*Department of Metabolism, Endocrinology and Molecular Medicine, Department of Nephrology, and Department of Geriatrics and Neurology, Osaka City University Medical School, Osaka, Japan; and Division of Internal Medicine, Inoue Hospital, Suita, Japan.
Correspondence to Dr. Tetsuo Shoji, Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, JAPAN. Phone: +81-6-6645-3806; Fax: +81-6-6645-3808; E-mail: t-shoji{at}med.osaka-cu.ac.jp
ABSTRACT. Insulin resistance is closely associated with atherosclerosisand cardiovascular mortality in the general population. Patientswith end-stage renal disease (ESRD) are known to have insulinresistance, advanced atherosclerosis, and a high cardiovascularmortality rate. We evaluated whether insulin resistance is apredictor of cardiovascular death in a cohort of ESRD. A prospectiveobservational cohort study was performed in 183 nondiabeticpatients with ESRD treated with maintenance hemodialysis. Insulinresistance was evaluated by the homeostasis model assessmentmethod (HOMA-IR) using fasting glucose and insulin levels atbaseline, and the cohort was followed for a mean period of 67mo. Forty-nine deaths were recorded, including 22 cardiovasculardeaths. Cumulative incidence of cardiovascular death by Kaplan-Meierestimation was significantly different between subjects in thetop tertile of HOMA-IR (1.40 to 4.59) and those in the lowertertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR)was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P = 0.026)in the univariate Cox proportional hazards model. In multivariateCox models, the positive association between HOMA-IR and cardiovascularmortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55;P = 0.001) and independent of age, C-reactive protein, and presenceof preexisting vascular complications. Further analyses showedthat the effect of HOMA-IR on cardiovascular mortality was independentof body mass index, hypertension, and dyslipidemia. In contrast,HOMA-IR did not show such a significant association with noncardiovascularmortality. These results indicate that insulin resistance isan independent predictor of cardiovascular mortality in ESRD.
Insulin resistance is associated with multiple risk factorsfor atherosclerosis, including hypertension, dyslipidemia, andglucose intolerance or type 2 diabetes mellitus. Clusteringof these risk factors in subjects with obesity has been called"syndrome X" (1), "deadly quartette" (2), "insulin resistancesyndrome" (3), or "visceral fat obesity syndrome" (4). Hyperinsulinemiais a good marker of insulin resistance in subjects without significanthyperglycemia and is used for epidemiologic studies. Studiesin the general population revealed that hyperinsulinemia andother indexes of insulin resistance were associated with prevalentatherosclerosis as evidenced by carotid artery intima-mediathickness (5–8), coronary angiography (9,10), and presenceof coronary heart disease (CHD) (11,12). Also, insulin levelwas associated with incident CHD (13), incident stroke (14),and predicted death from CHD (15–17) in the general population.
Patients with end-stage renal disease (ESRD) are known to haveinsulin resistance (18), multiple risk factors (19–21),advanced atherosclerosis (22,23), and a substantially elevatedcardiovascular mortality rate (24,25). So far, no study is availablein the literature that examines the possible relationship betweeninsulin resistance and cardiovascular mortality in ESRD.
We performed a prospective, observational cohort study in patientswith ESRD to evaluate the effect of insulin resistance on cardiovascularand noncardiovascular mortality.
Study Design and Subjects
We recently reported a prospective, observational cohort studythat evaluated the effects of metabolic changes on arteriosclerosisand prognosis in ESRD (The MAP ESRD Study) (26). The presentstudy is a subanalysis of the MAP ESRD cohort that includesonly 183 subjects with normal fasting glucose concentration.Table 1 summarizes baseline characteristics of the subjects.
