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Am J Physiol Regul Integr Comp Physiol 280: R1240-R1248, 2001;
0363-6119/01 $5.00
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Vol. 280, Issue 4, R1240-R1248, April 2001

Impaired muscle oxygen transfer in patients with chronic renal failure

Ernest Sala1, Elizabeth A. Noyszewski2, Josep M. Campistol1, Ramon M. Marrades1, Steffi Dreha2, Josep V. Torregrossa1, Jennifer S. Beers2, Peter D. Wagner3, and Josep Roca1

1 Servei de Pneumologia i Allèrgia Respiratòria, Unitat de Transplantament Renal, Departament de Medicina, Institut d'Investigacions Biomèdiques Pi i Sunyer, Hospital Clínic, Barcelona 08036, Spain; 2 Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and 3 Section of Physiology, Department of Medicine, University of California San Diego, La Jolla, California 92093


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We hypothesized that impaired O2 transport plays a role in limiting exercise in patients with chronic renal failure (CRF). Six CRF patients (25 ± 6 yr) and six controls (24 ± 6 yr) were examined twice during incremental single-leg isolated quadriceps exercise. Leg O2 delivery (QO2leg) and leg O2 uptake (VO2leg) were obtained when subjects breathed gas of three inspired O2 fractions (FIO2) (0.13, 0.21, and 1.0). On a different day, myoglobin O2 saturation and muscle bioenergetics were measured by proton and phosphorus magnetic resonance spectroscopy. CRF patients, but not controls, showed O2 supply dependency of peak VO2 (VO2peak) by a proportional relationship between peak VO2leg at each inspired O2 fraction (0.59 ± 0.20, 0.47 ± 0.10, 0.43 ± 0.10 l/min, respectively) and 1) work rate (933 ± 372, 733 ± 163, 667 ± 207 g), 2) QO2leg (0.80 ± 0.20, 0.64 ± 0.10, 0.59 ± 0.10 l/min), and 3) cell PO2 (6.3 ± 5.4, 1.7 ± 1.3, 1.2 ± 0.7 mmHg). CRF patients breathing 100% O2 and controls breathing 21% O2 had similar peak QO2leg (0.80 ± 0.20 vs. 0.79 ± 0.10 l/min) and similar peak VO2leg (0.59 ± 0.20 vs. 0.57 ± 0.10 l/min). However, mean capillary PO2 (47.9 ± 4.0 vs. 38.2 ± 4.6 mmHg) and the capillary-to-myocite gradient (40.7 ± 6.2 vs. 34.4 ± 4.0 mmHg) were both higher in CRF patients than in controls (P < 0.03 each). We conclude that low muscle O2 conductance, but not limited mitochondrial oxidative capacity, plays a role in limiting exercise tolerance in these patients.

chronic renal failure; exercise; oxygen transport; nuclear magnetic resonance spectroscopy; intracellular partial pressure of oxygen


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

IT IS WELL-KNOWN THAT PATIENTS with end-stage chronic renal failure (CRF) have abnormally low peak oxygen uptake (VO2) (10, 22), historically attributed to impaired convective O2 delivery due to anemia. Recently, however, it has been demonstrated that, even after treatment with erythropoietin (rHuEPO), peak VO2 did not improve as much as the rise in arterial oxygen content would predict (5, 12, 13, 16, 17). Different studies (14, 18) have suggested that this phenomenon is essentially explained by an abnormally low muscle capillary O2 conductance likely associated with poor muscle microcirculatory network and/or capillary-to-myocyte functional mismatching due to uremic myopathy. Moreover, assessment of cellular bioenergetics using 31-phosphorus magnetic resonance spectroscopy (31P MRS) (15, 18) seems to exclude impaired mitochondrial oxidative capacity as a limiting factor of peak VO2 in these patients. However, evidence of oxygen-supply dependency of maximal VO2 (VO2 max) by direct measurements of cell oxygenation is required to provide a more robust evidence for this hypothesis.

