Does Renal Failure Cause an Atherosclerotic Milieu in Patients with End-Stage Renal Disease? Robert Kennedy, BSc (Hons), Colin Case, MSc, Robert Fathi, MBBS, David Johnson, MBBS, PhD, Nicole Isbel, MBBS, Thomas H. Marwick, MBBS, PhD PURPOSE: Atherosclerotic vascular disease is the main cause of morbidity and mortality in patients with end-stage renal dis- ease, but the independent contribution of renal failure rather than associated risk factors is unclear. We sought to examine the relative contribution of these factors to the severity of athero- sclerosis by measuring intima-medial thickness and brachial ar- tery reactivity in uremic patients and controls. SUBJECTS AND METHODS: Cardiovascular risk factors, in- cluding lipid and homocysteine levels, were evaluated in 213 patients (69 on hemodialysis, 60 on peritoneal dialysis, and 82 nonuremic controls). High-resolution B-mode ultrasonogra- phy with automated off-line analysis was used to measure the intima-medial thickness in the common carotid artery and to measure the lumen diameter of the brachial artery at rest, dur- ing reactive hyperemia, and after sublingual nitroglycerine. The correlations of risk factors with intima-medial thickness and brachial reactivity were examined using a general linear regres- sion model. RESULTS: Patients with renal failure had a greater mean ( SEM) maximum intima-medial thickness than controls (0.83  0.02 mm versus 0.70  0.02 mm, P 0.05), but the brachial artery response to reactive hyperemia was not significantly dif- ferent between the renal failure patients and the control group (4.7%  6.1% versus 6.1%  8.6% dilatation, P 0.05). The uremic state was an independent predictor of intima-medial thickness (r 2 = 0.16, P 0.001) but not of brachial artery reac- tivity (P = 0.99). CONCLUSION: The atherosclerotic burden in patients with renal failure, as indicated by an increased intima-medial thick- ness, may reflect effects of uremia that are independent of car- diovascular risk factors. Am J Med. 2001;110:198 –204. 2001 by Excerpta Medica, Inc. A therosclerotic cardiovascular disease is the lead- ing cause of morbidity and mortality in patients with end-stage renal disease, accounting for 50% of all deaths (1). It is unclear, however, whether end-stage renal disease per se promotes an accelerated atherogenic state or whether this simply reflects a greater prevalence of cardiac risk factors (2,3). Both classic and new risk factors for atherosclerosis (4,5) are prevalent in dialysis patients (6), and many of these factors can be modified successfully. Atherosclerosis leads to alterations in the structure and function of the arterial wall, resulting in thickening of the intima (4) and reduced endothelium-dependent vasodi- latation (7). Intima-medial thickness can be reliably and noninvasively quantified by off-line automated digital analysis of high-frequency ultrasound images (8). This parameter is rapidly becoming accepted in nonuremic patients as a noninvasive marker for following the pro- gression of atherosclerosis (9), such as when lipid-lower- ing agents are used (10). Endothelial dysfunction, a pre- cursor of atherogenesis that is reflected by abnormal bra- chial artery reactivity, may also be used as a marker of early atherosclerosis (11). We used these tools to investi- gate the relative contribution of risk factors and the ure- mic state to atherosclerosis in patients with end-stage re- nal disease. METHODS Study Design This cross-sectional study involved patients with end- stage renal disease on peritoneal dialysis (n = 60) or he- modialysis (n = 69), and nonuremic control patients (n = 82). The sample size was chosen to have an 80% power to detect an intima-medial thickness difference greater than 0.10 mm (12), assuming a standard devia- tion of 0.18 mm (13) between uremic patients and con- trols, which required at least 50 subjects in the control and end-stage renal disease groups. For a power of 80% to detect a difference of 2% (14) with an assumed standard deviation of 4.5% (15) in brachial artery reactivity, we required at least 80 subjects in each group. There were no exclusion criteria, and all available dialysis patients were approached for study. The control patients were selected from patients with one or more risk factors who attended the investigators’ outreach clinic for cardiovascular screening or attended the investigators’ outpatient clinic or echocardiography laboratory for medical conditions other than end-stage renal disease. Other than the pres- ence of risk factors, there were no selection criteria apart From the University of Queensland, Brisbane, Queensland, Australia. Supported in part by a grant in aid from the Australian Kidney Foun- dation and the National Health and Medical Research Council of Aus- tralia. Requests for reprints should be addressed to Thomas H. Marwick, MBBS, PhD, University of Queensland Department of Medicine, Prin- cess Alexandra Hospital, Brisbane, Queensland 4102, Australia. Manuscript submitted December 3, 1999, and accepted in revised form October 4, 2000. 198 2001 by Excerpta Medica, Inc. 0002-9343/01/$–see front matter All rights reserved. PII S0002-9343(00)00695-1