The original cohort consisted of 265 ESRD patients. They hadbeen treated by regular hemodialysis for more than 3 mo at InoueHospital, Suita, Japan. The subjects were recruited from thosewho were dialyzed in morning sessions, so blood tests were doneafter an overnight fast. We excluded patients when they hadsevere illness or apparent acute inflammatory symptoms. Theoriginal cohort corresponded to 90% of those who received hemodialysisin morning sessions or 53% of the total hemodialysis patientsof this hospital. From the 265 subjects, we excluded 50 patientswho had been diagnosed to have type 2 diabetes mellitus on thebasis of past history and/or presence of overt fasting hyperglycemiaof 126 mg/dl (7.0 mmol/L) (27) and 32 patients showing impairedfasting glucose in the range of 110 to 125 mg/dl (6.1 to 6.9mmol/L). The remaining 183 patients with normal fasting glucose(<110 mg/dl or 6.0 mmol/L) were included in the present study.
The subjects were registered between June 1992 and June 1995.Mean (± SD) age at entry was 55.4 ± 10.7 yr, whichwas close to the mean age of the entire dialysis populationin Japan at the end of 1992 (56.0 ± 13.5 yr; n = 123,926).They received 3 to 5 h of hemodialysis three times a week usingbicarbonate dialysate. Median (range) duration of hemodialysisbefore inclusion was 7.4 (0.3 to 21.9) yr. They were followedthrough December 1998 with a mean follow-up period of 67 ±23 mo. They gave informed consent, and this study was approvedby the institutional ethical committee.
Definition of Dyslipidemia
Presence of dyslipidemia was diagnosed when a subject had oneor more of the following criteria (28): (1) LDL cholesterolof 100 mg/dl (2.58 mmol/L); (2) non-HDL cholesterol of 130 mg/dl(3.36 mmol/L); (3) plasma triglycerides of 150 mg/dl (1.69 mmol/L);(4) HDL cholesterol of 40 mg/dl (1.03 mmol/L); and (5) use ofone or more lipid-lowering drugs. According to the criteria,138 out of the 183 subjects were diagnosed to have dyslipidemiaat baseline.
Definition of Hypertension
BP was measured with a standard mercury sphygmomanometer andcuffs adapted to arm circumference after the subject had restedin the supine position for at least 5 min. The systolic anddiastolic BP levels were taken as the points of appearance anddisappearance of Korotkoff sounds, respectively. The averageof three measurements was used for analysis. Presence of hypertensionwas diagnosed when a subject had one or more of the followingcriteria (29): (1) systolic BP of 140 mmHg; (2) diastolic BPof 90 mmHg; and (3) use of one or more antihypertensive drugs.According to the criteria, 148 out of the 183 subjects werediagnosed to have hypertension at baseline.
Preexistence of Vascular Complications at Baseline
Presence of vascular complications was evaluated by clinicalinformation regarding coronary, cerebral, and peripheral arterydiseases and aortic aneurysm. Coronary artery disease was diagnosedwhen a subject had one of more of the following criteria: (1)past history of percutaneous coronary intervention or coronaryartery bypass grafting; (2) presence of significant stenosisby coronary angiography; (3) presence of ST-T abnormalitieson electrocardiogram associating typical symptoms attributableto angina pectoris; and (4) use of one or more medications forcoronary ischemia. Thirteen patients were diagnosed to havecoronary artery disease. Cerebrovascular disease was diagnosedby past history that had been confirmed by positive findingsof infarction or bleeding by x-ray computed tomography or magneticresonance imaging. Seventeen patients had such past history.Peripheral artery disease was diagnosed in four patients withintermittent claudication and/or leg pain at rest when significantarterial stenosis was confirmed by angiography. Diagnosis ofaortic aneurysm was made by x-ray computed tomography in onepatient. At baseline, 31 patients had one or more of the abovevascular complications.
Blood Sampling and Assays
Blood was drawn in the morning after an overnight fast of atleast 12 h before starting a dialysis session. Whole blood wasused for hematocrit and hemoglobin A1c, EDTA-plasma for glucose,insulin, and lipids, and serum for other biochemical assays.Glucose was measured by a glucose oxidase method. Insulin wasmeasured by radioimmunometric assay (Insulin RIA-BEAD II; DinabotCo., Tokyo, Japan). Total cholesterol and triglycerides weremeasured enzymatically. HDL-cholesterol was measured after precipitatingapolipoprotein B-containing lipoproteins with dextran sulfateand magnesium chloride. Non-HDL cholesterol was calculated bysubtracting HDL cholesterol from total cholesterol. LDL cholesterolwas calculated according to the Friedwald formula. Other measurementswere by routine methods.