In the present investigation we have examined the issues of O2 transport and metabolic limitations to exercise by incorporating two novel strategies. First, in vivo measurements of myoglobin saturation to estimate cell PO2 with proton magnetic resonance spectroscopy (1H MRS) and simultaneous assessment of skeletal muscle cell bioenergetics with 31P MRS were carried out in each subject during exercise while the subject breathed different inspired O2 fractions (FIO2). This approach has facilitated the analysis of the relationships between O2 transport and skeletal muscle bioenergetics. Second, we used a single knee-extensor exercise protocol because it induces a high convective O2 delivery relative to the small exercising muscle mass. In these conditions, central organ systems (lung function, systemic hemodynamics) do not constrain VO2 max as may occur in exercise modalities involving larger muscle mass. Finally, the study of young CRF patients without co-morbid conditions avoided the disease duration-related obscuring factors often seen in older patients with diabetes, longstanding hypertension, and ischemic heart disease.

The specific aims of the investigation were twofold: 1) to determine whether VO2 max is limited by O2 supply in CRF patients (by measuring VO2 max in subjects breathing 13, 21, and 100% O2) and 2) to estimate muscle O2 conductance at VO2 max in CRF patients and in healthy sedentary controls matched by age, activity, and anthropometric characteristics. Comparison of muscle O2 conductance between the two groups was done at similar levels of both convective O2 delivery and O2 consumption.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study group. Six young men [25 ± 6 (SD) yr] with CRF, who were free of other systemic diseases and undergoing regular hemodialysis, were examined during rHuEPO therapy. Individual and mean data on anthropometric characteristics, lung function, and hemoglobin concentration ([Hb]) are listed in Table 1. Six healthy sedentary men (24 ± 6 yr), matched by age and anthropometric characteristics and selected on the basis of no previous history of regular or even occasional physical exercise above that required for average daily activities, were used as the control group (Table 1). Informed consent was obtained according to both the Committee on Investigations Involving Human Subjects at the Hospital Clinic, Universitat de Barcelona, and the University of Pennsylvania Institutional Review Board for Human Subjects Research Committee.

                              
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  		Table 1.   Anthropometrics, hemoglobin concentration, pulmonary function, and peak exercise results

Overview of experimental protocol. Each subject performed three incremental knee-extensor exercise bouts until exhaustion, breathing different FIO2 (0.13, 0.21, and 1.0, respectively) on two different occasions after identical protocols, first in Barcelona (Spain) and <1 mo later in Philadelphia (PA). The order of the three FIO2 was balanced and identical for each patient in the two studies. The Barcelona study addressed femoral venous blood flow and muscle O2 transport/O2 consumption. In the Philadelphia study, we simultaneously measured 1) myoglobin saturation to estimate cell PO2 with 1H MRS and 2) intracellular pH (pHi) and inorganic phosphate concentration-to-phosphocreatine concentration ratio ([Pi]/[PCr]) with 31P MRS. Although the half-time of the [PCr] recovery after a light-intensity constant-work rate exercise was measured in all patients, technically adequate results could be obtained in only five of them in each group.

Exercise protocol. The knee-extensor ergometer was built at the Metabolic Magnetic Resonance Research and Computing Center (MMRRCC; Philadelphia, PA) for the left leg to replicate the device reported in previous research (24). This ergometer was constructed from nonmetallic materials to allow its use in both the human physiology laboratory in Barcelona and the MRS facility in Philadelphia. The subject lay supine on a padded bed with the knee-extensor ergometer placed in front of him. The resistance to knee extension was provided via a fiberglass bar attached to the crank of the ergometer and to a specially designed ankle brace worn by the subject. This ergometer was a prototype, and as such power output could not be measured in conventional units of work, but it was prescribed and measured as resistance [weight (g), resisting rotation of a flywheel] at the end of the preliminary graded maximal test. Sixty dynamic contractions of the knee-extensor muscles per minute were performed by all subjects, so that weight could be used to reflect power output. Contractions of the quadriceps femoris muscle caused the lower part of the leg to extend from 90 to 170° flexion. Throughout the exercise the thigh remained immobile. This stability was enhanced by the 45° angle of the exercising leg and the harness worn by each subject.

Whole body and one-leg measurements. Subject preparation, safety precautions, and technical aspects of the central measurements done in Barcelona (arterial and femoral venous blood gases and femoral venous blood flow) have been described in detail elsewhere (1, 14, 15, 25). Briefly, one catheter was placed in the radial artery of the arm contralateral to the arteriovenous fistula in CRF patients and in the nondominant arm in the control group. In the femoral vein of the left leg, a 7-Fr specially designed catheter was advanced 7 cm into the vessel with the tip oriented distally and a 2.5-Fr thermistor was advanced 5 cm proximally into the same vessel. Each subject performed three incremental knee-extensor exercise tests (200-g increment every 2 min in each subject, with an initial period of 2 min with no load), breathing three inspired O2 concentrations (0.13, 0.21, and 1.0) until exhaustion.

