD 363
directly measured both VAT, which is strongly as-sociated with insulin resistance and dyslipidemia,and SAT, and found that many but not all risk fac-tors associated with increased adiposity are in-creased in prevalent HD patients, regardless oftotal adiposity or visceral adipose mass. If theserisk factors are on the causal pathway to cardiovas-cular mortality, the incremental risks imposed bythese factors are not increased among obese dialy-sis patients. However, other risk factors specificallyassociated with TG-rich lipoproteins (TG and apoCIII levels) retain the same qualitative relationshipto body composition in dialysis patients as they doin subjects with normal renal function. Why obesedialysis patients avoid an increased mortality riskdespite the residual association between adiposityand these risk factors remains to be established.
AcknowledgmentsOur research was supported by the Renal Research Insti-
tute, by a grant from Dialysis Clinic, Inc., and by the Western
Human Nutrition Research Center and a grant from the
National Institutes of Health PO1 DK-42618.
References
1. Johansen KL, Young B, Kaysen GA, Chertow GM: Associ-
ation of body size with outcomes among patients beginning
dialysis. Am J Clin Nutr 80:324-332, 2004
2. Kalantar-Zadeh K, Kopple JD, Kilpatrick RD, et al: Associ-
ation of morbid obesity and weight change over time with cardio-
vascular survival in hemodialysis population. Am J Kidney Dis 46:
489-500, 2005
3. Kaysen GA, Muller HG, Young BS, Leng X, Chertow GM:
The influence of patient- and facility-specific factors on nutri-
tional status and survival in hemodialysis. J Ren Nutr 14:72-81,
2004
4. Wolfe RA, Ashby VB, Daugirdas JT, Agodoa LY, Jones CA,
Port FK: Body size, dose of hemodialysis, and mortality. Am
J Kidney Dis 35:80-88, 2000
5. Gotch FA, Levin NW, Port FK, Wolfe RA, Uehlinger DE:
Clinical outcome relative to the dose of dialysis is not what you
think: the fallacy of the mean. Am J Kidney Dis 30:1-15, 1997
6. Kotler DP, Tierney AR, Wang J, Pierson RN Jr: Magnitude
of body-cell-mass depletion and the timing of death from wasting
in AIDS. Am J Clin Nutr 50:444-447, 1989
7. Kamat AM, Shock RP, Naya Y, Rosser CJ, Slaton JW,
Pisters LL: Prognostic value of body mass index in patients under-
going nephrectomy for localized renal tumors. Urology 63:46-50,
2004
8. Le Blanc K, Ringden O, Remberger M: A low body mass
index is correlated with poor survival after allogeneic stem cell
transplantation. Haematologica 88:1044-1052, 2003
9. Curtis JP, Selter JG, Wang Y, et al: The obesity paradox: body
mass index and outcomes in patients with heart failure. Arch
Intern Med 10(165):55-61, 2005
10. Grundy SM, Brewer HB Jr., Cleeman JI, Smith SC Jr,
Lenfant C: American Heart Association: National Heart, Lung,
and Blood Institute definition of metabolic syndrome: report of
the National Heart, Lung, and Blood Institute/American Heart
Association conference on scientific issues related to definition.
Circulation 109:433-438, 2004
11. Ooi EM, Watts GF, Farvid MS, et al: High-density lipopro-
tein apolipoprotein A-I kinetics in obesity. Obes Res 13:
1008-1016, 2005
12. Yeun JY, Levine RA, Mantadilok V, Kaysen GA: C-
reactive protein predicts all-cause and cardiovascular mortality in
hemodialysis patients. Am J Kidney Dis 35:469-476, 2000
13. Zimmermann J, Herrlinger S, Pruy A, Metzger T,
Wanner C: Inflammation enhances cardiovascular risk and mor-
tality in hemodialysis patients. Kidney Int 55:648-658, 1999
14. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH:
Plasma concentration of interleukin-6 and the risk of future
myocardial infarction among apparently healthy men. Circulation
18:1767-1772, 2000
15. Mohamed-Ali V, Goodrick S, Rawesh A, et al: Subcutane-
ous adipose tissue releases interleukin-6, but not tumor necrosis
factor-alpha, in vivo. J Clin Endocrinol Metab 82:4196-4200,
1997
16. Bastard JP, Maachi M, Van Nhieu JT, et al: Adipose tissue