Assessment of Insulin Resistance Using HOMA-IR
Insulin resistance was assessed using the homeostasis modelassessment (HOMA-IR) originally described by Mathew et al. (30).HOMA-IR was calculated using the following formula:
HOMA-IR has close correlation with the insulin sensitivity indexby the standard euglycemic hyperinsulinemic clamp as shown byMathew et al. (30) and by us (31). This index can be appliedto subjects with renal failure (32).
Outcome Data Collection
During the follow-up, one patient underwent renal transplantation.He was censored at the time of transplantation. Twelve patientswere also censored when they moved away from Inoue Hospital.The outcome data of 170 out of the 183 patients could be obtained.At the end of the follow-up, 121 patients were confirmed tobe alive on hemodialysis and 49 to be dead.
Date and cause of death were obtained by reviewing the hospitalrecord forms. In the cases that moved away to other dialysisunits but the follow-up could be continued, we reviewed thequestionnaire forms filled by the attending physicians at theunits. The 49 deaths during the follow-up included 22 fatalcardiovascular events: 2 deaths attributable to coronary heartdisease, 5 to cerebrovascular disease, 8 to congestive heartfailure, and 7 to sudden death. Sudden death was defined asa witnessed death that occurred within 1 h after the onset ofacute symptoms and with no evidence of accident or violence.The 27 fatal noncardiovascular causes were cancer (n = 5), infectiousdisease (n = 8), and others (n = 14).
Statistical Analyses
Continuous variables were summarized as mean ± SD. Median(range) was given for duration of hemodialysis, triglycerides,C-reactive protein, fasting plasma insulin, and HOMA-IR becauseof their skewed distribution. Survival curves were estimatedby the Kaplan-Meier method followed by log rank test. Prognosticvariables for survival were first examined using the univariateCox proportional hazards regression models, and significantvariables were forced into the multivariate Cox model. P <0.05 was considered significant. All these analyses were performedusing statistical software (StatView 5; SAS Institute Inc.,Cary, NC) for Windows personal computers.
Distribution of HOMA-IR
HOMA-IR showed a skewed distribution with a median of 1.16 (Figure 1).Because of the non-normal distribution, HOMA-IR was enteredas a categorical variable instead of a continuous one in theCox proportional hazards model below.
Figure 1. Distribution of homeostasis model assessment (HOMA-IR) at baseline. HOMA-IR showed skewed distribution. The 33rd and 67th percentile levels were 0.88 and 1.40, respectively.
Univariate Association between Mortality and HOMA-IR
In a preliminary analysis in which the subjects were dividedinto tertiles according to HOMA-IR, those in the top tertile(HOMA-IR, 1.40 to 4.59) had a significantly higher risk of cardiovasculardeath compared with those in the middle tertile (HOMA-IR, 0.89to 1.39; HR, 3.39; 95% CI, 1.09 to 10.52; P = 0.035), whereasthe risk did not differ between the lowest (HOMA-IR, 0.28 to0.88) and middle tertiles (HR, 1.64; 95% CI, 0.46 to 5.81; P= 0.444), suggesting that there was a threshold level of HOMA-IRin relation to cardiovascular mortality. Therefore, the riskwas calculated between the top and the combined lower two tertiles(Table 2). In such analyses, the patients in the top tertileof HOMA-IR showed a significantly higher risk of cardiovascularmortality (HR, 2.61; 95% CI, 1.12 to 6.01; P = 0.026). Figure 2shows the survival curves estimated by the Kaplan-Meier method.
Figure 2. Kaplan-Meier curves showing association between HOMA-IR and outcome. Survival curves were estimated by the Kaplan-Meier method and compared between the subjects with and without increased HOMA-IR of 1.40 or higher. P values by log rank test.
