In fact, when rHuEPO became available and hematocrit was successfully treated, it was expected that exercise capacity would likewise increase. Five research groups measured V˙O2peak as a part of the early studies of rHuEPO treatment in dialysis patients (see (10) for specific studies). In these studies, the hematocrit target was 33% (not normalized). V˙O2peak increased with increasing hematocrit, but the V˙O2 response was less than what had been shown in studies of hematocrit manipulation in normal healthy individuals. Figure 5 is a summary of six studies that manipulated (increased or decreased) hemoglobin with red cell infusion or through phlebotomy in normal healthy subjects. Also presented in Figure 5 is the V˙O2 response to changes in hemoglobin in the original five dialysis studies. The V˙O2peak response to increasing hematocrit in dialysis patients was clearly blunted (10).
J. Stray-Gunderson et al. (unpublished manuscript/observation, 1997) used rHuEPO to gradually increase hematocrit in hemodialysis patients and measured the determinants of V˙O2. Figure 4 indicates that, as arterial oxygen content increased with rHuEPO treatment from the anemic condition, there was a parallel increase in venous oxygen content with no increase in a-vO2 difference. This suggests a fixed limitation in skeletal muscle oxygen extraction. Although the patients improved with elevated hematocrit, medical treatment was not sufficient. The lack of expected improvement and the documentation of no change in a-vO2 difference suggest that the limitation in V˙O2peak may be, in part, due to impaired skeletal muscle function. The impaired skeletal muscle function may be improved with exercise training.
Documentation of Exercise Training Effectiveness
It is well documented that exercise training improves exercise capacity in patients treated with hemodialysis. In a meta-analysis of exercise training in patients receiving maintenance hemodialysis, Cheema and Singh (2) report 29 trials, including 9 uncontrolled trials, 7 controlled trials, and 13 randomized controlled trials. Although a few trials reported no significant improvement in V˙O2peak, most reported significant improvement with aerobic exercise between 17% and 23% (2,4,11,12).
Interestingly, those studies that included a combination of strengthening and aerobic training reported changes in V˙O2peak from 41% to 48%. The training responses are similar in patients with anemia (before availability of rHuEPO) and those treated with rHuEPO for anemia (4). Thus, there may also be other systemic limitations to V˙O2peak because of the disease and/or treatment in these patients (as suggested in Fig. 2).
The measurement of V˙O2peak may not always be the most appropriate measure of physical functioning, especially in older patients who experience frailty, significant concomitant comorbidities, and debilitation. In these patients, other measures of physical functioning are used, such as muscle strength, 6-min walk distance, sit-to-stand-to-sit test time, and gait speed. These measures of physical functioning improve with exercise training (2,11,15).
It is important to note that the natural course of functioning in a given population with chronic disease may be deterioration. Thus, if improvement is not observed or is minimal, it may be because of the natural course of functioning. In such cases, the maintenance of functioning or slight improvements is considered a positive result when the expectation would be deterioration in functioning. This concept was well demonstrated in the data from the Renal Exercise Demonstration Project (15), where all performance-based measures deteriorated in the experimental group that received no intervention but increased slightly or remained stable in the intervention group (15). Thus, the comparison of the change over time in the intervention and usual-care groups were significantly different; even a minimal improvement in the intervention group was a positive outcome.
CLINICAL BENEFITS OF EXERCISE TRAINING
In addition to the improvements in exercise capacity or physical functioning, the impact of exercise interventions on clinical conditions is equally important. For example, exercise training in patients with ESRD has been documented to improve cardiac functioning (left ventricular (LV) mass index, ejection fraction, cardiac output index, and stroke volume index) and heart rate variability (2). Muscle structure and neuromuscular control also improved after 6 months of combined aerobic and resistance training. Specifically, increased cross-sectional area of Type I and II muscle fibers, near normalized ratio of Types I to II fibers, improved capillarity and mitochrondia density. These observed exercise-induced skeletal muscle changes are important in patients with a chronic disease because many of the patients experience sarcopenia. Nerve condition also improved. Blood pressure control is improved with aerobic exercise with lower antihypertensive medication requirements (2,11). Several authors report improved fasting glucose and insulin concentrations, with apparent improvement in insulin sensitivity, and others report improved lipid profiles (increased high-density lipoprotein cholesterol and reduced very low density lipoprotein and plasma triglyceride) (2,11). These exercise-induced changes are important benefits that positively affect the secondary cardiovascular comorbidity in this population.
Likewise, quality of life, specifically the "physical domains" are improved with exercise training. The Short-Form 36 (SF-36) health status questionnaire is used as the assessment tool for the quality-of-life measurement in dialysis patients. The benefits in quality of life are most notable in those with the lowest baseline levels (14). Thus, if the benefits in physical functioning are not an adequate justification for implementing exercise, there are important benefits in clinical concerns and in quality of life that may be gained from the incorporation of exercise in the population with chronic disease.
