Kidney transplantation is the treatment of choice for individuals with end-stage kidney disease (1). Despite the improvements in graft and patient survival after transplant, approximately 40% of kidney transplant recipients (KTR) die with a functioning graft (2). Although death with a functioning graft may be an indication of successful transplantation and the goal of kidney transplant programs, death from cardiovascular disease is the leading cause of mortality and morbidity in KTR (1). This increased cardiovascular risk has primarily been attributed to “traditional” risk factors (hypertension, dyslipidemia, diabetes, smoking, renal failure, and obesity) present before and/or after transplantation (3). However, increased attention is being paid to other risk factors associated with a sedentary lifestyle such as low aerobic capacity and peripheral vascular endothelial dysfunction. Indeed, Sietsema et al. (4) found that decreased exercise capacity was the strongest predictor of mortality in patients with end-stage renal disease. Further, Blacher et al. (5) found that increased arterial stiffness was an independent predictor of cardiovascular and all cause mortality in end-stage renal disease. Despite this evidence in end-stage renal failure patients, no study to date has examined the global cardiovascular function (i.e., aerobic endurance and arterial compliance) of patients who have undergone kidney transplantation. As a crucial first step in this area of investigation, we conducted a pilot study to examine the arterial compliance and aerobic endurance of KTR.
MATERIALS AND METHODS
This study was conducted between July and September 2004. Ethics approval for this investigation was obtained from the University of Alberta Hospital Health Research Ethics Board and informed consent was obtained prior to commencement of any study-related procedures. The participants for this study included 62 randomly selected, clinically stable, outpatient KTR who attended the Renal Transplant Clinic. The Renal Transplant Clinic provides comprehensive follow-up care for approximately 900 KTR from urban and rural northern Alberta. Subjects were not considered for this study if orthopedic limitations prevented them from performing the six-minute walk test or if they were unable to understand English and a suitable translator was not readily available.
Assessment of Large and Small Arterial Compliance
Resting systolic and diastolic blood pressure and small and large artery compliance were assessed noninvasively using computerized arterial pulse waveform analysis (Hypertension Diagnostics, Eagan, MN). This technique involves the use of applanation tonometry which requires the placement of a transducer over the radial artery. The analysis of the 30-second signal averaged arterial pulse wave forms was performed by the tonometry unit and arterial compliance of the large and small arteries were derived from the analysis of the diastolic waveform decay using the modified Windkessel model of circulation. This technique has been validated previously with invasive arterial waveform measurements (6). The mean of two measurements was used for analysis. Age-predicted values were determined based on a regression equation for 164 healthy individuals between 21 and 56 years of age studied previously in our laboratory.
Aerobic endurance was determined using the 6-minute walk test which has been used to assess aerobic endurance in several different clinical populations (7–9). The six-minute walk test was performed on a flat 20-m corridor during which time the participants were asked to “cover as much distance as possible” in the six-minute period. Healthy age-predicted six-minute walk distance values were determined from the regression equation published by Gibbons et al. (10).
Comparison between KTR and age-predicted healthy values for heart rate, blood pressure, arterial compliance and distance walked in six minutes was performed with one-way analysis of variance (ANOVA) using MedCalc (Mariakerke, Belgium) software. In order to examine the effect of aging on arterial pressure and compliance, KTR were categorized into two groups based on median age (i.e., ≤51 years versus >51 years) and compared using one-way ANOVA. Finally, correlation analysis was performed to assess the relationship between time since transplant and small and large artery compliance. The alpha level was set “a priori” at P<0.05. Data are presented as mean±SD.
During the three-month study period we recruited 62 eligible KTR (41 males). Participant characteristics are described in Table 1. The mean age was 51±14 years, ranging between the ages of 21 and 73 years. The mean time since transplantation was 7.3±6.5 years (range: 0.04 to 27.9 years). Notably, 25% of participants were diabetic requiring treatment with oral hypoglycemics or insulin (Table 1).
Resting heart rate was significantly higher in KTR (72±3 beats/min) compared to healthy age-matched predicted values (67±3 beats/min, P=0.0016). No significant difference was found for systolic (SBP) or diastolic (DBP) blood pressure between KTR (SBP: 133±14 mm Hg and DBP: 78±8 mm Hg) and healthy age-matched predicted values (SBP: 129±7 mm Hg and DBP: 77±6 mm Hg, P=0.150 and 0.626, respectively). Small artery compliance was 30% lower in KTR (5.5±3 ml/mm Hg × 100) compared to healthy age-predicted values (7.9±0.9 ml/mm Hg × 100, P<0.0001, Figure 1) with no difference for large artery compliance between groups (KTR: 16.0±7.0 ml/mm Hg × 10 vs. age-predicted healthy values: 15±1 ml/mm Hg × 10, P=0.4). No significant correlation was found between the time since transplant and small or large artery compliance.
