Introduction
Chronic kidney disease affects approximately 7% of the world’s population with an expected increase in dialytic treatments annually [1]. Hemodiafiltration is a dialysis option that has demonstrated the highest capacity for removing small solutes and middle molecules. Additionally, high-volume hemodiafiltration has been associated with potential increased survival benefits in some studies [2,3].
Advanced kidney disease patients on hemodialysis often experience functional losses such as fatigue, muscle wasting, cognitive decline, and diminished aerobic capacity, impacting their physical activity, quality of life, and mortality [4]. In addition, dialysis sessions also contribute to low physical activity due to related symptoms of the procedure. Therefore, preserving function and quality of life is a priority for these patients. Exercise training and physical activity are increasingly popular to mitigate chronic diseases and reduce symptoms in patients with chronic conditions [5,6]. However, current literature regarding chronic kidney disease patients and exercise implementation focuses on hemodialysis, rather than hemodiafiltration.
Earlier studies have explored various aspects of exercise in relation to hemodialysis, including aerobic exercise, muscle strength, and program duration [7–11]. Research has also investigated the impact of exercise on hemodialysis quality, examining factors such as inflammation markers, sarcopenia, and cardiovascular capacity [5,12–14]. Additionally, physical activity does positively correlate to improved mental health, sleep quality, and physical function of daily activities [15,16]. There is evidence that indicates exercise improves physical abilities and quality of life during dialytic sessions [7,8,17–20]. However, there is no current evidence that supports hemodiafiltration patients benefiting from exercise. Furthermore, there is a gap in the literature regarding when exercise should be performed, during the dialysis sessions or the interdialytic interval.
This study’s goals were to first, understand if the combination of hemodiafiltration and exercise was an efficacious treatment compared to usual care in chronic kidney failure. Second, to explore the effectiveness of exercise within dialysis sessions (intradialytic) or between dialysis sessions (interdialytic).
Methods
An observational multicenter study was conducted within the chronic kidney disease patient cohort at the Fenix Nephrology Group. The study population comprised sedentary adult males and females undergoing maintenance hemodiafiltration. Inclusion criteria involved patients with optimized medication treatment and willingness to participate in the exercise program.
All patients at the Fenix Nephrology clinics were invited to participate in the rehabilitation program without exception. Patients self-selected into either the exercise or control group based on their willingness to participate. Those who chose to exercise further decided whether to perform the protocol during (intradialytic) or between (interdialytic) dialysis sessions. Once this choice was made, patients were encouraged to maintain their selected timing throughout the study duration to ensure consistency in the protocol. A control group consisted of individuals in the study who did not perform the exercise protocol and did not receive a physical evaluation from a physical therapist. In addition, prior to the initiation of the study, all participants, including those in the control group, were assessed for their physical activity levels and confirmed to be sedentary. Data collected from this study group only pertained to dialysis adequacy.
Patients were assessed at the initiation of the exercise program (baseline), and again after 6 months. Exclusion criteria encompassed patients with less than 80% attendance to the exercise program, those who underwent kidney transplantation during the study period, and patients with missing data in their medical records. This study was approved by the Federal University of Sao Paulo – UNIFESP Research Ethics Committee (No. 60256122.0.0000.5505) and was registered in the Registry of Clinical Trials (NCT#06448598). All participants signed the informed consent.