EFFECTS OF EXERCISE AS AN ADJUNCTIVE THERAPY TO STANDARD CLINICAL INTERVENTIONS
Exercise training may be an important adjunct therapy to standard medical or surgical interventions because it may either improve the therapy or optimize exercise capacity with the treatment. There is evidence that clearance of solutes during the hemodialysis treatment is improved when cycling exercise is used during the treatment. Vaithilingam et al. (19) reported statistically greater weekly phosphate removal in 12 patients who exercised during the dialysis treatment compared with those who did not exercise. The phosphate removal with exercise was similar to increasing dialysis time by 1 h per session. Kong et al. (7) studied 11 patients who were on paired dialysis session: one with exercise and the other as a control. The rebound of urea, creatinine (an indication of urea clearance), and potassium were reduced significantly with the exercise treatment. The rebound of urea dropped from 12.4% to 10.9%; creatinine, from 21.2% to 17.2%; and potassium, from 62% to 44%. The authors concluded that the improvement in dialysis adequacy with exercise training was equivalent to extending the length of the hemodialysis treatment by 30 min. The mechanism of these increases in clearance with exercise is thought to be increased skeletal muscle blood flow, which exposes more tissue to the dialysis process.
The hypothesis that exercise training will enhance the effects of improved hematocrit on exercise capacity by improving muscle function was tested as a part of a study by Painter et al. (13) to determine the effects of normalization of hematocrit with rHuEPO. Patients were randomized into two hematocrit groups (30%-33%, which is standard care) and 40%-42% (experimental group). A second randomization was done within each of these hematocrit groups, to exercise and no exercise. The exercise groups in both hematocrit groups improved V˙O2peak, whereas normalizing hematocrit had no effect on V˙O2peak. The findings clearly indicate that exercise training maximizes the effect of rHuEPO treatment, regardless of hematocrit target level.
Surgical intervention in ESRD with kidney transplant may also remove some of the pathological factors that limit V˙O2peak. It has been documented that V˙O2peak in dialysis patients is significantly improved (although not necessarily normalized) with successful renal transplantation. Two studies report significant increases in V˙O2peak soon (8 and 12 wk, respectively) after successful kidney transplant, in which the uremic state was removed (Fig. 6 - represented by the dotted line between the closed triangles to open squares) (9). Although transplantation improves exercise capacity, it does not completely restore exercise capacity. In an uncontrolled trial of patients, 3 yr after transplant, who underwent strenuous training for the transplant games, there was a 28% improvement in V˙O2peak (Fig. 6, closed square). A cross-sectional study of participants at the 1998 U.S. Transplant Games revealed V˙O2peak levels that averaged 110% above age-predicted reference values (9) (single closed circle). In a randomized controlled trial of exercise over the first year after transplant, V˙O2peak increased an average of 26% (intent-to-treat analysis) (Fig. 6, open square to closed diamond), whereas the usual-care group did not improve over baseline testing and had levels similar to exercise-trained dialysis patients (16). Thus, there is robust evidence that exercise training after transplant maximizes exercise capacity and optimizes the effects of transplantation on physical functioning.
Nandrolone decanoate (an anabolic steroid) is sometimes used in dialysis patients with severe muscle wasting. A randomized clinical trial in hemodialysis patients (four groups: nandrolone only, resistance exercise only, resistance exercise plus nandrolone decanoate, and controls) demonstrated that, despite increased lean mass, there was minimal improvement in quadriceps muscle strength in the group that received the drug alone (5), whereas resistance exercise alone and the nandrolone-plus-resistance exercise groups showed significant gains in muscle strength, with minimal change inlean mass (Fig. 7). Thus, it is clear that the exercise intervention optimized the results of the pharmacological intervention in terms of functional outcomes.
EFFECTS OF EXERCISE ON PATIENT OUTCOMES
Overall patient outcomes seem to be the driving force in medical treatment. If exercise has a positive impact on overall outcomes such as morbidity, hospitalizations, or mortality, then there is a greater chance of it becoming a part of the routine care. Outcome studies are costly and often difficult, especially in patients with chronic conditions because continuous and/or long-term exercise training may not be possible because of the challenges in exercise research mentioned previously. Until those studies can be done, epidemiological evidence is informative. The United States Renal Data System is a very large database that includes clinical data and outcomes of all patients with CKD started on dialysis in the United States. Over a period of 2 yr, a question of physical activity participation was included in the survey (Morbidity and Mortality Survey). These data were analyzed by O'Hare et al. (8) to dichotomize patients into sedentary (never or almost never participate in physical activity during leisure time) and nonsedentary (participation in some physical activity during leisure time). Of the 2264 patients who reported physical activity data, 35% were categorized as sedentary. Eleven percent of the sedentary patients died over the 1-yr follow-up period compared with 5% of the nonsedentary patients (P < 0.001). The patients classified as sedentary at the time of initiation of dialysis showed a 62% greater risk of mortality over 1 yr compared with nonsedentary patients with adjustment for other variables associated with survival in these patients (perception of general health, cardiac disease, peripheral vascular disease, creatinine, hematocrit, dialysis modality, education level, male sex, diabetes, and phosphorous level). Stack et al. (18) also analyzed these data and showed similar results. Specifically, patients who reported more frequent exercise (i.e., up to four to five times per week) had improved survival.