On-line breath-by-breath calculations of whole body VO2, CO2 output (VCO2), minute ventilation, respiratory exchange ratio, heart rate, and respiratory rate were averaged sequentially over 15-s intervals and displayed on a screen monitor to observe the progress of the tests. In each subject, simultaneous arterial and femoral venous blood samples were collected at rest and during the 2nd min of each incremental work rate. Femoral venous blood flow measurements were made by short-term steady-state thermodilution by use of iced saline (1, 25) immediately after femoral venous blood sampling. In each instance, the following measurements were made: 1) PO2, PCO2, pH (IL, pH/blood gas analyzer model 1302 and tonometer model 237, Instrumentation Laboratories, Milan, Italy), oxyhemoglobin saturation, [Hb] (IL 482 cooximeter), and whole blood lactate concentrations (YSI 23L blood lactate analyzer, Yellow Springs Instruments, Yellow Springs, OH) from simultaneous arterial and femoral venous blood samples; and 2) femoral venous blood flow (Qleg) and arterial pressure. Technical aspects of these measurements have been previously provided in detail (1, 14, 15, 25).

In the present study, blood O2 content was calculated as [(1.39 × [Hb] × measured oxyhemoglobin saturation) + (0.003 × PO2)]. This was done for arterial (CaO2) as well as femoral venous (CfvO2) blood. The O2 delivery to the exercising leg (QO2leg) was calculated as the product of arterial O2 content and leg blood flow [QO2leg = CaO2×Qleg]. Leg O2 uptake (VO2leg) was obtained as the product of Qleg and the arterial-femoral venous difference of O2 content [VO2leg = Qleg × (CaO2 - CfvO2)]. Leg O2 extraction ratio (O2ER) was calculated as the ratio of the arterial to femoral venous O2 content difference and the arterial O2 content [O2ER = 100 × (CaO2 - CfvO2)/CaO2]. In each subject, measured O2 saturation and the corresponding PO2 from all samples were used to estimate the P50 of hemoglobin. Calculations of mean muscle capillary PO2 (PcO2) and the corresponding value of muscle O2 conductance (DO2) at peak exercise for each FIO2 were obtained by numerical integration (4, 26, 31, 33, 34); the assumptions involved in this analysis have been previously described in detail (33). It should be noted that DO2 is a lumped parameter that reflects both diffusional conductance and the effects of functional heterogeneities of VO2 with respect to blood flow.

Magnetic resonance measurements. The exercise protocol done in Barcelona was reproduced using a similar ergometer in the MMRRCC. Measurements were performed on a 2-T Oxford magnet with custom-built spectrometer. Experiments utilized a single-turn transmitter/receiver coil double tuned to proton (86.13 MHz) and phosphorus (34.95 MHz) frequencies (28).

Water suppression was achieved through the MEDUSA sequence (20). The MEDUSA water suppression sequence for proton acquisition utilized a 9.0-ms hyperbolic secant pulse centered 140 Hz upfield from the water resonance for inversion and a 0.5-ms gaussian pulse centered 6,650 Hz downfield from the water resonance for excitation. Five hundred twelve points were sampled over a 20-kHz bandwidth with a repetition time of 80 ms. The MEDUSA sequence was paused to collect phosphorus signals using a 0.16-ms hard pulse and acquiring 1,024 points over a 2-kHz bandwidth. Forty proton averages and one phosphorus signal were acquired for each 4-s time point. Another three proton free induction decays before each data point were eliminated to achieve steady state for suppression.

Data were Fourier transformed after summing to 20-s resolution and exponentially weighting by 100 Hz. Intensities for the peaks resonating ~74 ppm from the water resonance were obtained using a singular-value decomposition method (23) written for Interactive Data Language (Research Systems, Boulder, CO). Maximum signal-to-noise ratio for these studies averaged 9:1 with 7% variance in signal at the end of the cuff.