Physical assessments (aerobic and resistance) involved the Young Men’s Christian Association (YMCA) step test for endurance, handgrip, and one-repetition maximum for muscle strength. Tests were conducted by a trained team following a standardized protocol across all centers. The team received extensive training and detailed guidance to ensure standardization of measurements across centers. Patient-reported outcomes were evaluated using the Kidney Disease Quality of Life Short Form (KDQOL-SF). Dialysis adequacy was assessed using three Kt/V measures: single-pool Kt/V (spKt/V), standard Kt/V (stdKt/V), and equilibrated Kt/V (eKt/V). The formulae [21] used for these calculations were:
• spKt/V = –ln (R – 0.008 × t) + (4 – 3.5 × R) × UF/W (where R is the post-/pre-dialysis blood urea nitrogen ratio, t is the dialysis time in hours, UF is the ultrafiltration volume in liters, and W is the post-dialysis weight in kg)
• stdKt/V = spKt/V × (1 – 0.47/t)
• eKt/V = spKt/V – 0.6 (spKt/V/t) + 0.03
Exercise protocol
Patients meeting the inclusion criteria decided to carry out the exercise activities either during the hemodiafiltration session (intradialytic) or during the interdialytic interval (interdialytic) (Fig. 1). Interdialytic exercise activities were scheduled on days without planned hemodiafiltration sessions (patients had to come into the clinic for their exercise). Intradialytic sessions were seamlessly integrated into the hemodiafiltration session.
Patients adhered to a consistent exercise program, encompassing aerobic and resistance exercises, and both intradialytic and interdialytic exercise sessions that lasted 30 to 45 minutes. Aerobic exercises were performed at 70% of the maximum heart rate achieved in the YMCA step test, while resistance exercises were executed at 60% of the one-repetition maximum weight.
The exercise protocol was implemented across multiple Fenix Nephrology centers, with all physiotherapists receiving standardized training to ensure consistent application. Before each session, physiotherapists assessed patients’ clinical and physical conditions, including measurements of systolic and diastolic blood pressure, heart rate, and subjective perception of effort using the Borg scale [22]. Exercise intensity was adjusted based on these parameters to ensure patient safety and comfort.
For intradialytic exercise, sessions were seamlessly integrated into the hemodiafiltration treatment, with timing varying according to the patient’s clinical condition. Exercises were conducted at various periods throughout the session, including at the beginning, during, and near the end of the dialysis treatment. Patients used a bedside cycle ergometer for aerobic training, with workload adjusted according to individual tolerance. Resistance exercises utilized dumbbells, targeting major muscle groups with three sets of 10 to 12 repetitions (as determined by the 60% one-repetition maximum weight threshold), while avoiding the limb with arteriovenous fistula.
Interdialytic exercise sessions were performed on non-dialysis days, usually within 24 hours after the previous dialysis session. Interdialytic exercise offered patients a choice between a treadmill or cycle ergometer for aerobic training, with intensity tailored to patient tolerance. Resistance training incorporated dumbbells and ankle weights, following a similar protocol to intradialytic sessions.
Aerobic and resistance exercises were alternated between sessions to prevent overload and maintain clinical stability. The exercise regimen remained consistent for both groups, with loads adjusted weekly to maintain the correct intensity. The program spanned 6 months, with sessions occurring twice weekly. Throughout each session, the access limb was properly positioned and continuously monitored for patency, dysfunction, and potential complications, while vital signs were closely observed. This comprehensive approach ensured a balanced and adaptable exercise regimen for all participants.
Strength test and handgrip
Strength testing involved two components: assessment of one-repetition maximum for resistance exercise and handgrip strength evaluation. For patients with an arteriovenous fistula, the one-repetition maximum assessment was performed on the limb contralateral to the dialysis access, where we determined the maximum weight patients could lift for a single repetition while maintaining proper form. For patients with tunneled catheters, we followed a similar protocol, assessing the one-repetition maximum on a suitable limb that did not interfere with the catheter placement. Participants performed a warm-up and after a brief rest, three to five repetitions at 60% to 80% of the perceived maximum was performed. Subsequently, small increments were added until the participant could not complete a repetition with proper form [23]. The 1RM (one-repetition maximum) was determined within three to five trials with rest periods of 2 to 3 minutes between attempts. This test aimed to evaluate the maximal strength of the participants, and was used for exercise prescription, following the American College of Sports Medicine protocol [24].
