Determinants of Exercise Capacity in CKD Patients Treated With Hemodialysis

Determinants of Exercise Capacity in CKD Patients Treated With Hemodialysis Patricia Painter, Ph.D. There are many ways to measure physical functioning. Oxygen uptake at peak exercise is considered to be the most objective or ‘gold-standard’ measure and is determined by the integrated functioning of multiple physiological systems. Renal failure can affect the functioning of several of these systems which results in low levels of peak oxygen uptake. This review examines the determinants of oxygen uptake as defined by the Fick Equation, and presents data from studies that have reported these physiological measures. It becomes clear that there are many factors that may limit peak oxygen uptake in these patients and any one mechanism may be difficult to identify. Q 2009 National Kidney Foundation, Inc. All rights reserved. Key Words: Exercise capacity, End stage renal disease, Oxygen delivery

Introduction

I

t is well documented that physical functioning is low in patients with CKD treated with dialysis,1-3 whether measured using objective laboratory measures such as peak oxygen uptake (VO2peak), physical performance measures, or self-report. It is also well known that low cardiorespiratory fitness as measured by VO2peak and low self-reported physical function (as measured using health-status questionnaires such as the SF-36) are independent predictors of poor outcomes in these patients.4-6 Exercise training interventions improve VO2peak,1-3 physical performance measures, and self-reported physical functioning, however, the mechanisms of limitations and changes with exercise interventions remain undetermined and elusive. The purpose of this review is to clarify terminology in exercise research and present what is known about physiological limitations to exercise in patients with CKD with the goal of presenting the difficulty of determining specific mechanisms.

Definition of terms associated with exercise Clarification of terms and concepts may be important to avoid confusion of measurement and concepts associated with physical functioning. For example, it may be assumed that ‘exercise is exercise’, whereas the reality is that cardiovascular exercise training results in specific physiologic changes that may be quite different than those resulting from resistance exercise training. Likewise, outcome measurements

must be consistent and appropriate to address the research question and are specific to the type of intervention. For example, if an outcome measure has a ceiling effect, exercise training may not result in a change in the measure. The widely used, non-specific term ‘‘physical functioning’’ is used clinically and encompasses many concepts. Exercise, physical fitness, physical activity and physical functioning are different and unique concepts but are often inappropriately used interchangeably. Physical Functioning It is the author’s preference to define physical functioning as an individual’s ability to perform activities of daily living (ADL) or required tasks as measured by either success in performing tasks or limitations in performing tasks. Most often, physical functioning is measured using self-report, such as questionnaires that include a physical functioning scale (i.e. SF-36 Health Status Questionnaire). Most of these self-report tools assess limitations in activities of daily living (ADLs) or required tasks. On most standardized questionnaires, no information is provided as to whether the tasks can actually be performed or at what level they can be performed. There are also standardized measures (physical performance

Associate Professor, School of Nursing, University of Minnesota, 308 Harvard ST SE, Minneapolis, MN 55104, Phone: 612-625-4943 E-mail: [email protected] Ó 2009 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/09/1606-0006$36.00/0 doi:10.1053/j.ackd.2009.09.002

Advances in Chronic Kidney Disease, Vol 16, No 6 (November), 2009: pp 437-448

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Clinical Factors • symptoms fatigue shortness of breath weakness pain depression • cognitive function • neuromuscular dysfunction • orthopedic problems • other clinical problems Sensory Factors • vision • hearing Environmental Factors • social support • education level • access to facilities • professional support / encouragement • information /advice

Physical Fitness • cardiorespiratory fitness • muscle strength • muscle endurance • flexibility

Behavioral Factors • regular exercise • preference of activity • perception of ability • physical self-confidence • satisfaction with activity • nutritional practices • smoking

Basic Physical Movements •walk •climb stairs •stand up from chair •bend, stoop, kneel •reach overhead •push, pull objects •grip, hold, twist •lift, carry •writing • holding utensils

Independent Living Activities • ADL’s • IADL’s • Role/Obligatory activities Discretionary Activities • Travel • Work • Social activities • Yard/housework • Volunteer activities • recreational activities • sports/ fitness

Figure 1. Determinants of Physical Function (from Painter & Stewart ref 8).