In addition to the value of physical activity in predicting outcomes, physical functioning as measured by V˙O2peak and self-reported functioning (SF-36) also are predictive of outcomes. The self-reported physical functioning scale and the overall physical composite scale on the SF-36 health status survey are independent predictors of hospitalization and death in studies with large numbers of patients (up to 16,000 patients followed over 2 yr) (6). Similar results using V˙O2peak were reported by Sietsema et al. (17), which found V˙O2peak to be the strongest independent predictor of death (P = 0.009) in 175 hemodialysis patients who were followed over a 3.5-yr period. Although the definitive outcomes trial (i.e., a randomized controlled trial of exercise training on morbidity and mortality) has not been done, there is strong epidemiological data that suggest that interventions to increase physical activity and/or physical functioning may be important to optimize outcomes in patients treated with hemodialysis.
Because the medical community is focused on interventions that improve overall patient outcomes - specifically hospitalization/institutionalization, morbidity, and death - documenting that low levels of physical activity and physical functioning are significant predictors of outcomes will justify interventions to increase physical activity and improve physical functioning.
There is a Need to Determine Appropriate Outcome Measures
The implementation of exercise programs as a part of the routine care and development of research in chronic disease will require the identification of evaluation measures for research outcomes and for tracking progress in clinical programs. The "gold standard" measure of exercise capacity (e.g., V˙O2peak) may not be the most appropriate measure in some patient groups. In CKD, patients are older (>60% are older than 65 yr), have significant muscle weakness and often orthopedic limitations, have transportation limitations in getting to a center where V˙O2 can be measured, and exhibit clinical factors that may limit their performance and interpretation of a graded exercise test (e.g., hypertension and electrocardiographic abnormalities). Considering all these factors, other types of tests such as standardized physical performance (i.e., 6-min walk, shuttle walk, gait speed, get-up-and-go test, and sit-to-stand test) may be more appropriate. Patients with CKD treated with hemodialysis achieve less than 65% of age-predicted values on these tests, and they are documented to be sensitive to change resulting from physical activity interventions (16).
Interpretation of test results from exercise interventions in chronic disease populations may need to be reconsidered. Usually, if an intervention group shows minimal or no change in exercise capacity, then the interpretation would be that the intervention was unsuccessful. However, if the natural course of the disease is for exercise capacity to deteriorate over time, then maintenance of physical functioning is a positive result. This was well demonstrated in the data from the Renal Exercise Demonstration Project (15), where all performance-based measures deteriorated in the group that received no intervention but increased slightly or remained stable in the intervention group. Thus, the comparison of the change over time in the intervention and usual-care groups were significantly different; even a minimal improvement in the intervention group was a positive outcome.
Considering the Delivery of Exercise Training
Although the cardiopulmonary rehabilitation program model of 3-d-wk−1 exercise at an outpatient center has worked well for the cardiac and pulmonary populations, this model may not be feasible for other patient groups. For patients who are elderly and have significant comorbidity and/or treatment time burden, coming in to a supervised exercise center may not be practical. Many patients will have transportation issues and time constraints. For example, patients treated with hemodialysis have to go to the dialysis clinic three times per week for treatments of 3-4 h in duration. Travel and setup procedures can extend that time to 5-6 h. It is therefore understandable that adherence to a standard outpatient cardiac rehabilitation program on nondialysis days is low. Thus, creative approaches of delivery of exercise are needed. Use of a cycle ergometer during the dialysis treatment is feasible and results in good adherence and positive benefits.
Implementation of such programs within the patient care setting requires a close working relationship with the dialysis clinic staff, and it is usually necessary to address the corporate policies of the providers to develop new interventions. Independent home exercise with encouragement from the care providers and regular follow-up and support from exercise professionals may also be feasible. Home exercise has been shown to result in positive benefits in hemodialysis patients and in transplant recipients (12,16).
The numbers of people with diagnosed chronic disease is steadily growing. Surgical procedures and medical therapies are constantly improving, so these patients are living with chronic disease for much longer than ever before. Many of the known physiological benefits of exercise can be realized by patients with chronic disease, and exercise training may have a positive impact on clinical concerns and overall quality of life and well-being. Involvement of exercise professionals in the care of these patients is long overdue; however, integration of exercise counseling and encouragement into the routine care requires research and education of the health care providers. Exercise professionals must reach out and work closely with those health care providers to determine the most effective and practical way to include exercise research and/or interventions into the routine care. As we gain the research knowledge and clinical experience, practice guidelines can be developed for exercise in the various populations with chronic disease, and it may eventually become routine practice and covered by third-party payers. The ultimate goal is common to the health care providers and patients: to optimize physical functioning, quality of life, and overall medical and surgical outcomes.
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Keywords:©2008 The American College of Sports Medicine
exercise training; chronic kidney disease; exercise research; renal failure; physical functioning