Handgrip strength was measured using a calibrated hydraulic hand dynamometer (Jamar; Lafayette Instrument Company) following standardized procedures [25]. Participants were seated with the elbow of the arm contralateral to the access flexed at 90°, the forearm in neutral position, and the wrist extended between 0° and 30° extension. Their hips and knees were also flexed at 90°. A maximal contraction was performed with the dominant hand and repeated a total of three times, with a 120-second rest provided between each attempt. The highest recorded value, in kg, from the three attempts was considered the final measurement.
Step test
The YMCA step test was conducted using a 30-cm step platform with no handrails. Participants were instructed to step up and down at their own pace for 3 minutes. They were encouraged to maintain the pace, with an examiner offering verbal encouragement throughout the test. Heart rate and arterial oxygen saturation (SpO2) were assessed continuously. A modified Borg scale [22] of perceived exertion and blood pressure were measured before, immediately after, and 2 minutes after the test. The test score was the 60-second recovery heart rate, measured while participants remained standing immediately after completing the steps. Lower recovery heart rates indicated better cardiovascular fitness. The peak heart rate obtained at the end of the step test was used as a reference for aerobic exercise prescription in the study [24].
Fat-free mass
Fat-free mass was assessed using the Seca MBCA 525 medical body composition analyzer with Analytics 115 software (Seca GmbH & Co. KG). This noninvasive device utilizes a multi-frequency phase-sensitive 8-electrode system for total body composition analysis. Four pairs of standard surface electrodes were placed on the hands and feet in anatomical positions, connected to a central analyzer linked to a computer.
All measurements were conducted immediately before dialysis for both interdialytic and intradialytic groups, with patients resting for 10 minutes in a standardized supine position on a nonconductive surface. The examination, lasting approximately 75 seconds, provided comprehensive data on body composition, including reliable fat-free mass measurements for our study population.
Statistical analyses
Before each statistical test, normality testing was conducted using the Kolmogorov-Smirnov test. The initial phase focused on assessing changes within the entire hemodiafiltration exercise group compared to controls. Descriptive statistics informed the baseline and postexercise variables, and month-to-month dialysis comparisons with two-way analysis of variance (ANOVA), and McNemar test for categorical variables. Following this, the study diverged into a comparative analysis between patients engaging in intradialytic exercise activities and those opting for sessions on non-dialysis days (interdialytic). The comparison involved two-way ANOVA for continuous variables and chi-square tests for categorical variables. For all analyses, p-values < 0.05 were considered statistically significant. All statistical analyses were conducted and analyzed by authors MFO and ATH.
Results
A total of 267 participants were recruited to engage in the exercise program. Among them, 81 (30.3%) declined to participate. From the enrolled 186 individuals, we further refined the cohort, excluding 64 patients (34.4%) based on several exclusion criteria (Fig. 2). The final analysis included 122 patients, of which 89 (73.0%) were in the exercise group and 33 (27.0%) were enrolled in the control group. Of those 89 patients who performed exercise, 54 patients (60.7%) engaged in the intradialytic exercise group, and 35 patients (39.3%) performed exercise outside of the hemodiafiltration (interdialytic exercise group).
Control versus exercise group analysis
There were no statistically significant differences in demographics, comorbidities, or medications among participants (Table 1). In the exercise group, 82.1% had arteriovenous fistula access for dialysis, compared to 66.7% in the control group (p > 0.05). There were no interruptions to the exercise protocol due to adverse events (i.e., hypotension, arrhythmia, reduced blood oxygenation, or arteriovenous fistula issues) in the exercise group for the duration of the study.