tests) that evaluate specific tasks, such as the sit to stand test, gait speed, six minute walk, standing balance, and the ‘get-up and go’’ test. These tests are widely used in the gerontology population, and there are large databases for age-gender normative comparison. There is no way to assess physiological mechanisms of limitations using these tests. Physical fitness is a set of attributes that a person has or achieves that facilitates the participation in exercise or physical activity.7 The terms ‘‘exercise capacity’’ and ‘‘physical capacity’’ are often used interchangeably to refer to physical fitness, even if only one attribute is being described. The components of physical fitness have objective measurements. 1) Cardiorespiratory fitness is a measure of integrated functioning of oxygen transport from the atmosphere to the working muscles and is measured by maximal oxygen uptake (often referred to as exercise capacity) that is obtained during exercise testing on a treadmill or cycle ergometer. 2) Muscle strength is the amount of external force that a muscle can exert and is measured using isokinetic, dynamic or isometric tests. 3) Muscle endurance is the ability of muscle groups to exert force repetitively on successive exertions and is measured

by isokinetic or dynamic tests. 4) Flexibility is the range of motion available at a joint and is assessed using goniometry, which measures joint angles. Determinants of Physical Functioning Determinants of physical functioning among patients with CKD are many, and, although many are related to the pathophysiology of the disease, others may be related to aging, environment and other non-physiologic factors. Figure 1 is a diagram developed by Stewart and Painter8,9 that illustrates the many factors that may determine the ability to perform simple and complex activities. Physical fitness is a basic determinant of overall physical functioning. The components of physical fitness vary in importance relative to health, with various disease entities causing limitations in specific components. However, common to most chronic illnesses is the reduction in physical fitness, specifically losses in cardiorespiratory fitness and muscle strength, both of which will contribute to low physical functioning. Muscle strength and function have been thoroughly discussed in other contributions to this journal issue. The following, therefore, is a thorough discussion of the

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OXYGEN TRANPORT NORMAL

END STAGE RENAL DISEASE

Oxygen Pulmonary Ventilation

Frequency Tidal Volume VA=VD /VT

Pulmonary Gas Exchange

Diffusion V/Q Ratio

Arterial O2

Hemoglobin Saturation Heart Rate

O2 Dissociation Autonomic Function

Cardiac Output Stroke Volume

Muscle Blood Flow

Muscle O2 Utilization

Vascular Resistance

Contractility Afterload Preload Autonomic Fnx Metabolic State Temperature

Capillary Density Fiber Type Enzyme Levels /Activities

Endocrine Controls Metabolic Demand

Substrate Availability

Anemia Autonomic Dysfunction Serum K+ Serum Ca++ Cardiomyopathy Hypertension Anemia Hypervolemia a-v Shunt Autonomic Dysfunction Metabolic Acidosis Carnitine Pyruvate Kinase Glc-6-P Dehydrogenase PFK Insulin Resistance B receptor affinity

Figure 2. Oxygen Transport from the atmosphere to the working muscles in normals and possible systems affected by ESRD (Painter, 1988, ref 13).

physiological determinants of cardiorespiratory fitness (i.e. VO2peak) in patients with CKD treated with dialysis. In the general population, cardiorespiratory fitness is independently predictive of all-cause and cardiovascular mortality.10 Cardiorespiratory fitness improves with exercise training in most populations, and these changes are associated with improved cardiovascular risk profile (see Bronas, this issue). The initial studies in exercise in dialysis patients focused on cardiorespiratory fitness as the primary outcome measure, probably because it is a gold standard objective measure and has significant health implications.

Challenges in identifying mechanisms of limitation to cardiorespiratory fitness Despite the complexity of measurement of maximal oxygen uptake, it is considered the ‘Gold standard’ measure of cardiorespiratory fitness and may be the best physiological model to identify limitations to exercise in patients with CKD. There are well accepted

criteria for achievement of a true maximal level (VO2max),11 but most people with chronic disease do not meet these criteria, thus the measure is usually symptom-limited maximal level or VO2peak. VO2peak in dialysis patients averages 17-20 mlkg21min21.2,12 Although VO2peak increases around 20-25% with exercise training, it remains less than sedentary normal values, suggesting there may be a physiological limit to the achievable levels in these patients. In 1986 Painter et al published a model that was designed to serve as a guide for study of limitations to oxygen transport in patients with end stage renal disease (ESRD).13 This model presented the integrated functioning of multiple physiologic systems required to facilitate transport of oxygen from the atmosphere to the working muscles and indicated where the pathophysiology of renal failure might affect this system (Figure 2). In 2000 the model was expanded by Moore14 to illustrate how the dialysis treatment and other medical treatments or conditions might contribute to limitations in oxygen transport (Figure 3). It is clear that the physiology of