IL-6 content correlates with resistance to insulin activation of
glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab
87:2084-2089, 2002
17. Hocher B, Ziebig R, Altermann C, et al: Different impact
of biomarkers as mortality predictors among diabetic and nondia-
betic patients undergoing hemodialysis. J Am Soc Nephrol 14:
2329-2337, 2003
18. Bologa RM, Levine DM, Parker TS, et al: Interleukin-6
predicts hypoalbuminemia, hypocholesterolemia, and mortality
in hemodialysis patients. Am J Kidney Dis 32:107-114, 1998
19. Koch M, Kutkuhn B, Grabensee B, Ritz E,
Apolipoprotein A: fibrinogen, age, and history of stroke are pre-
dictors of death in dialysed diabetic patients: a prospective study
in 412 subjects. Nephrol Dial Transplant 12:2603-2611, 1997
20. Mekki K, Prost J, Bouchenak M, Remaoun M, Belleville J:
Plasma lipoprotein lipase, hepatic lipase activities, VLDL, LDL
compositions at different times of hemodialysis. Atherosclerosis
169:269-277, 2003
21. Lee DM, Knight-Gibson C, Samuelsson O, Attman PO,
Wang CS, Alaupovic P: Lipoprotein particle abnormalities and
the impaired lipolysis in renal insufficiency. Kidney Int 61:
209-218, 2002
22. Zoccali C, Mallamaci F, Tripepi G, et al: Adiponectin, met-
abolic risk factors, and cardiovascular events among patients with
end-stage renal disease. J Am Soc Nephrol 13:134-141, 2002
23. Ohashi N, Kato A, Misaki T, et al: Association of serum
adiponectin levels with all-cause mortality in hemodialysis
patients. Intern Med 47:485-491, 2008
24. Nordfors L, Lonnqvist F, Heimburger O, Danielsson A,
Schalling M, Stenvinkel P: Low leptin gene expression and hyper-
leptinemia in chronic renal failure. Kidney Int 54:1267-1275,
1998
25. Daschner M, Tonshoff B, Blum WF, et al: Inappropriate
elevation of serum leptin levels in children with chronic renal fail-
ure. European Study Group for Nutritional Treatment of Chronic
Renal Failure in Childhood. J Am Soc Nephrol 9:1074-1079,
1998
26. Bodary PF, Gu S, Shen Y, Hasty AH, Buckler JM,
Eitzman DT: Recombinant leptin promotes atherosclerosis and
KAYSEN ET AL364
thrombosis in apolipoprotein E-deficient mice. Arterioscler
Thromb Vasc Biol 25: 3119-e122, 2005
27. Kougias P, Chai H, Lin PH, Yao Q, Lumsden AB, Chen C:
Effects of adipocyte-derived cytokines on endothelial functions:
implication of vascular disease. J Surg Res 126:121-129, 2005
28. Fruhbeck G: A heliocentric view of leptin. Proc Nutr Soc
60:301-318, 2001
29. Singhal A, Farooqi IS, Cole TJ, et al: Influence of leptin on
arterial distensibility: a novel link between obesity and cardiovas-
cular disease? Circulation 106:1919-1924, 2002
30. Havel PJ: Update on adipocyte hormones: regulation of
energy balance and carbohydrate/lipid metabolism. Diabetes
53(Suppl 1):S143-S151, 2004
31. Cnop M, Havel PJ, Utzschneider KM, Swarbrick MM,
Havel PJ: Relationship of adiponectin to body fat distribution,
insulin sensitivity and plasma lipoproteins: evidence for indepen-
dent roles of age and sex. Diabetologia 46:459-469, 2003
32. Swarbrick MM, Havel PJ: Physiological, pharmacological,
and nutritional regulation of circulating adiponectin concentra-
tions in humans. Metab Syndr Relat Disord 6:87-102, 2008
33. Goldstein BJ, Scalia R: Adiponectin: a novel adipokine
linking adipocytes and vascular function. J Clin Endocrinol Metab
89:2563-2568, 2004
34. Menon V, Li L, Wang X, et al: Adiponectin and mortality
in patients with chronic kidney disease. J Am Soc Nephrol 17:
2599-2606, 2006
35. Lee RC, Wang Z, Heo M, Ross R, Janssen I,
Heymsfield SB: Total-body skeletal muscle mass: development
and cross-validation of anthropometric prediction models. Am
J Clin Nutr 72:796-803, 2000
36. Beckman Instruments, Inc.: Beckman instructions 015-
248545-F, November 1994. Brea, CA: Beckman Instruments,
Inc., 1994
37. Flannery W, Teukolsky B, Vetterling WT: Kolmogorov-
Smirnov Test. In: Numerical recipes in FORTRAN: the art of
scientific computing, 2nd ed. Cambridge, UK: Cambridge Uni-
versity Press, pp 617-620, 1992.