A comparison of the control group versus the exercise group (Fig. 3) shows statistically significant differences in dialysis efficiency parameters. Both control and exercise groups showed improvements in single-pool (Fig. 3A), standard (Fig. 3B), and equilibrated Kt/Vurea (Fig. 3C) from baseline to month 6; however, the increases were greater in the exercise group. Analysis of pre- and post-dialysis urea values revealed a trend toward improved urea clearance in the exercise group over the 6-month protocol. Pre-dialysis urea levels decreased from 126.3 ± 35.2 mg/dL at pre-rehabilitation (month 1) to 116.8 ± 29.8 mg/dL at post-rehabilitation protocol (month 6). Post-dialysis urea levels also reduced, from 41.7 ± 17.9 mg/dL at pre-rehabilitation (month 1) to 35.0 ± 15.0 mg/dL at post-rehabilitation protocol (month 6).
For all of the exercise variables measured in the exercise group, there was an increase in fat-free mass, handgrip strength, and number of steps completed in the step test (Table 2). Regarding patient-reported outcomes, there were statistically significant improvements in general health during the program (baseline vs. post-6-month exercise program: 55.74 ± 23.1 vs. 61.0 ± 21.5, p < 0.02), physical functioning (64.6 ± 22.1 vs. 72.3 ± 23.4, p < 0.01), and social function (72.8 ± 26.0 vs. 80.6 ± 21.0, p < 0.01). However, no statistically significant change in overall health (65.9 ± 20.7 vs. 67.9 ± 18.3, p > 0.05) or cognitive function (77.2 ± 22.3 vs. 79.6 ± 22.3, p > 0.05) were observed.
Interdialytic versus intradialytic group analysis
There were no statistically significant differences between participants in the interdialytic and intradialytic demographics and comorbidities throughout the study (Table 1). No differences were observed between interdialytic and intradialytic related to arteriovenous fistula for dialysis sessions (82.9% vs. 78.2%, respectively). We excluded people who participated with less than 80% adherence, with the intradialytic group showing 86.1% ± 5.2% compliance and the interdialytic group showing 87.0% ± 4.3% compliance, with no statistically significant difference between the groups (p = 0.55). We would like to emphasize that no adverse effects or changes in exercise performance were reported in relation to the timing of the exercise.
Kt/Vurea showed no statistically significant differences between the interdialytic and intradialytic groups, in either single-pool, standard, or equilibrated metrics (Table 3). On the other hand, both groups had statistically significant changes in the fat-free mass, step test, and handgrip measurements within both interdialytic and intradialytic (Table 2).
Although there was an overall improvement in quality of life between baseline and after the 6-month program assessments, there were no statistically significant increases in cognitive function scores in either group of the interdialytic (76.9 ± 24.3 vs. 79.8 ± 22.9, p > 0.05) or the intradialytic (77.4 ± 21.2 vs. 79.5 ± 22.2, p > 0.05). Similarly, no statistically significant differences were observed in overall health scores for both the interdialytic (65.7 ± 21.6 vs. 69.5 ± 18.4, p > 0.05) and the intradialytic (66.1 ± 20.2 vs. 66.9 ± 18.3, p > 0.05). However, the interdialytic group showed statistically significant increases in physical functioning (63.3 ± 23.0 vs. 71.1 ± 23.8, p < 0.05) and social function (69.1 ± 27.6 vs. 82.7 ± 21.3; p < 0.001), while the intradialytic group had statistically significant increase in physical functioning (65.4 ± 21.7 vs. 73.3 ± 23.3, p < 0.01) and general health (53.9 ± 23.1 vs. 60.1 ± 21.0, p < 0.02), but not in social function.
Discussion
This study aimed to evaluate if exercise was effective for patients utilizing hemodiafiltration, and secondly, to compare the benefits of exercise during or between dialysis sessions. Our results indicate increased dialysis efficiency and beneficial exercise metrics based on Kt/Vurea, step test, handgrip, and quality-of-life questionnaire results. There were statistically significant improvements in dialysis efficiency and patient-reported outcomes for all exercise participants. Notably, none of the participants experienced dialysis or exercise-related adverse events. Additionally, no differences were observed in exercise benefits when comparing timing, either interdialytic or intradialytic.