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Figure 3. Modification of the Oxygen transport diagram to account for dialysis treatment and other factors (Moore, 2000, ref 14).

exercise in renal disease is complex, rendering identification of specific mechanisms of limitations difficult. Although measurement of one part of the system may be interesting, it is the integrated functioning that determines oxygen uptake and thus exercise capacity.

A closer look at the physiology According to the Fick Equation, oxygen uptake is the product of cardiac output and arterial-venous oxygen difference (a-vO2dif). The Fick equation can be broken down into oxygen delivery and oxygen extraction (Figure 4). It is documented in hemodialysis patients that VO2peak averages between 55-65% of age-predicted levels. Using the Painter model it may appear that the best way to study each of these steps would be an intervention that directly acts on that particular system. However, with the exception of the treatment of anemia with rHu-erythropoeitin, it is unlikely that

such interventions are possible. Another approach is to study factors that change with exercise training, which is known to improve the integrated measure of VO2peak, but exercise training typically elicits change in a number of these physiologic systems, thus we only have associations of changes in any given measure with the change in VO2peak. Removal of uremia through successful transplantation may be another intervention that increases VO2peak,15,16 however, again it is difficult to pinpoint which of the multiple systems involved in oxygen transport is responsible for this improvement. Likewise, some of the medications required after transplant could impose additional limitations and/or mask improvements in some systems contributing to the improvements. Most exercise studies have too few subjects to perform multiple regression analysis to identify specific limiting factors and control for the multiple contributors. Thus we are left primarily

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Fick Equation VO2 = Cardiac Output x arterio-venous O2 difference VO2 = CO x a - v O2 diff delivery utilization C.V. System

Muscle

Figure 4. Fick Equation: Determinants of Oxygen Uptake.

with correlational data of isolated measures with VO2peak, which may be misleading. There has been only one published study in which the determinants of VO2peak were actually measured, e.g. simultaneously measured VO2 and cardiac output during exercise. Moore et al17 measured the components of the Fick equation at rest and at maximal exercise. VO2 was measured at the mouth, cardiac output through the a-v fistula (using dye-dilution techniques), arterial oxygen content drawn

from the a-v fisula and heart rate was measured continuously. These measures allowed calculation of stroke volume and venous oxygen content. They found that (Figure 5) at rest, the components of the Fick equation were similar to normal reported values. However at maximal exercise, both components of the Fick equation were reduced: the cardiac output was reduced, primarily due to a blunted heart rate response (with a normal stroke volume) and a reduced a-vO2dif, due to a reduced arterial oxygen content (due to anemia– preEPO). Thus oxygen supply to the working muscles (via cardiac output and arterial oxygen content) was reduced. It appeared that the oxygen extraction by the muscles (as evidenced by the low venous oxygen content) was similar to published studies in individuals with normal kidney function, suggesting normal oxygen utilization by the muscle. However, an unpublished study by Straygundersen, et al[18] revealed that when arterial oxygen content was increased with r-Hu-EPO,

VO2 = CO x a-vO2dif A-vO2 difference

Cardiac Output 30

normals

15

normals 25

13

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11

mL/ 100ml

L/ min 15

9 7

10

hemodialysis

hemodialysis

5

5 3 rest

rest

max 120

175

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125

hemodialysis

100

Stroke Volume

heart rate

150

max

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100

hemodialysis 80

60

75 40

50

rest

max

rest

Figure 5. Determinants of oxygen uptake at rest and at maximal exercise in healthy subjects and hemodialysis patients (data from Moore, et al 1993, ref 17).