Details of the theory behind oxygen-sensitive myoglobin (Mb) signals have been published previously (3). The heme iron exhibits oxygen-dependent spin states that in turn influence nearby protons. The N-Lambda proton on proximal histidine F8, one of the ligands coordinated to the iron, is particularly sensitive to these changes. When oxygen is bound to the active site, the resonance of this proton is hidden below the dominant water signal. However, when Mb becomes deoxygenated, changes in the iron spin state shift this peak to a temperature-dependent position that is clearly distinct from all other resonances. At physiological temperature, this peak resonates ~73 ppm downfield from the water resonance. This O2-dependent signal can be calibrated to obtain values for Mb desaturation; these values can be converted to intracellular O2 tensions by use of O2-binding curves for Mb (35).

Data analysis. Results are expressed as means ± SD. Repeated-measures ANOVA (one-way ANOVA) was used to test, within each group of subjects, the influence of different FIO2 values in the main variables. Likewise, nonparametric tests were computed to study differences between variables for a given FIO2 within (Wilcoxon) or between groups (Mann-Whitney U). Statistical significance was set at P <=  0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

One-leg O2 transport and VO2 while subjects breathed room air. One-leg Qleg at a given submaximal work rate was similar between CRF patients and healthy sedentary controls. Close to peak exercise (Table 2), Qleg was slightly higher in CRF patients, but differences did not reach statistical significance. As part of the usual therapeutic strategy with rHuEPO, [Hb] was kept slightly below normal values. Consequently, CaO2 was lower in CRF patients (P < 0.03) than in controls. Hence, QO2leg was also lower in the patients both during submaximal exercise and at peak work rate (P < 0.05 each). O2 extraction ratio (O2ER) during exercise was similar in CRF and control groups. At peak exercise, VO2leg was lower in CRF patients than in controls (P < 0.05). Femoral venous lactate concentrations ([La]fv), at any given exercise level, were not different between groups.

                              
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  		Table 2.   Whole body and O2 transport variables during incremental single knee-extensor exercise in normal subjects and CRF patients breathing room air

O2 supply dependency of VO2 max. Peak VO2leg data of subjects breathing 13, 21, and 100% O2 were plotted against 1) peak external mechanical work expressed as pan weight in grams (Fig. 1A), 2) peak oxygen delivery (Fig. 1B), 3) variables that reflect tissue oxygen availability, such as measured PfvO2 and mean capillary PO2 estimated by Bohr integration (Fig. 2, A and B, respectively), and 4) direct measurements of Mb saturation and cell PO2 with 1H MRS (Fig. 3, A and B, respectively). Numerical data for all these variables at peak exercise are indicated in Table 3.


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  		Fig. 1.   Peak quadriceps oxygen uptake VO2 (y-axis) plotted against peak power output (x-axis, A) and peak O2 delivery (x-axis, B). triangle , Healthy subjects; , chronic renal failure (CRF) patients. Results correspond to mean (±SE) group data for subjects breathing 13, 21, and 100% inspired O2 fractions (FIO2) of 0.13, 0.21, and 1.0, respectively. See text for further explanations.



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  		Fig. 2.   Peak quadriceps VO2 (y-axis) plotted against peak femoral venous PO2 (x-axis, A) and peak mean capillary PO2 (x-axis, B). triangle , Healthy subjects; , CRF patients. Results correspond to mean (±SE) group data for subjects breathing 13, 21, and 100% FIO2 of 0.13, 0.21, and 1.0, respectively. See text for further explanations.



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  		Fig. 3.   Peak quadriceps VO2 (y-axis) plotted against oxymyoglobin saturation (x-axis, A) and peak cellular PO2 (x-axis, B). triangle , Healthy subjects; , renal patients. Results correspond to mean (±SE) group data for subjects breathing 13, 21, and 100% FIO2 of 0.13, 0.21, and 1.0, respectively. See text for further explanations.


                              
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  		Table 3.   Peak exercise results at each inspired O2 fraction

In CRF patients, peak work rate and peak VO2 both increased, and in proportion to one another, as FIO2 rose from 0.13 to 1.0 (Fig. 1A), but no significant changes with FIO2 were observed in the control group. Likewise, CRF patients at peak exercise displayed a proportional relationship between VO2leg and O2 delivery (P < 0.03) not seen in healthy sedentary controls. The discontinuous lines through the origin in Fig. 1 graphically indicate O2 supply dependency of peak VO2leg in the renal group, not seen in healthy sedentary subjects. It is of note (Fig. 1B) that CRF patients breathing 100% O2 and controls breathing 21% O2 showed identical convective O2 delivery and O2 consumption (Table 3), which provide unique conditions for analyzing DO2 under conditions of equal O2 delivery and utilization, as described in DO2 and cellular bioenergetics.

