Exercise After Renal Transpantation

Exercise After Renal Transplantation Patricia Painter Renal transplant recipients experience troublesome side effects of the immunosuppression medication, many of which may be attenuated or ameliorated with regular physical activity. Preliminary data show that exercise training after transplantation increases exercise capacity and muscle strength and may contribute to higher quality of life after transplantation. © 1999 by the National Kidney Foundation, Inc. Index Words: Exercise; physical functioning; renal transplant; health-related quality of life.

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enal transplantation is an important treatment option for patients with end-stage renal disease (ESRD); more than 12,000 renal transplantations are performed each year in the United States. Nationwide I-year graft survival is 8S% and patient survival is 90%. Five-year rates are 67% graft survival and 8S% patient survival. The main causes of graft loss are chronic rejection (2S%), cardiovascular deaths (20.3%), infectious deaths (8.7%), and acute rejection (10.2%). Patient deaths occur mainly because of cardiovascular disease (CVD) (S1.1 %) and infection (21.6%).1 The long-term consequences of immunosuppression medications are often quite troublesome to patients. These include hypertension; hyperlipidemia; weight gain; glucose intolerance; and/ or steroid-induced diabetes, bone loss, and muscle weakness. Although many of these problems are attributed to the immunosuppression, many of them may be attenuated or ameliorated by regular physical activity. Regular physical activity has been recommended for all Americans by the United States Surgeon General, the American Heart Association, and the Centers for Disease Control and Prevention. Regular physical activity may be especially important for transplant recipients and may contribute to a higher quality of life over the long term.

Cardiovascular Risk After Transplantation CVD is the most common cause of death in the late postrenal transplant period,1-7 with coronary artery disease accounting for 14% to SO% of deaths.6-9 As other causes of death (ie, infection) decrease, the percentage of deaths resulting from CVD has increased from 31.4% in the 1970s to S1.1% in the 1980s. 6,10 Death from CVD is roughly 6 times higher in nondia-

betic transplant recipients and 20 times higher in diabetic patients compared with the general population. 6 Kasiske 9 reported that ischemic heart disease (defined as angina and/ or myocardial infarction) was diagnosed in IS. 1% of 403 transplant recipients over 10 years, a rate of four times greater than expected for a normal population of patients matched for age and sex. Even when excluding those with preexisting disease, the incidence was 11.0%, three times higher than the calculated incidence in the normal population. Despite new immunosuppression protocols and more effective management of risk factors (specifically hypertension), CVD continues to be a major cause of morbidity and mortality after kidney transplantation? Factors that contribute to post-transplant CVD have been identified using multivariate analysis. Kasiske 8,9 reported independent risk factors for post-transplant cardiovascular disease to be pretransplant CVD, diabetes, age, male gender, serum cholesterol level, and cigarette smoking. Others have confirmed that pretransplant vascular disease was more common among patients who experienced posttransplant cardiovascular events. 9Diabetes has been associated with high incidence of CVD after transplant, and both age and pretransplant disease increased the risk of posttransplant vascular disease in diabetic patients. Many have confirmed that cholesterol and triglyceride levels are higher in those who develop CVD, and hypertension and smoking were also more prevalent in patients with From the Department of Physiologic Nursing, University of California at San Francisco, SanFrancisco, CA. Address correspondence to Patricia Painter, PhD, Dept of Physiologic Nursing, UCSF Box 0610, San Francisco, CA 941943; e-mail: [email protected]. © 1999 by the National Kidney Foundation, Inc. 1073-444919910602-0007$3.0010