Univariate Association between Mortality and Other Covariates Table 2 shows univariate association between mortality and othercovariates. Among these, greater age, elevated C-reactive protein,presence of vascular complications, and increased HOMA-IR werefound to be significant univariate predictors of cardiovascularmortality. In contrast, significant univariate predictors ofnoncardiovascular mortality were greater age, lower serum albumin,elevated C-reactive protein, and male gender. HOMA-IR was notassociated with noncardiovascular mortality.
Independent Predictors of Cardiovascular Mortality
Independent predictors of cardiovascular mortality were identifiedby the multivariate Cox models (Table 3). The first model, includingthe four significant univariate predictors, indicated that HOMA-IRand three other covariates were significant and independentpredictors of cardiovascular mortality. To examine whether theeffect of HOMA-IR on cardiovascular mortality was independentof body mass index, hypertension, and dyslipidemia, each ofthe three factors was added to the model as the fifth covariate(model 2, 3 and 4). HOMA-IR remained significant and independentof these covariates.
Insulin resistance plays an important role in clustering riskfactors of atherosclerosis such as hypertension, dyslipidemia,and abnormal glucose metabolism. Many (5–17) but not allstudies (33,34) in the general population show positive associationof indices of insulin resistance with arterial wall changes,coronary artery disease, and cardiovascular mortality. In thepresent study, we revealed for the first time that HOMA-IR,an index of insulin resistance, was an independent predictorof cardiovascular mortality in a cohort of nondiabetic ESRDpatients.
Clustering of risk factors synergistically increases the riskof atherosclerosis (35). The current hypothesis of "multiplerisk factor syndrome" is that insulin resistance is the importantmechanism for the clustering of hypertension, dyslipidemia,and abnormal glucose metabolism (2–4,36). We thereforeexpected that the association between HOMA-IR and cardiovascularmortality would be dependent on these risk factors and thatthe association would become insignificant when these individualrisk factors were included in the multivariate Cox model. However,the association between HOMA-IR and cardiovascular mortalityremained significant and independent of these major risk factors.There are several possibilities to explain this observation.First, because the Cox analysis evaluated the independent effectof individual risk factors on cardiovascular mortality, thesynergistic effect of these risk factors may have been reflectedon the significant association with insulin resistance, a commonbasis of the multiple risk factors. Second, HOMA-IR may representinsulin resistance-associated risk factors that were presentin renal failure but not included in the model, such as increasedplasminogen-activator inhibitor 1 (37,38), hyperhomocystinemia(39,40), and the small-dense LDL phenotype (36,41). Third, althoughall subjects showed normal fasting glucose, it is possible thatthose with increased HOMA-IR had impaired glucose tolerance,a risk factor for cardiovascular mortality (42).
Obesity in the general population is closely associated withinsulin resistance and is an unfavorable factor for cardiovasculardisease. Paradoxically, an increased body mass index is a predictorof lower mortality rate from cardiovascular disease in ESRDpatients (43). This has been interpreted to indicate that malnutritionis an important factor predicting poor survival in these subjects.In the present study, HOMA-IR was a significant predictor ofcardiovascular mortality that was independent of body mass index.Insulin resistance and adiposity per se may have different rolesin cardiovascular death in the ESRD population.
Insulin resistance may develop in the presence of inflammation.Also, chronic inflammation has been shown to be an independentpredictor of cardiovascular mortality (44,45). Therefore, therewas a possibility that the observed association between increasedHOMA-IR and cardiovascular mortality was mediated by chronicinflammation. However, this study showed that the effect ofHOMA-IR was independent of C-reactive protein. In addition,there was no significant correlation between HOMA-IR and C-reactiveprotein levels (rs = -0.057; P = 0.358 by Spearman’s rankcorrelation). These data clearly indicate that insulin resistanceand chronic inflammation independently affect cardiovascularmortality in the ESRD population.
What causes insulin resistance in ESRD? Physical inactivitywould be one of the possible explanations (46). In addition,cytokines secreted by adipocytes (adipocytokines) play importantroles in insulin resistance in obese subjects; another possibilitymay therefore be increased adipocytokine levels in uremic plasma.Adipocytokines that can induce insulin resistance include tumornecrosis factor- (TNF-) (47,48) and leptin (48,49). Plasma concentrationsof these molecules are increased in patients with renal failure(50–52). Therefore, although ESRD subjects are not necessarilyobese, the increased cytokine levels may be one of the causesfor "insulin resistance syndrome without obesity." Clearly,further studies are needed to prove such a hypothesis.
