8
ORIGINAL RESEARCH Relationship Between Adiposity and Cardiovascular Risk Factors in Prevalent Hemodialysis Patients George 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 Ó 2009 by the National Kidney Foundation, Inc. A LTHOUGH THE RELATIVE risk of mor- tality is high among dialysis patients, one fac- tor that predicts survival is a higher body mass index (BMI). 1–3 Body mass index is imprecise as a measure of body composition, and does not dis- tinguish between muscle and fat mass. Neverthe- less, the lack of an increase in mortality among a population with a very high BMI (.35 kg/m 2 ) *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. # 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] Ó 2009 by the National Kidney Foundation, Inc. 1051-2276/09/1905-0002$36.00/0 doi:10.1053/j.jrn.2009.04.002 Journal of Renal Nutrition, Vol 19, No 5 (September), 2009: pp 357–364 357

Relationship Between Adiposity and Cardiovascular Risk Factors in Prevalent Hemodialysis Patients

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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.

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