Advances in Renal Replacement Therapy, Vol 6, No 2 (April), 1999: pp 159-164

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vascular disease. ll Most of these risk factors are similar to those identified in nontransplant populations. In addition, Kasiske 8 reported that the number of acute rejection episodes was an independent risk factor for CVD, possibly as a result of higher cumulative doses of glucocorticoids used for treatment of rejection. Physical inactivity has been determined to be an independent risk factor for developing CVD. The accumulating evidence for the role of physical activity in the prevention and treatment of CVD is thoroughly presented by the National Institutes of Health Consensus Conference on Physical Activity and Cardiovascular Health.l2 Although regular physical activity exerts a significant positive effect on other risk factors such as blood pressure and blood lipid levels, the increase in mortality associated with physical inactivity is not entirely explained by the association with these other risk factors. There is an inverse relationship between physical activity and indices of obesity, and there is significant evidence that physical activity facilitates weight loss and, when adopted with dietary energy restriction, can enhance and maintain loss of body weight and body fat mass.l 2,13 Several studies in non-ESRD patients with known heart disease have shown that exercise training significantly reduces overall mortality, as well as death caused by myocardial infarction. 12 Other conditions such as hypertension, hyperlipidemia, weight management, depression, diabetes mellitus, and arthritis also are improved with regular physical activity.13,14 Changes in treadmill exercise performance (max METs*) along with the Framingham Risk Score were the strongest predictors of regression of diseased coronary vessels in the Stanford Cardiovascular Risk Intervention Trial. 14 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (NHBPEP)15 stated that lifestyle modifications (specifically, weight management, physical activity and dietary modifications are effective in preventing hypertension, and in lowering

blood pressure). Even when lifestyle modifications alone do not adequately control hypertension, they may reduce the number and/or dosage of antihypertensive medications needed for control. Likewise, dietary modification and increased physical activity are the essential first steps in treatment of high cholesterol. The National Cholesterol Education Project (NCEP)16 includes physical activity and weight management as basic components of lipid management. No data exist as to whether exercise reduces the cardiovascular risk in transplant recipients. However, preliminary evidence from the 1996 United States Transplant Games showed differences in risk factors for cardiovascular disease in active compared with inactive patients. Patients who participate in regular physical activity had significantly lower body mass index (BMI) than inactive patients (24.5 ± 4.1 v 26.9 ± 4.1) (P = .01) and lower percent body fat (23.8 ± 8.1% v 28.4 ± 9.5%) (P = .01).17 Total cholesterol was also lower in the active patients (213 ± 42 v 234 ± 41 mg/ dL) (NS), and dietary intake of cholesterol was lower (183 ± 117 v 197 ± 169 mg/ day (NS) (P. Painter, unpublished data, 1997). The overall cardiovascular risk scoret18 was not different between the groups (Painter, unpublished data). There remains a significant need to study the effects of lifestyle interventions such as diet and exercise on cardiovascular risk in transplant recipients.

'MET is a unit of metaboic energy expenditure. One MET is equivilent to the average resting oxygen uptake of 3.5ml· kg-I· min-I.

tFramingham Risk Score is an algorithm that computes 5 or 10 year risk using age, gender, blood pressure, cholesterol, smoking, diabetes.

Physical Functioning After Transplantation In addition to the potential reduction of cardiovascular risk after transplantation, exercise can also help to optimize physical functioning. It is reported that exercise capacity is higher in transplant recipients than in dialysis patients. 19,20 Removal of uremia with successful transplant directly results in increased exercise capacity as shown when patients were tested immediately before and again soon after transplantation. 20 There is a significant increase averaging 28% in exercise capacity soon after transplantation that is not explained by in-