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normals

O2 content (mL/dL)

20

Hemodialysis patients* 15

Mixed venous

10

Arterial 5

0 7

9

12

15

Hemoglobin (g/dL)

Figure 6. Changes in arterial oxygen content and mixed venous oxygen content., with resulting a-vO2dif at different hemoglobin levels in hemodialysis patients. (From Stray-Gunderson 1997, ref 18).

the a-vO2 difference did not widen at peak exercise suggesting a limitation in extraction at the muscle during exercise (Figure 6). Thus, both oxygen delivery AND utilization at the muscle contributed to the low VO2peak.19

Oxygen Delivery The oxygen delivery limitation may be multifactorial. It is clear from the data reported by Moore, et al above, that the cardiac output response to exercise is blunted, primarily due to a blunted heart rate response to exercise, which was 2 standard deviations below normal predicted levels. They reported a normal stroke volume at peak exercise. This is consistent with the many reports of blunted chronotropic responses to exercise in dialysis patients, where peak heart rate is reported to be 75-80% of age-predicted maximal levels in many studies.16,17,20-22 More evidence is the data reported by Painter, et al16 in which testing was performed before and 8 weeks following successful kidney transplant. VO2peak increased from 1.68 6 0.35 to 2.13 6 0.42 L/ min without exercise training. Peak heart rates increased from 155 6 11 pre transplant to 178 6 10 beats/min following transplant. Likewise, at 70% of VO2peak, the heart rates were lower pre transplant than at 70% of the post transplant VO2peak (127 6 16 vs. 143 6 15 beats/min post transplant). This was unexpected, since the hematocrits were lower pre transplant (25.4 6 6.1 vs 35.6 6 3.8% post

transplant). In individuals with normal kidney function, anemia results in a higher heart rate at a submaximal exercise. This blunted chronotropic response could be a manifestation of autonomic dysfunction reported in uremic patients. We have measured VO2peak and cardiac output before and after kidney transplant. Preliminary data indicates that the VO2 increase pre to post transplant (2.16 6 0.50 to 2.35 6 0.54 L/min) was due primarily to increases in cardiac output and not improvement in the ability to widen a-vO2difference. The increased cardiac output at peak exercise post transplant was the result of increased peak heart rate, (143 6 22 to 159 6 24 beats/min) as there were no changes in stroke volume. Figure 7 shows the preliminary data of changes in 8 patients pre transplant and 6 months post transplant compared to 8 patients who remained on conventional hemodialysis. This blunted heart rate response to exercise may be a manifestation of autonomic dysfunction, which has been well described in uremia. Evoked tests of autonomic function (heart rate response to Valsalva, breathing, assuming a standing position) are markedly abnormal in dialysis patients.23-25 Heart rate variability (HRV) is a much more significant quantitative marker of cardiac autonomic activity. Markedly reduced HRV index has been reported in up to 42% of dialysis patients.23,26 The abnormalities are observed in both time domains and frequency domains, with peritoneal dialysis patients showing the greatest compromise in autonomic function of the ESRD treatment modes studied.23,26 Elevated serum norepinephrine levels and excessively high sympathetic nervous activity are reported in hemodialysis patients,27 leading to the general belief that neurohumoral control of vasoreactivity is impaired. Ketner, et al28 report that despite excessively high levels of plasma norepinephrine levels during submaximal exercise, hemodialysis patients showed a blunted heart rate response compared to individuals with normal kidney function. The lack of heart rate response in the dialysis patients raises the possibility of resistance to the cardiovascular actions of catecholamines in patients with ESRD treated with hemodialysis.28

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4 p=.04

3 PEAK VO2 (Liters/min)

TX

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PEAK Cardiac 20 Output (Liters/min)

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baseline

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TX p=.04

PEAK 150 Heart Rate (bt/min)

150 PEAK Stroke Volume 125 (mL/bt)

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75 baseline

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Figure 7. Changes in Determinants of peak oxygen uptake in patients before and after transplant and those remaining on hemodialysis (unpublished data from Painter).

Autonomic dysfunction may also affect the ability to divert blood flow to the working muscles during exercise. Although no studies have reported any direct association between VO2peak and leg blood flow, it is well known that most dialysis patients stop exercise due to leg fatigue. This fatigue is probably multifactorial, but the factor that could affect the determinants of VO2 could be limited blood flow to the exercising muscle. Bradley et al29 reported significantly impaired nutritive skeletal muscle blood flow in patients with chronic renal failure. Six patients had resting calf blood flow (measured by plethysmography) that was similar to 12 normal controls. However, the increase in calf blood flow with submaximal exercise was significantly

lower in patients than controls, and blood flow at symptom-limited maximal exercise in the patients was only 35% of normal controls.