There are a few limitations in this study. First, the numberof fatal events was relatively small, and statistical powermay not be large enough to detect important cardiovascular riskfactors such as hypertension and dyslipidemia. Second, thisstudy included only subjects treated in morning dialysis sessions.This may affect the generalizability of the findings, becausea recent study (53) showed that morning-shift hemodialysis patientssurvived significantly longer than afternoon-shift patients.
In conclusion, the present study revealed that insulin resistance,as assessed by HOMA-IR, was an independent predictor of cardiovascularmortality in a cohort of nondiabetic ESRD patients. Insulinresistance is a modifiable risk factor; reduction of insulinresistance may therefore be a new target in treating these patients.
Acknowledgments
Part of this study was presented at the 2001 ASN/ISN World Congressof Nephrology, San Francisco, California, and appears in anabstract form (J Am Soc Nephrol 12: A245, 2001). The authorsgratefully acknowledge the special effort by Mr. Narutoshi Odakaand Ms. Sugako Muro at Inoue Hospital in accumulating clinicaldata. The authors also thank the following doctors for theirkind help in collecting the outcome data; Dr. Masamitsu Fujii(Osaka Kosei-Nenkin Hospital), Dr. Akira Hashimoto (Ueno GeneralMunicipal Hospital), Dr. Yasuyuki Hayashi (Osaka PrefecturalSenri Critical Care Center), Dr. Takashi Honjo (Saiseikai IbarakiHospital), Dr. Hiroshige Ikeda (Ikeda Clinic), Dr. YoshihikoImamura (Nissan Tamagawa Hospital), Dr. Mitsuo Inada (KansaiMedical University), Dr. Toshiaki Kawanaka (Ishikiriseiki Hospital),Dr. Naohiko Kishida (Kishida Clinic), Dr. Haruhiko Kikuchi (NationalCardiovascular Center), Dr. Takashi Kiyose (Kiyose Hospital),Dr. Takashi Kuwahara (Saiseikai Nakatsu Hosipital), Dr. AkiraMoriya (Asakayama Hospital), Dr. Masayuki Nagahara (HigashiNagahara Hospital), Dr. Tetsuro Nagai (Nagai Iin), Dr. ToshihideNaganuma (Kitaosaka Clinic), Dr. Shoichi Nishio (Fuchu Hospital),Dr. Hiroji Okada (Saiseikai Suita Hospital), Dr. Sunghyo Shin(Osaka Seamen’s Insurance Hospital), Dr. Kiyoshi Shozu(Kouseikai Kyoritsu Hospital), Dr. Junya Takahara (Sone Hospital),Dr. Koji Takahashi (Takahashi Clinic), Dr. Hiroshi Tanaka (Ohno-KinenHospital), Dr. Mikihiro Tsuboniwa (Terada Clinic), Dr. MasaruUmeda (Nogami Hospital), Dr. Kunihiko Ueda (Kyoritsu Hospital),Dr. Ibuki Yajima (Kadoma Clinic), Dr. Kiyomichi Yoshimaru (IshikiriseikiHospital), and Dr. Tetsuo Yukioka (Osaka University Hospital).
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Received for publication December 28, 2001.
Accepted for publication April 11, 2002.
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Top
Abstract
Introduction
126 mg/dl (7.0 mmol/L) (27) and 32 patients showing impaired fasting glucose in the range of 110 to 125 mg/dl (6.1 to 6.9 mmol/L). The remaining 183 patients with normal fasting glucose (<110 mg/dl or 6.0 mmol/L) were included in the present study. 
40 mg/dl (1.03 mmol/L); and (5) use of one or more lipid-lowering drugs. According to the criteria, 138 out of the 183 subjects were diagnosed to have dyslipidemia at baseline. 
(TNF-