Exercise After Renal Transplantation

creased hematocrit or increased physical activity.20 Although the transplant population as a whole shows a higher exercise capacity, there is still an important relationship between activity level and exercise capacity. A study of participants in the 1996 United States Transplant Games showed that physically active patients (ie, self-reported participation in cardiovascular aerobic exercise three or more times a week for more than 20 minutes per session at a perceived exertion described as "somewhat hard" or higher) had significantly higher peak oxygen uptake (V02peak) than inactive patients. 17 When the data from the renal transplant patients were analyzed, the values were 34.6 mL/kg-1/min- 1 for the active patients and 23.6 mL/kg-1/min- 1 for the inactive patients. 21 This study reported V02peak in terms of age-predicted values and showed that the active subjects achieved 109% of age-predicted values, whereas the inactive subjects achieved only 78%. We recently completed a randomized trial of usual care versus aerobic exercise training after kidney transplantation. Preliminary data results show that usual care patients have significantly lower exercise capacity at 1 year post-transplant than those in the exercise intervention (exercise) group. These data are in agreement with the Transplant Games data in that the peak V02 for the usual care patients is only slightly better than that reported for dialysis patients (P. Painter, unpublished data, 1998). Two studies reported that cardiovascular exercise training in kidney transplant recipients resulted in significant improvements in exercise capacity.22,23 Miller et aF2 reported results of a study in which renal transplant recipients participated in a supervised cardiac rehabilitation-based exercise training program initiated within 17 days. After 40 days of supervised training, peak exercise values increased from 5.1 METs to 9.7 METs. The patients were then encouraged to exercise independently and were retested at 2 years post-transplant. A total of 7 of 10 patients adhered to regular exercise at home. Exercise capacity increased in all patients further to 10.9 METs.22 Another study that was initiated in a group of kidney transplant recipients who

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were an average of 3 years post-transplant resulted in improved (V02peak) from 29.0 to 37.5 mL/kg-l / min- 1 after 6 months of cardiovascular exercise training. 23 This program consisted of walking, cycling, and progression up to jogging 3 days a week for 60 minutes at an intensity of 80% to 90% of their maximal heart rate. In addition to the striking increases in exercise capacity, this study also showed increased muscle strength, evidence of bone remodeling, and reduction in antihypertensive blood pressure medications in 8 of 12 hypertensive patients after 6 months of cardiovascular training. Figure 1 shows the effects of transplantation alone and transplantation plus exercise training on peak V02 and how these changes compare with normal sedentary values. Kempeneers et aF3 concluded that renal transplant recipients remained limited in exercise capacity by musculoskeletal factors. The muscle wasting effects of glucocorticoids are well known, and it is documented that quadriceps muscle strength of renal transplant recipients is only 70% of normaF4,25 This side effect, however, may be counteracted by resistance exercise training. Horber et aF4,25 trained a 50

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changes pretransplant to post-transplant and changes with exercise training post-transplant. This figure compares the values to general population data for sedentary males and females across the decades. The studies are averages for the study groups, which included both males and females. D pretransplant; 6. post-transplant untrained; 0 posttransplant trained; • transplant games participants. Sedentary males and females are derived from data from the general population. Data from Painter et al,20 Miller et al,22 Kempeneers et at 23 and Gallagher-Lepak. 27

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group of patients who were an average of 3 years post-transplant (all on glucocorticoid therapy) by using isokinetic muscle training (resistance training) for 57 days. Quadriceps muscle strength was normalized after the training, as was the fat/muscle ratio. The increased muscle mass resulting from resistance exercise training not only counteracts the muscle wasting effects of glucocorticoid therapy but also physical functioning, specifically in actions such as stair climbing or getting up out of a chair-actions that are difficult for many inactive transplant recipients. The level of exercise capacity that can be achieved after kidney transplantation is not known. High fitness levels have been demonstrated by participants in the United States and World Transplant Games who achieve impressive times in competitions in swimming, running, and cycling. 26 Reports of transplant recipients participating at high level vigorous activities include completion of marathons, triathalons, cross-country ski races, semiprofessional soccer competitions, competitive National Collegiate Atletic Association diving, and high-level tennis competitions. Obviously fitness also depends on the functioning of the transplanted organ, the past medical history, and concomitant medical problems. However, the otherwise healthy transplant recipient has the potential to achieve fairly high levels of physical functioning. The challenge appears to be motivating the noncompetitive patient to regain strength and endurance after transplantation to allow them to return to work and other desired activities. 120

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Health-Related Quality of Life