Oxygen extraction Muscle blood flow and oxygen delivery abnormalities during exercise have been documented in dialysis patients in an elegant study by Marrades et al.22 They measured leg blood flow in hemodialysis patients before and after rHuEPO therapy and matched control subjects. They measured muscle blood flow, oxygen delivery to the muscle, oxygen conductance within the muscle, oxygen extraction ratio in the muscle and oxygen uptake of the muscle. In the baseline condition (Hb ¼ 7.5 6 2.0

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gdL21), leg blood flow in the patients was not significantly different than controls at the same relative percent of of VO2peak or at peak exercise. However oxygen delivery in the patients (cardiac output x CaO2) was significantly lower at both exercise levels. Thus the leg VO2 was significantly lower than controls at both exercise levels (0.28 vs 0.56 Lmin21 at 30% peak and 0.44 vs 0.71 Lmin21 at peak exercise). Following rHuEPO treatment (Hb 12.5 6 1.0 gdL21), they found that the relative increase in leg VO2 (33%) was much less than the increase in arterial oxygen content (59%). There was an increase in oxygen delivery (0.61 vs 0.83 Lmin-1;137%) and an increase in muscle oxygen conductance of 31%, however these increases were offset by a reduction in leg blood flow of -37% (5.6 vs 4.9 Lmin21). Thus, when compared to controls, the patients remained significantly lower in oxygen delivery to the muscle at 30% VO2peak (0.57 vs .80 Lmin21) and at peak exercise (0.61 vs 0.98 Lmin21). Blood flow redistribution to the working muscles during exercise may be impaired in dialysis patients because of endothelial dysfunction. Endothelial dysfunction has been documented in dialysis patients using pulse-wave velocity30 and flow mediated vasodilation.31,32 Flow mediated endothelium-dependent dilation is reduced in patients with chronic renal failure not yet treated with dialysis,33 suggesting that uremia alone may affect endothelial function. Endothelial function is not normalized after transplantation. Hausberg, et al34 report significantly reduced flow- mediated vasodilation in renal transplant recipients compared to healthy individuals. Abnormal nitric oxide metabolism35,36 and remarkably high levels of Endothelin-1 (6 times higher than normal controls)37 may participate in regulation of blood flow during exercise by constricting non-active tissue beds. To date there have been no studies to assess the relationship between endothelial function and VO2peak in ESRD. It may also be possible that poor microcirculatory network and /or capillary to myocyte functional mismatching that has been identified from muscle biopsy in uremic patients contributes to the limitation to exercise. Data from 31PMRS (magnetic resonance spectros-

copy) in dialysis patients and controls reported by Moore, et al30 suggests that subnormal oxidative metabolism in hemodialysis patients is caused not by impaired mitochondrial oxidative capacity, but rather limited exchange of metabolites between blood and muscle. Another elegant study was reported by Sala, et al38 using both H1 MRS to estimate intracellular PO2, and simultaneous assessment of skeletal muscle cell bioenergetics with 31P MRS while breathing different inspired oxygen fractions. They used isolated single leg knee extension exercise to avoid confounding factors of central organ system limitations. Their studies confirmed that low muscle oxygen conductance and not limited mitochondrial oxidative capacity plays a role in limiting exercise tolerance in these patients. The inability to widen the a-vO2 difference may be due to myopathy associated with renal disease. Uremic myopahty is frequently described and primarily affects proximal muscles. Wasting of the quadriceps is common, with intact sensation and preservation of muscle reflexes. Hip flexors, hip extensors, and shoulder abductors are most often affected.39 Muscle biopsy reveals type II fiber atrophy, variably-sized fibers and rounding of fibers with few internal nuclei.21,40,41 Biopsy of ‘uremic myopathy’ also reveals ‘moth-eaten’ fibers, mitochondria myopathy (i.e., mitochondrial swelling, ragged red fibers), fiber rarefaction and distortion, Z band degeneration, lipid inclusions and numerous other pathological changes.40,42-44 In many specimens, the fibers show wide variability in size and shape, suggesting heterogeneity in structure and possibly function.21,41-43,45 These structural abnormalities plus low capillary density result in an increased diffusion distance for oxygen between the capillary and myocyte, resulting in a low diffusional oxygen conductance within the muscle.14,22

