Journal Logo

Original Articles: Clinical Transplantation

Impaired Arterial Compliance and Aerobic Endurance in Kidney Transplant Recipients

Riess, Kenneth J.1; Gourishankar, Sita2; Oreopoulos, Antigone1; Jones, Lee W.3; McGavock, Jon M.4; Lewanczuk, Richard Z.5; Haykowsky, Mark J.1,6

Author Information
doi: 10.1097/01.tp.0000233347.40682.21

Abstract

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

Subjects

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

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).

Statistical Analysis

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.

RESULTS

Participant Characteristics

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).

TABLE 1
TABLE 1:
Participant characteristics

Cardiovascular Function

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.

FIGURE 1.
FIGURE 1.:
Small artery compliance in kidney transplant recipients and age-matched predicted values for healthy individuals. *P<0.0001 vs. kidney transplant.

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.

Aerobic Endurance

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).

DISCUSSION

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.

Limitations

A limitation of this investigation is our small sample size and cross-sectional analysis; therefore, our findings may not be generalizable to all KTR.

Summary

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.

REFERENCES

1. Magee CC, Pascual M. Update in renal transplantation. Arch Intern Med 2004; 164: 1373.
2. Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307.
3. Bostom AD, Brown RS Jr., Chavers BM, et al. Prevention of post-transplant cardiovascular disease–report and recommendations of an ad hoc group. Am J Transplant 2002; 2: 491.
4. Sietsema KE, Amato A, Adler SG, Brass EP. Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease. Kidney Int 2004; 65: 719.
5. Blacher J, Guerin AP, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999; 99: 2434.
6. McVeigh GE, Bratteli CW, Morgan DJ, et al. Age-related abnormalities in arterial compliance identified by pressure pulse contour analysis: aging and arterial compliance. Hypertension 1999; 33: 1392.
7. Haykowsky M, Riess K, Figgures L, et al. Exercise training improves aerobic endurance and musculoskeletal fitness in female cardiac transplant recipients. Curr Control Trials Cardiovasc Med 2005; 6: 10.
8. Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985; 132: 919.
9. Hung C, Daub B, Black B, et al. Exercise training improves overall physical fitness and quality of life in older women with coronary artery disease. Chest 2004; 126: 1026.
10. Gibbons WJ, Fruchte N, Sloan S, Levy RD. Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years. J Cardiopulm Rehabil 2001; 21: 87.
11. Sullivan MJ, Binkley PF, Unverferth DV, et al. Prevention of bedrest-induced physical deconditioning by daily dobutamine infusions. Implications for drug-induced physical conditioning. J Clin Invest 1985; 76: 1632.
12. Saltin B, Blomqvist G, Mitchell JH, et al. Response to exercise after bed rest and after training. Circulation 1968; 38: VII 1–78.
13. Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346: 793.
14. McVeigh GE, Burns DE, Finkelstein SM, et al. Reduced vascular compliance as a marker for essential hypertension. Am J Hypertens 1991; 4: 245.
15. McVeigh G, Brennan G, Hayes R, et al. Vascular abnormalities in non-insulin-dependent diabetes mellitus identified by arterial waveform analysis. Am J Med 1993; 95: 424.
16. McVeigh GE, Morgan DJ, Finkelstein SM, et al. Vascular abnormalities associated with long-term cigarette smoking identified by arterial waveform analysis. Am J Med 1997; 102: 227.
17. Grey E, Bratteli C, Glasser SP, et al. Reduced small artery but not large artery elasticity is an independent risk marker for cardiovascular events. Am J Hypertens 2003; 16: 265.
18. Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005; 46: 454.
19. Tanaka H, Dinenno FA, Monahan KD, et al. Aging, habitual exercise, and dynamic arterial compliance. Circulation 2000; 102: 1270.
20. Sugawara J, Inoue H, Hayashi K, et al. Effect of low-intensity aerobic exercise training on arterial compliance in postmenopausal women. Hypertens Res 2004; 27: 897.
21. Parnell MM, Holst DP, Kaye DM. Exercise training increases arterial compliance in patients with congestive heart failure. Clin Sci (Lond) 2002; 102: 1.
Keywords:

Aerobic endurance; Arterial compliance; Kidney transplant

© 2006 Lippincott Williams & Wilkins, Inc.