The Surgeon General's Report on Physical Activity and Health states that "physical activity appears to improve health-related quality of life by enhancing psychological well-being and by improving physical functioning in persons compromised by poor health."13 This may be particularly important in transplant recipients. The study of participants in the 1996 United States Transplant Games17 reported that physically active patients had higher (less limitation or better) scores on the following scales on the SF-36 Health Status Questionnaire: physical functioning, role function related to physical concerns, bodily pain, general health, vitality, and social functioning. The active subjects scored above the average value for physical functioning, bodily pain, general health, vitality, and social functioning (Fig 2). The difference in scores in general health raises questions about whether inactivity is due to poor health or whether physical activity results in better health in this population. Because the Transplant Games participants are clearly a select group of patients, we collected SF-36 questionnaires from a random group of kidney transplant recipients who were thought to be more representative of the general transplant population. These 104 patients were 5 years or more postkidney transplantation. 2I Results showed that physically active patients had higher scores on the following scales: physical functioning, role function related to physical concerns, and vitality, with

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no significant differences in general health between active and inactive patients (Fig 3). Thus, physical activity may positively affect quality of life in longer term transplant recipients. Both of the preceding studies are crosssectional and descriptive. There is clearly a need for further prospective study of the relationship between physical activity or physical fitness and quality of life after transplantation. Practice Implications Although it is assumed that patients will spontaneously increase their physical activity after transplantation, that is not always the case. Gallagher-Lepak27 reported that despite significant improvements in exercise capacity after kidney transplantation, daily activity as measured by questionnaire did not significantly improve at 6 months posttransplant. Despite feeling better, many transplant recipients are fearful of doing anything that would harm their new organ. Likewise, family members may be protective and discourage vigorous activity. The transplant team must provide patients with specific information on how to gradually increase activity after transplantation. If this information is not explicitly provided, the message may be that exercise is not important or safe for transplant recipients. A statement on the part of the transplant team such as "just take it easy" may be misinterpreted by the patient to mean "don't do anything." Patients should be encouraged immediately after surgery to adopt a program of regular activity after transplantation as a part

of their long-term transplant care. Exercise should be reduced in duration and intensity, but not necessarily discontinued during rejection episodes. The ideal program of exercise for transplant recipients has not been determined. However, recommendations for the general population for improving cardiovascular fitness, muscle strength and health are probably safe and appropriate for most patients. Guidelines for exercise prescription for individuals with special conditions (eg, orthopedic problems, heart disease, diabetes )28-31 have been published and are appropriate for transplant recipients as applicable. Vigorous exercise training for competition is not contraindicated for healthy transplant recipients. However, patients must gradually increase their cardiorespiratory fitness and strength before embarking on more vigorous training for sports participation. Summary There is clearly a need for research in the area of exercise in transplant recipients. However, there is sufficient evidence that regular physical activity should be incorporated into the routine care of renal transplant recipients for many reasons. These include increased risk of cardiovascular disease, high prevalence of risk factors for developing cardiac disease, and several side effects of the immunosuppression drugs, which affect overall health and physical functioning. Evidence that regular physical activity is beneficial for many of these conditions is well documented for the nontransplant population and should be not be ignored by the transplant community. Faced with a

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serious shortage of organs for transplantation, the transplant community should optimize physical functioning and overall health in those who are fortunate enough to receive a transplant. In doing so, we make the best use of a scarce but valuable resource.