38. Adams KF, Schatzkin A, Harris TB, et al: Overweight, obe-
sity, and mortality in a large prospective cohort of persons 50 to 71
years old. N Engl J Med 355:763-778, 2006
39. Pischon T, Boeing H, Hoffmann K, et al: General and ab-
dominal adiposity and risk of death in Europe. N Engl J Med 359:
2105-2120, 2008
40. Wassink AM, Olijhoek JK, Visseren FL: The metabolic
syndrome: metabolic changes with vascular consequences. Eur
J Clin Invest 37:8-17, 2007
41. Davy KP, Hall JE: Obesity and hypertension: two epi-
demics or one? Am J Physiol Regul Integr Comp Physiol 286:
R803-R813, 2004
42. Elsayed EF, Sarnak MJ, Tighiouart H, et al: Waist-to-hip
ratio, body mass index, and subsequent kidney disease and death.
Am J Kidney Dis 52:29-38, 2008
43. Elsayed EF, Tighiouart H, Weiner DE, et al: Waist-to-hip
ratio and body mass index as risk factors for cardiovascular events
in CKD. Am J Kidney Dis 52:49-57, 2008
44. Lang CH, Dobrescu C, Bagby GJ: Tumor necrosis factor
impairs insulin action on peripheral glucose disposal and hepatic
glucose output. Endocrinology 130:43-52, 1992
45. Ikewaki K, Schaefer JR, Frischmann ME, et al: Delayed in
vivo catabolism of intermediate-density lipoprotein and low-
density lipoprotein in hemodialysis patients as potential cause of
premature atherosclerosis. Arterioscler Thromb Vasc Biol 25:
2615-2622, 2005
46. Wang C, McConathy WJ, Kloer HJ, Alaupovic P: Modu-
lation of lipoprotein lipase activity by apolipoproteins: effect of
apolipoprotein C-III. J Clin Invest 75:384-390, 1985
47. Brown WV, Baginsky ML: Inhibition of lipoprotein lipase
by an apoprotein of human very low density lipoprotein. Biochem
Biophys Res Commun 46:375-382, 1972
48. Saland JM, Ginsberg HN: Lipoprotein metabolism in
chronic renal insufficiency. Pediatr Nephrol 22. 1095–1012, 2007.
49. Lee DM, Knight-Gibson C, Samuelsson O, Attman PO,
Wang CS, Alaupovic P: Lipoprotein particle abnormalities and
the impaired lipolysis in renal insufficiency. Kidney Int 61:
209-218, 2002
50. Lofgren I, Herron K, Zern T, et al: Waist circumference is
a better predictor than body mass index of coronary heart disease
risk in overweight premenopausal women. J Nutr 134:1071-1076,
2004
51. Kimmel PL, Phillips TM, Simmens SJ, et al: Immunologic
function and survival in hemodialysis patients. Kidney Int 54:
236-244, 1998
52. Stenvinkel P, Heimburger O, Lindholm B, Kaysen GA,
Bergstrom J: Are there two types of malnutrition in chronic renal
failure? Evidence for relationships between malnutrition, inflam-
mation and atherosclerosis (MIA syndrome). Nephrol Dial Trans-
plant 15:953-960, 2000
53. Pou KM, Massaro JM, Hoffmann U, et al: Visceral and sub-
cutaneous adipose tissue volumes are cross-sectionally related to
markers of inflammation and oxidative stress: the Framingham
Heart Study. Circulation 116:1234-1241, 2007
54. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR: Com-
parison of C-reactive protein and low-density lipoprotein choles-
terol levels in the prediction of first cardiovascular events. N Engl
J Med 347:1557-1565, 2002
55. Axelsson J, Rashid Qureshi A, et al: Truncal fat mass as
a contributor to inflammation in end-stage renal disease. Am
J Clin Nutr 80:1222-1229, 2004
56. Cignarelli M, DePergola G, Picca G, et al: Relationship of
obesity and body fat distribution with ceruloplasmin serum levels.
Int J Obes Relat Metab Disord 20:809-813, 1996
57. Kaysen GA, Dubin JA, Muller HG, et al: Impact of
albumin synthesis rate and the acute phase response in the dual
regulation of fibrinogen levels in hemodialysis patients. Kidney
Int 63:315-322, 2003
58. Rao M, Li L, Tighiouart H, Jaber BL, Pereira BJ,
Balakrishnan VS: Plasma adiponectin levels and clinical outcomes
among haemodialysis patients. HEMO Study Group. Nephrol
Dial Transplant 23:2619-2628, 2008
59. Lo JC, Go AS, Chandra M, Fan D, Kaysen GA: GFR, body
mass index, and low high-density lipoprotein concentration in
adults with and without CKD. Am J Kidney Dis 50:552-558, 2007