For patients utilizing dialysis, improved Kt/Vurea indicates more effective dialysis [28]. Dialysis is associated with a pro-inflammatory state which can lead to cardiovascular complications and increased mortality risk [29]. Current literature shows significant exercise benefits coupled with increased dialysis efficiency, by reducing the systemic inflammatory effect associated with dialysis [30,31]. Improved dialytic efficiency has been shown to have anti-inflammatory effects in chronic kidney disease patients utilizing hemodialysis [32,33]. Low-intensity exercise increases the removal of small solutes in hemodialysis patients [12]. As seen in our study, Kt/Vurea increased statistically significantly for all patients regardless of when exercise was performed vis-à-vis the dialysis window. Our patients utilized 70% of their maximal heart rate (moderate intensity), indicating increased clearance during the dialysis session. Even though the control group had increased Kt/Vurea, the exercise participants saw comparatively greater benefits, suggesting that exercise played an important role for this patient population. Our findings of improved exercise capacity and dialysis efficiency align with previous research on the benefits of intradialytic exercise in hemodialysis patients. Reboredo et al. [34] demonstrated that an intradialytic aerobic training program significantly improved exercise tolerance and oxygen uptake kinetics in patients with end-stage renal disease.
Utilizing exercise programs during dialysis sessions has been shown to be effective and reliable based on current literature. Our study goes deeper into this point. Importantly, we found no statistically significant differences in dialytic efficiency or exercise outcomes when directly comparing the intradialytic and interdialytic exercise subgroups. While intradialytic exercise is known to increase solute clearance through enhanced blood flow to low-perfusion areas like muscle and skin, our results suggest that the timing of exercise may not be the critical factor in improving dialysis efficiency for hemodiafiltration patients. This suggests that the key factor influencing better solute clearance and physical functioning was adherence to the prescribed exercise program, not the specific timing of exercise delivery. Regular exercise training, whether intradialytic or interdialytic, can improve microvascular perfusion and oxygen delivery to exercising muscles, thereby enhancing dialysis efficiency and overall exercise capacity in chronic kidney disease patients.
Improvements were previously seen in muscle mass and beneficial to muscle metabolic control and exercise tolerance [35]. More importantly, sarcopenia has been shown to be a predictor of mortality for patients with chronic conditions [36]. It has even been shown that exercise induces changes in body mass, and increases skeletal muscle quality and other adaptations, with resistance training [37,38]. Additionally, muscle functionality is lost before muscle mass and may be due to many catabolic mechanisms, such as systemic inflammation, acidosis, protein-energy malnutrition, comorbid illnesses, corticosteroid use, and dialysis [39]. Implementing exercise has been shown to improve muscle quality, strength, and the pro-inflammatory state [38]. Handgrip strength is shown to independently predict muscle strength, sarcopenia, mortality, and frailty [40]. Importantly, we had an increase in the handgrip test and fat-free mass, indicating improved muscle strength. This may also be due to nitric oxide bioavailability. Also, the observed increase in fat-free mass and muscle strength may have contributed to improved Kt/V values, as increased muscle mass can enhance solute removal and potentially reduce the risk of intradialytic hypotension, leading to more effective dialysis sessions [41]. Increasing muscle mass and function in chronic kidney disease patients can improve their quality of life, coupled with exercise benefits.
Implementing exercise with dialysis has shown increases in health-related quality of life symptoms [42]. Previous research indicates mixed and indecisive results as to whether interdialytic exercise has benefits for chronic kidney disease patients [16,19,20]. Our patients experienced statistically significant improvement in their social function, general health, and physical functioning, indicating an overall improvement in the quality of life of those on hemodiafiltration and exercise.