Figure 2 displays a proportional relationship between peak VO2 and PfvO2 (and mean capillary PO2) of CRF patients, but not of control subjects, breathing different FIO2 amounts. The slope of the discontinuous line through the origin drawn in each plot of Fig. 2 reflects the estimate for DO2 in the CRF group. In vivo cell PO2 measurements are depicted in Fig. 3. It is of note that healthy sedentary subjects showed similar peak VO2leg results at different levels of cellular oxygenation (Mb saturation or cell PO2). In contrast, CRF patients breathing normoxia and hypoxia showed a well defined relationship between maximum VO2leg and cellular oxygenation. The key observation, however, is that the two groups displayed the same overall relationship between peak VO2 and intracellular PO2.

DO2 and cellular bioenergetics. Because CRF patients breathing 100% O2 and the control group breathing 21% O2 showed identical peak VO2leg and peak convective O2 delivery, these conditions offered an appropriate scenario for analyzing the behavior of O2 transfer from muscle capillary to myocyte. According to the Fick's first law of diffusion (VO2 max = DO2 × PO2 gradient from muscle capillary to myocyte) (31), estimated DO2 by Bohr integration was significantly lower in CRF patients than in controls (12.9 ± 3.8 vs. 17.0 ± 4.4 l · min-1 · mmHg-1, respectively; P < 0.03). Consequently, mean capillary PO2 (47.9 ± 4.3 vs. 38.2 ± 4.6 mmHg; P < 0.03) and the PO2 gradient from capillary to cell (40.7 ± 6.2 vs. 34.4 ± 4.0 mmHg; P < 0.03) were higher in CRF patients, as indicated in Fig. 4. Moreover, cellular bioenergetic status (31P MRS) was similar in the two groups at equivalent levels of convective O2 delivery and O2 consumption (CRF patients breathing 100% O2 and controls breathing 21% O2). As displayed in Fig. 5, no differences between groups were observed in pHi or in [PCr]/[Pi] at a given exercise level. The results of half-time of [PCr] recovery, after a slighter intensity constant work rate exercise keeping pHi unchanged, were also close in the two groups (43.4 ± 19.4 vs. 37.8 ± 12.3, patients and controls, respectively).


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  		Fig. 4.   Muscle O2 transport at peak exercise. CRF patients at peak exercise and breathing room air (A) showed lower O2 delivery (QO2) and lower O2 uptake (VO2) than controls, but no differences in PO2 gradient between capillary and cell (Pcap O2 and Pcell O2) were seen between the 2 groups. However, at similar conditions of OO2 and VO2 (CRF patients breathing 100% O2 and controls breathing 21% O2; B), the PO2 gradient from capillary to cell was significantly higher in CRF patients than in controls. See text for further explanations.



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  		Fig. 5.   Intracellular pH (pHi; A) and ratio of inorganic phosphate-to-phosphocreatine concentrations ([Pi]/[PCr]; B) are plotted vs. VO2leg (x-axis). triangle , Healthy subjects breathing 21% O2; , CRF patients breathing 100% O2. See text for further explanations.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The three major findings in the present study are 1) demonstration of O2 supply limitation of VO2 max in CRF patients, assessed by measurements of both leg VO2 and cellular oxygenation with 1H MRS; 2) confirmation of an abnormally low DO2 in CRF patients that seems to play a significant role in limiting VO2 max; and 3) a normal cellular bioenergetic status assessed by changes in [PCr]/[Pi] and in pHi during incremental exercise and a normal mitochondrial oxidative capacity assessed by [PCr] recovery measured after slighter intensity constant-work rate exercise.

Choice of exercise paradigm. The incremental knee-extensor exercise protocol used in the study provided two major advantages for investigating muscle O2 transfer of the quadriceps at peak exercise. First, the VO2 max achieved by the muscle group examined is substantially higher than that expected by the same muscle group during exercise involving a larger muscle mass, such as during cycle ergometer or treadmill protocols. This is because quadriceps peak exercise is not limited by constraints imposed by 1) regulation of systemic pressure during exercise (27) or 2) potential limitations in O2 transport due to central organ systems such as pulmonary or cardiac function. Moreover, the convective O2 delivery (QO2leg) relative to the exercising muscle mass is markedly higher than during cycling exercise. For these reasons, knee-extensor exercise provides a unique model for exploring potential abnormalities in the relationships between muscle O2 supply and O2 utilization due to intrinsic muscle dysfunction. Second, knee-extensor exercise allowed subjects to exercise within the magnet and, consequently, to reproduce identical exercise protocols between the O2 transport study and the simultaneous 1H MRS and 31P MRS measurements, and to study these in the quadriceps.