Low Oxygen Demand? In a letter to the editor in response to the publication by Moore et al,17 Noakes, et al,46 suggested that the limitation in VO2peak is the result of neuromuscular abnormalities that prevent the patients from generating muscle

Determinants of Exercise Capacity

contractions adequate to perform adequate external work to achieve adequate VO2peak. Thus, they suggested it is not a ‘central’ oxygen delivery issue, nor necessarily an extraction issue, but neuromuscular and/or contractile dysfunction. Since leg muscle fatigue is the most common reason for stopping exercise testing, either peripheral neuropathy or myopathy or both could be limiting factors. Both are well characterized in uremia. Neuropathological findings in uremia indicate decreased numbers of large myelinated fibers. In the remaining fibers, the sheath is swollen and fragmented, with degeneration of the axon cylinders. The myelin sheath is damaged only where there is a degenerated axon. This leads researchers to believe that uremia causes a metabolic defect that leads to a decrease in the size of the axon, causing a rearrangement of myelin that results in destruction of the nerve fiber.47,48 Neuromuscular dysfunction is present in a significant number of uremic patients.49 Somatic neuropathy is manifested by symptoms of pain, burning and tingling in the distal extremities. Lower extremities are affected more often than upper, with progressive weakness and atrophy of muscles occurring over time.48,49 It is reported that 93% of patients demonstrate decreased deep tendon reflexes, with 50% exhibiting clinical or electrical evidence of neuropathy.48,50 Polyneuropathy has been documented in 84% of hemodialysis patients studied by Bazzi, et al.51 Muscle weakness is nearly universal in dialysis patients and may contribute to the inability to generate adequate oxygen demand. Muscle weakness persists following transplant.52-54 A decrease in the ability to generate force per unit mass (specific strength) and a reduction in the capacity of the central nervous system to active otherwise normal motor units (central activation failure), or a combination of these mechanisms may cause the muscle weakness in this population.55,56 Skeletal muscle strength is more closely linked to VO2peak than oxygen carrying capacity.53 Diesel et al53 reported that VO2 peak correlates with isokinetic cycling power (r ¼ .84) and isokinetic knee extension (r ¼ .68), but not with hematocrit or hemoglobin concentration (r ¼ 0.35 and 0.33 respectively). Johansen,

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et al57 showed that gait speed was significantly correlated with muscle contractile cross-sectional area (r ¼ 63, p , 0.0001), but dialysis subjects had a slower gait speed even after adjustment for contractile area (p ¼ 0.0008). This certainly lends support to the idea that muscle atrophy and resulting weakness is an important cause of reduced physical functioning in the dialysis population.

Case Study The author had the opportunity to test a young man who had been treated with hemodialysis for 22 years, who was a trained triathlete. He was 33 years of age, with the etiology of renal disease being membranous proliferative glomerulonephritis type 1. His BMI was 23.5 (20.9% body fat), dialyzed every other day for 4.5 hours per session. His medications were renagel, sensipar, folic acid, multivitamin and 3000 U of EpogenÒ every treatment. His hematocrit was 34.8%. He was on no blood pressure medications. He had completed an ironman distance triathalon (3.8Km swim, 185 Km bicycle, 42 Km run) and several shorter triathalon distances. He followed a standard triathalon training program, which is well described on his website: http://www. ironshad.com/training.php#training. We performed a maximal treadmill test on this dialysis athlete during which we measured VO2, and cardiac output and heart and we calculated stroke volume and a-vO2 difference. We considered his test to be maximal, in that the VO2 leveled off during the last two stages, and he achieved a respiratory exchange ratio of 1.15. His VO2max was 2.06 L/min. The VO2max for triathletes of his age are reported to be 4.2 to 4.8 L/min. Table 1 shows the determinants of VO2 (Fick Equation) at maximal exercise. Also presented are expected values for each determinant in trained athletes of this age. In this dialysis athlete, it would be expected that his training has optimized his muscle function and cardiac function, thus his VO2max. Thus, any limitation would be expected to be due to his disease and/or treatment. From the data available, it appears that he is limited in delivery, primarily due to a blunted maximal heart rate, and in utilization as evidenced by a lower than expected a-