Clinical implications
This study demonstrates that implementing exercise as part of rehabilitation therapy is feasible for patients on maintenance hemodiafiltration. Additionally, exercise can be performed either during or in between dialysis sessions. We observed comparable improvements in exercise-related outcomes and dialysis adequacy measures like Kt/Vurea when directly comparing the intradialytic and interdialytic exercise groups. The observed improvements in both urea clearance and Kt/V suggest that the exercise protocol may have enhanced overall dialysis efficiency, potentially through increased blood flow and improved solute removal. The absence of statistically significant differences between these two exercise modalities (interdialytic and intradialytic) strongly suggests that adhering to a supervised exercise regimen, irrespective of whether it is performed intra- or inter-dialytically, is the key determinant of positive treatment effects in hemodiafiltration patients.
We believe that some similarities in the effects of exercise prescription between conventional hemodialysis and hemodiafiltration patients could be expected; however, there are potential differences that could be anticipated. Hemodiafiltration’s superior ability to remove both small and middle-sized molecules might lead to better exercise tolerance and potentially allow for more intense or longer exercise sessions. The improved hemodynamic stability associated with hemodiafiltration could result in better exercise tolerance during intradialytic sessions. Additionally, hemodiafiltration’s effectiveness in reducing inflammation and oxidative stress might contribute to improved exercise capacity and recovery.
However, it is important to note that our study focused specifically on hemodiafiltration patients and did not include a direct comparison with conventional hemodialysis patients. Our study demonstrates the benefits of exercise in hemodiafiltration patients, but further research directly comparing exercise effects in hemodialysis versus hemodiafiltration patients would be necessary to confirm these potential differences.
Study limitations
While this study employed reliable methods, including handgrip strength as a validated measure of muscle function in chronic kidney disease and Kt/Vurea as the gold standard for assessing dialysis adequacy, there are some limitations that warrant acknowledgment. Firstly, the lack of muscle cross-sectional area measurements and blood sample analyses for inflammatory markers (such as C-reactive protein or interleukin-6), nitric oxide levels, and oxidative stress indicators precluded a more comprehensive understanding of the exercise intervention’s effects on muscle morphology and biochemical pathways influencing dialysis efficiency. These markers could have provided additional insights into the physiological mechanisms underlying the observed improvements in dialysis efficiency and physical function. Additionally, our study focused exclusively on hemodiafiltration, and future research should explore the potential benefits of exercise training across other dialysis modalities.
A limitation of our study is the lack of detailed physiological measurements such as blood flow dynamics and solute kinetics. While we observed similar benefits in dialysis efficiency and physical function for both intradialytic and interdialytic exercise, the underlying mechanisms remain unclear. Intradialytic exercise could theoretically enhance solute clearance through increased muscle blood flow and capillary recruitment during the dialysis session. Conversely, interdialytic exercise might improve overall cardiovascular function and muscle metabolism (muscle blood flow and capillary recruitment), potentially contributing to better solute clearance during subsequent dialysis sessions. However, without specific measurements, these hypotheses remain speculative. The superior solute removal capabilities of hemodiafiltration may have minimized potential differences between exercise timings. Future research incorporating blood flow measurements, detailed solute kinetics, and markers of cardiovascular adaptation would be valuable in elucidating the specific physiological mechanisms underlying the benefits of exercise in hemodiafiltration patients.
Another limitation is the absence of long-term follow-up data, as our study only evaluated participants at baseline and after 6 months of the exercise program. Longitudinal assessments over an extended period could provide valuable insights into the maintenance of the observed improvements and the potential need for exercise program modifications or progressions to maintain or enhance the therapeutic effects.
Conclusion
This study demonstrated that exercise during hemodiafiltration is effective, yielding substantial improvements in patient-reported and performance outcomes. Notably, we observed significant increases in Kt/V values in the exercise group, indicating enhanced dialysis efficiency. The absence of statistically significant differences between intradialytic or interdialytic exercise programs suggests that adhering to a supervised exercise regimen is the key determinant of positive treatment effects in hemodiafiltration patients, regardless of timing. These findings underscore the importance of incorporating exercise as an adjunctive therapy in hemodiafiltration treatment.
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