Maximum quadriceps VO2 was defined as the level at which VO2leg showed a plateau despite further increases in the resistance to knee extension, expressed as weight resisting the flywheel rotation of the ergometer. It is of note that, in the present study, evidence for O2 supply limitation of VO2 max in CRF patients is supported by several independent data, as described in RESULTS (Figs. 1-3 and 5).

In contrast, healthy sedentary controls showed similar levels of VO2 while breathing 13, 21, and 100% O2 despite significant differences in blood O2 transport (Fig. 1B) and cellular oxygenation, as indicated in Fig. 3 and Table 3. Figures 1-3 indicate that VO2 max in healthy sedentary subjects, in contrast to athletes (24, 26) and trained subjects (25), is not O2 supply dependent (6) but likely limited by the functional capacity of the cellular biochemical machinery to utilize O2.

Matching between groups. One important point in the patient inclusion criteria of the study group was to exclude young CRF patients free of any co-morbid condition (i.e., diabetes mellitus, collagen diseases, and the like). Selection of appropriate control subjects was also an important concern in the study design. As indicated in Table 1, CRF patients and healthy sedentary subjects were carefully matched by age, anthropometric characteristics (height, weight, and body mass index), and amount of daily physical activity. It is of note, however, that despite EPO, the two groups showed differences in [Hb] (10.9 and 15.3 g/dl, CRF and controls, respectively; P < 0.001), which explain the lower peak QO2leg (P < 0.05) and, in part, the lower peak VO2leg (P < 0.05). Such a difference in [Hb] was unavoidable, because EPO therapy was established on clinical grounds by the team in charge of the patient. Although the optimal level of [Hb] to be achieved after rHuEPO therapy is still a controversial issue, it is well accepted that [Hb] should be kept moderately below normal levels to improve health-related quality of life and submaximal exercise capacity without increasing the risk of cardiovascular complications associated with rHuEPO therapy (5).

DO2. The assumptions and constraints involved in the assessment of O2 transfer from muscle capillary to mitochondria at maximum exercise have been analyzed in Ref. 32. A requirement for estimation of DO2 by use of Fick's first law of diffusion (VO2 max = DO2 × PO2 gradient from capillary to myocyte) is evidence of O2 supply dependency of VO2 max. This was shown in Figs. 1 and 2 for CRF patients in all conditions and also in Fig. 3, while the patients were breathing hypoxic and normoxic gas mixtures. Likewise, DO2 calculated by numerical integration used measured cell PO2 rather than an assumed zero value, as is usually the case. DO2 did not show significant differences among the three FIO2 values, as indicated in Table 3. In contrast, O2 supply dependency of VO2 max was not seen in the control group. In healthy sedentary subjects, DO2 values obtained with the breathing of normoxic and hyperoxic gas mixtures were underestimated, whereas DO2 obtained while subjects were breathing 13% O2 (19.2 ml O2 · min-1 · mmHg-1) was likely the one closest to the true value of O2 conductance for sedentary subjects. Thus our results provide support to the notion that CRF patients show an abnormally low O2 conductance from muscle capillary to mitochondria.

The effects of peripheral (DO2) and central (QO2) components of muscle O2 transport on the difference in VO2leg at peak exercise between CRF patients and controls (Table 2) were estimated by numerical analysis. An increase in DO2 alone up to the value seen in the control group (17 ml · min-1 · mmHg-1) would have increased peak VO2leg in CRF patients by 0.055 l/min. Likewise, if only convective O2 delivery (0.79 l/min) was increased up to normal levels, keeping DO2 (13.7 ml · min-1 · mmHg-1) unchanged, peak VO2leg rose by 0.043 l/min. The simultaneous rise of both DO2 and QO2 up to the levels seen in healthy sedentary controls increased the estimated VO2leg by 0.098 l/min, which fully accounted for the observed difference in this variable between the two groups (by 0.10 l/min).