References 1. United States Renal Data System: USRDS 1991 Annual Data Report, Bethesda, MD, National Institutes of Health, NIDDK, 1991 2. Mahony JF: Long-term results and complications of transplantation: The kidney. Transplant Proc 21(part 1 of 2):1433-1434,1989 3. Grapin C, Michel F, Charpentier B, et al: Long-term prognosis of renal transplantation: Retrospective study of 90 patients living more than 10 years with a functioning allograft. Transplant Proc 19:3765-3766, 1987 4. Vanrenterghem Y, Roels L, Lerut T, et al: Long-term prognosis after cadaveric kidney transplantation. Transplant Proc 19:3762-3764, 1987 5. Braun WE: Long-term complications of renal transplantation. Kidney Int 37:1363-1378, 1990 6. Scweitzer EJ, Mata AJ, Gillingham KJ, et al: Causes of renal allograft loss: Progress in the 1980s, challenges for the 1990s. Ann Surg 214:679-688,1991 7. Kasiske BL, Guijarro C, Massy ZA, et al: Cardiovascular disease after renal transplantation. J Am Soc NeprhoI7:158-165,1996 8. Kasiske BL: Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med 84:985-992, 1988 9. Kasiske BL: Risk factors for cardiovascular disease after renal transplantation. Miner Electrolyte Metab 19:186-195,1993 10. Braun WE, Marwick TH: Coronary artery disease in renal transplant recipients. Cleve Clin J Med 61:370385,1994 11. Drueke TB, Abdulmassih Z, LaCour B, et al: Atherosclerosis and lipid disorders after renal transplantation. Kidney Int 31:524-S28, 1991 12. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health: Physical activity and cardiovascular health. JAMA 276:241-246,1996 13. Office of the u.s. Surgeon General: Physical activity and health: A Report of the Surgeon General, U.s. Department of Health and Human Services, Public Health Service, 1996 14. Haskell WL, Alderman EL, Fair JM, et al: Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac eents inmen and women with coronary artery disease: The Stanford Coronary Rlks Interention Project (SCRIP). Circulation 89:975-990, 1994

15. Joint National Committee VI: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, National Heart, Lung and Blood Institute, 1997 16. NCEP: Second Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, NIH-NHLBI, 1993 17. Painter PL, Luetkemeier MJ, Dibble S, et al: Health related fitness and quality of life in organ transplant recipients. Transplantation, 1997 18. Wilson PWF, D' Agostino RB, Levy D, et al: Prediction of coronary heart disease using risk factor categories. Circulation 97:1837-1847,1998 19. Painter PL, Messer-Rehak D, Hanson P, et al: Exercise capacity in hemodialysis, CAPD and renal transplant patients. Nephron 42:47-51, 1986 20. Painter P, Hanson P, Messer-Rehak D, et al: Exercise tolerance changes following renal transplantation. Am J Kidney Dis 10:452-456, 1987 21. Painter PL, Stewart A, Tomlanovich S, et al: Healthrelated quality of life in hemodialysis patients and transplant recipients: The effects of physical activity. J Am Soc Nephrol 9:220A, 1998 (abstr) 22. Miller TD, Squires RW, Gau GT, et al: Graded exercise testing and training after renal transplantation: A preliminary study. Mayo Clin Proc 62:773-777, 1987 23. Kempeneers G, Myburgh KH, Wiggins T, et al: Skeletal muscle factors limiting exercise tolerance of renal transplant patients: Effects of a graded exercise training program. Am J Kidney Dis 14:57-65, 1990 24. Horber FF, Scheidegger JR, Grunig BE, et al: Thigh muscle mass and function in patients treated with glucocorticoids. Eur J Clin Invest 15:302-307,1985 25. Horber FF, Sheidegger JR, Grunig BE, et al: Evidence that prednisone-induced myopathy is reversed by physical training. J Clin Endocrinol Metab 61:83-88, 1985 26. National Kidney Foundation: Official Results of the 1994 U.s. Transplant Games. New York, NY, National Kidney Foundation, 1994 27. Gallagher-Lepak S: Functional capacity and activity levels before and after renal transplantation. Am Nephrol Nurs Assoc J 18:378-382,1991 28. American College of Sports Medicine: Guidelines for Exercise Testing and Prescription (ed 4). Philadelphia, PA, Lea & Febiger, 1991 29. American College of Sports Medicine: Exercise Management for Chronic Disease and Disabilities. Champaigne, IL, Human Kinetics Inc, 1997 30. American Diabetes Association, American College of Sports Medicine: Diabetes Mellitus and Exercise. Joint Position Statement. Med Sci Sports Exerc 29:i-vi, 1997 31. American College of Sports Medicine: Physical activity, physical fitness, and hypertension. Med Sci Sports Exerc 25:i-x., 1993