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Table 1. Measured values for the determinants of VO2max in a dialysis athlete (unpublished data) and expected values for well trained athletes of similar age (from published studies). Determinant

Tested

Expected

% expected

VO2max (L/min)(ml/kg/min) Cardiac Output (L/min) Heart Rate (b/min) a-vO2dif (ml O2/100 mL) Stroke Volume (ml/bt)

2.1631.4 16.2 137 12.6 116.8

4.5- 4.8 20–22 187 17.5–18.5 110-117

48% 80% 73% 72% Within normal values

vO2difference. It is unknown whether increasing hemoglobin to normal levels in a welltrained dialysis athlete would result in increased VO2peak. However, even with an increased oxygen content, oxygen delivery would remain lower than expected due to the blunted heart rate response. From the data of Stray-Gundersen,18 there is no change in extraction at the muscle (i.e. a-vO2dif) with increasing hematocrit. In the study of normalization of hematocrit plus exercise training, Painter, et al, reported that in the usual care hematocrit (hct: 30-33%), exercise training brought the VO2peak more in concordance with hemocrit (i.e. 72.8% of age predicted VO2peak vs. 75% of normal hematocrit) whereas the high hematocrit group achieved 64% of age-predicted VO2peak vs. 100% of normal hematocrit group. There were no changes in peak heart rate after normalization of hematocrit or with exercise training. Thus, due to other physiological limitations, it is not expected that normalization of hematocrit in the dialysis athlete would further increase VO2max.

Summary There are many challenges in our ability to identify mechanisms of limitations in this population. Comorbidities and polypharmacy complicate analysis and interpretation of studies. Since less than half of dialysis patients are physically capable of performing a symptomlimited exercise testing with measurements to determine limitations, the data obtained is not generalizable to the population of CKD patients. Obviously use of physical performance testing will not allow determination of mechanisms. The physiology of exercise in renal disease is complex, rendering identification of specific mechanisms of limitations difficult and focus on just one or two determinants

may not be informative, since it is the integrated functioning of multiple systems that determines oxygen uptake and thus exercise capacity. Thus, the focus on mechanisms may not be with our reach in this patient population, nor is it necessary to begin implementing exercise interventions that are known to improve overall functioning and quality of life.

References 1. Johansen KL: Exercise in the end-stage renal disease population. J Am Soc Nephrol 18:1845-1854, 2007 2. Painter P: Physical functioning in end-stage renal disease patients: update 2005. Hemodialysis Int 9: 218-235, 2005 3. Cheema B, Singh MAF: Exercise training in patients receiving maintenance hemodialysis: a systematic review of clinical trials. Am J of Nephrol 25:352-364, 2005 4. Sietsema KE, Amato A, Adler SG, Brass EP: Exercise capacity as a prognostic indicator among ambulatory patients with end stage renal disease. Kidney Int 65: 719-724, 2004 5. Knight E, Ofsthun N, Teng M, Lazarus JM, Curhan GC: The association between mental health, physical function and hemodialysis mortality. Kidney Int 63:1843-1851, 2003 6. DeOreo PB: Hemodialysis patientassessed functional health status predicts continued survival, hospitalization and dialysis-attendance compliance. Am J of Kidney Dis 30:204-212, 1997 7. 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 8. Painter PL, Stewart AL, Carey S: Physical functioning: definitions, measurement, and expectations. Adv Renal Repl Ther 6:110-123, 1999 9. Stewart AL, Painter PL: Issues in measuring physical functioning and disability in arthritis patients. Arthritis Care Res 10:395-405, 1997 10. Blair SN, et al: Physical fitness and all-cause mortality: a prospective study in healthy men and women. JAMA Assoc 262:2395-2401, 1989 11. Holly RG: Measurement of the maximal rate of oxygen uptake, in Durstine L, et al. (eds.): Resource Manual for Guidelines for Exercise Testing and Prescription 2nd Ed. Philadelphia, Lea & Febiger, 1992

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