Uremic myopathy and O2 transport. The term uremic myopathy is commonly used to describe a constellation of skeletal muscle structural (8, 30) and physiological abnormalities seen in CRF patients (10, 22, 29). Fatigue, muscle weakness, and limited exercise tolerance are the most characteristic findings of the problem. Clinical manifestations of uremic myopathy can be aggravated by different risk factors, such as anemia, aging, poor nutrition, a sedentary lifestyle, and presence of co-morbid conditions.

In 1993, Moore et al. (18) reported no differences in cellular oxidative capacity (31P MRS) among 1) CRF patients under regular hemodialysis, 2) patients after renal transplantation, and 3) healthy subjects, suggesting impairment in O2 transport in the muscle microcirculation as the primary explanation for the limited increase in VO2 max after rHuEPO therapy. Further investigations (14, 15) confirmed the dissociation between a marked increase in [Hb] after EPO therapy and its rather reduced impact on VO2 max. It was shown (14, 15) that correction of anemia with rHuEPO reduces the hyperdynamic response seen in these patients and consequently decreases blood flow to normal levels. This, in turn, plays a role in offsetting the increase in VO2 max that would be expected from the rise in [Hb]. The study suggested that CRF patients, even after rHuEPO therapy, showed markedly lower DO2 than controls. It must be noted, however, that O2 supply limitation of VO2 max in Ref. 15 could not be formally assessed and that limitations of the 31P MRS analysis (14) did not exclude intrinsic abnormalities in the muscle biochemical machinery of these patients. The present study provides evidence indicating that CRF patients, in contrast to healthy sedentary controls, show O2 supply dependency of maximum O2 uptake due to 1) reduced convective O2 transport from anemia and 2) abnormally low O2 conductance from muscle capillary to mitochondria. Mitochondrial metabolic capacity does not play a significant role in limiting VO2 max in these patients.

Muscle biopsies in CRF patients (2, 19) indicate that muscle fiber-to-capillary dissociation and/or a low number of capillaries per muscle fiber could constitute the structural basis for a low DO2 in patients with uremic myopathy. Moreover, it is conceivable that functional abnormalities of skeletal muscle, such as heterogeneity of perfusion/VO2 ratios and/or abnormal synthesis or function of muscle cell myoglobin due to long-standing high levels of metabolic by-products (urea, creatinine, and the like), may also play a role in limiting O2 availability to mitochondria in these patients.

Perspectives

The present study provides clear evidence of reduced muscle O2 transfer from capillary to mitochondria in uncomplicated end-stage renal patients compared with control subjects. The similar figures of VO2 and work rate at peak exercise (both whole body and single-knee extensor exercise) observed in the two groups suggest that the reduced O2 conductance seen in CRF patients cannot be ascribed only to a sedentary lifestyle. Our study, however, prompts the need for further investigations to explore the molecular basis of the mechanisms involved in the reduced DO2 observed in renal patients. The beneficial effects (7, 9, 11) of both rHuEPO therapy and exercise training further support the pivotal role of an abnormal O2 transport in these patients. It is nowadays well accepted (11) that the response to rHuEPO is closely associated with the quality of the hemodialysis. Moreover, it has been recently demonstrated that endurance training significantly decreases the risk of cardiac arrhythmias. Reduction in heart rate variability, in turn, shows an inverse correlation with the increase in aerobic capacity induced by physical training.


    ACKNOWLEDGEMENTS

We are grateful to Felip Burgos, Jaume Cardús, and all the technical staff of the Lung Function Laboratory for their skillful support during the study and to Mirjam Hillenius for secretarial skill in preparing the present manuscript.


    FOOTNOTES

This study was supported by Grants FIS 97-2102 and 97-0794 from the Fondo de Investigaciones Sanitarias, National Institutes of Health Grant RR-02305, and a grant from Comissionat per a Universitats i Recerca de la Generalitat de Catalunya (1997 SGR-0086).

E. Sala was a Research Fellow supported by the Hospital Clínic (1997-98).

Address for reprint requests and other correspondence: J. Roca, Servei de Pneumologia, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain (E-mail: jroca{at}clinic.ub.es).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 23 March 2000; accepted in final form 8 December 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 280(4):R1240-R1248
0363-6119/01 $5.00 Copyright © 2001 the American Physiological Society


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