Effect of Aging on Cardiovascular Function in KTR
Systolic blood pressure was significantly higher in older KTR (141±16 mm Hg) compared to younger KTR (133±13 mm Hg, P=.05). No difference was found between groups for DBP (older KTR: 78±7 mm Hg vs. younger KTR: 78±8 mm Hg, P=0.85) or heart rate (older KTR: 69±11 beats/min vs. younger KTR: 71±13 beats/min, P=0.47). Older KTR had significantly lower small (old: 4.4±2.1 mm Hg/ml × 100 vs. young: 5.9±3.0 mm Hg/ml × 100, P=0.026) and large artery compliance (old: 12.5±5.8 ml/mm Hg × 10 vs. young: 17.0±6.4 ml/mm Hg × 10, P=0.005) compared to younger KTR.
The distance walked in six minutes was 28% lower in KTR (495±92 m) compared to age-predicted values (692±56 m, P<0.0001). Also, the distance walked in six minutes was significantly lower in older KTR (466±76 m) versus younger KTR (523±98 m, P=0.013). Finally, the distance walked in six minutes was positively correlated with small (r=0.25, P<0.05) and large artery compliance (r=0.33, P<0.01).
The main finding of this investigation is that KTR have a significantly lower small artery compliance and aerobic endurance compared to age-matched healthy individuals. The second key finding is that older KTR have significantly lower small and large artery compliance and aerobic endurance compared to younger KTR.
Kidney Transplantation and Aerobic Endurance
Our finding that KTR had severely reduced aerobic endurance may be secondary to deleterious effects of pretransplant end stage renal disease as well as posttransplant deconditioning coupled with normal aging. Specifically, increased age and a sedentary lifestyle are known to be associated with alterations in cardiovascular function that result in a decline in oxygen delivery to the working muscle (11, 12). Consistent with this hypothesis, we found that older KTR had the greatest impairment in arterial compliance and aerobic endurance. Thus, the abnormal exercise capacity found in our KTR may be due to their impaired peripheral vascular function. A consequence of the decreased fitness is that it may increase the risk for cardiovascular disease. For example, Myers et al. (13) found peak exercise capacity was the strongest predictor of cardiovascular and all-cause mortality even when controlling for established cardiovascular risk factors in healthy males with or without underlying cardiovascular disease. Sietsema et al. (4) demonstrated that reduced exercise capacity was a powerful predictor of mortality in individuals with end-stage kidney disease. Thus, it is possible that the increased cardiovascular mortality found in KTR may be related, in part, to the reduced aerobic fitness. Future investigations are required to determine if improving aerobic fitness results in favorable cardiovascular outcomes.
Kidney Transplantation and Arterial Compliance
Previous investigators (14–16) have shown that small artery compliance is reduced in individuals with hypertension, diabetes mellitus, and/or smokers. Given that these cardiovascular risk factors are prevalent in KTR our finding of a significant decline in small artery compliance in these individuals is not surprising. The consequence of the impaired vascular function is that it may be an important prognostic indictor for future cardiovascular events. Specifically, Gray et al. (17) reported that a two-unit decline in small artery compliance was associated with a significant increase in a future cardiovascular event in individuals between 25 and 89 years of age. Notably, our KTR small artery compliance was 2.4 units lower than expected for age-matched healthy individuals studied in our laboratory. The mechanism responsible for the posttransplant abnormality in small artery compliance was not examined in this study; however, it may be secondary to abnormalities in endothelial function associated with hypertension, diabetes, obesity, pretransplant renal failure, posttransplant immunosuppression therapy, or as a consequence of a sedentary lifestyle. Consistent with this hypothesis, our diabetic KTR small and large artery compliance was 20 to 30% lower than nondiabetic KTR.
Arterial Compliance in Older KTR
Advancing age has been shown to result in a significant and marked decline in small and large artery compliance (6). Similarly, we found that small and large artery compliance was 25% lower in older compared to younger KTR. The age-mediated decline in arterial stiffness is secondary to the increase in collagen content and concomitant decline in elastin (18). Previous studies have demonstrated that exercise training can improve arterial compliance in different aging populations including middle aged and older sedentary men (19), postmenopausal women (20), and patients with congestive heart failure (21). Consistent with this result, we found that KTR with the highest aerobic endurance also had the greatest arterial compliance. Future studies are required to determine if exercise training can attenuate the decline in aerobic endurance and arterial compliance found in older KTR.
A limitation of this investigation is our small sample size and cross-sectional analysis; therefore, our findings may not be generalizable to all KTR.
We have demonstrated that KTR have severely reduced aerobic endurance and small and large artery compliance. Future investigations are required to determine if interventions that can improve aerobic fitness and arterial compliance result in favorable cardiovascular outcomes in KTR.
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