Comparisons of fatigue between dialysis modalities: A cross-sectional study.

BACKGROUND
Fatigue is one of the most frequent complications in dialyzed patients and is associated with poorer patient outcomes. Multiple factors are reported to be associated with fatigue development. Of them, the impacts of dialysis modalities remain unknown.


METHODS
A total of 194 dialysis patients (mean age, 61±11 years; 134 males; modalities included hemodialysis (HD) in 26, online hemodiafiltration (HDF) in 74, peritoneal dialysis (PD) in 68, and combined therapy with PD and HD in 26 cases) were recruited for this cross-sectional study. Fatigue was assessed using the Profile of Mood States (POMS), a Visual Analogue Scale (VAS), and our original scale of fatigue, and depression was assessed by the Beck Depression Inventory-second edition (BDI-II). Our original scale of fatigue was administered both on dialysis and dialysis-free days to patients on HD and online HDF.


RESULTS
The scores of the POMS, VAS, and our original scale were weakly but significantly inter-related (rho = 0.58, P<0.01; rho = 0.47, P<0.01, and rho = 0.42, P<0.01 between POMS and VAS, POMS and our original scale for fatigue, and VAS and our original scale for fatigue, respectively). The scores of these 3 tests showed no significant differences among the 4 modalities. On multivariate analysis, age, body mass index, creatinine, and employment status were associated with the presence or severity of fatigue, whereas dialysis modality was not. A similar result was obtained in 122 patients without depression. The prevalence of fatigue by our original scale was significantly lower on dialysis-free days than on dialysis days in patients on HD and online HDF.


CONCLUSIONS
The results suggest that there is no significant association between different dialysis modalities including HD, online HDF, PD and combined therapy with PD and HD and the prevalence or severity of fatigue.


Introduction
Fatigue is one of the most frequent complications in patients receiving renal replacement therapy, and its prevalence has been reported to range from 42% to 89%, depending on patients' characteristics and assessment tools [1]. Notably, the presence of fatigue was associated with higher mortality in dialyzed patients [2][3][4]. Several factors, including physiological, psychological or behavioral, sociodemographic, and dialysis-related factors are associated with the development of fatigue [5]. Among them, physiological factors such as anemia, inflammation, malnutrition, uremia, and comorbidities are thought to be important because they are all modifiable. Depression, the most important psychological factor, is strongly associated with fatigue [6,7] and is also associated with worse outcomes in patients on dialysis [8][9][10]. There have been several therapeutic strategies including both pharmacological and non-pharmacological approaches [1,5].
Hemodialysis (HD) per se could induce fatigue through several factors such as bio-incompatibility of the dialyzer and dialysis apparatus which could induce production of pro-inflammatory cytokines or acute reduction of body fluid along with a decrease in blood pressure, whereas peritoneal dialysis (PD) per se could induced fatigue through dwelling of a bio-incompatible PD solution, chronic overhydration status, or a physiological burden [1,5]. However, there have been only limited studies comparing the severity of fatigue between HD and PD patients [2,11,12]. Additionally, studies assessing the fatigue of patients receiving hemodiafiltration (HDF) have been very sparse [13].
The aim of this cross-sectional study was to compare the prevalence and severity of fatigue among patients receiving different dialysis modalities, including HD, online HDF, PD, and combined therapy with PD and HD. Furthermore, the state of depression was assessed in order to exclude possible psychological factors related to fatigue in these patients.

Assessments of fatigue and depression
The patients' fatigue was evaluated using the Profile of Mood States (POMS), a Visual Analogue Scale (VAS), and our original scale of fatigue, whereas depression was assessed using the Beck Depression Inventory-second edition (BDI-II). All questionnaires were written format. The POMS scale is a questionnaire measuring six mood states: tension-anxiety (tension), depression-dejection (depression), anger-hostility (anger), fatigue-inertia (fatigue), vigoractivity (vigor), and confusion-bewilderment (confusion) on a five-point scale from 0 (not at all) to 4 (extreme); the fatigue subscale was used for the analysis. The VAS is a unidimensional scale in which a 100-mm line is anchored at either end by 'no tiredness at all' at the left end and 'complete exhaustion' at the other. The intensity of fatigue is measured in millimeters from the low (left) end of the scale. Our original scale of fatigue is a five-grade evaluation including Grade 1 (inexhaustible, feels well, and extremely active), Grade 2 (tireless, acts in the ordinary way without a sense of fatigue), Grade 3 (mild fatigue, acts in the ordinary way but feels tired), Grade 4 (moderate fatigue, feels tired with light work), and Grade 5 (intense fatigue, very tired, and falls asleep). Grades 3, 4 and 5 are regarded as fatigued states. We have already used this scale for the assessment of fatigue in two previous studies [14,15]. Although the effectiveness of this scale has not yet been validated, we used this scale because of its usability and lower cost than other scales. Our original scale of fatigue was administered both on dialysis and dialysis-free days to patients on HD and online HDF.
The BDI-II is a 21-item, self-reported inventory designed to assess the presence and severity of depressive symptoms. Each item is rated on a 4-point scale ranging from 0 to 3, and the total score ranges from 0 to 63. A cutoff score of 14 indicates at least a mild-to-moderate level of depression [16,17]. For all scales, higher scores indicate an increased level of fatigue or depression. Patients receiving PD or combined therapy with PD and HD answered all selfreported questionnaires at regular outpatient visits. Patients receiving HD or online HDF answered all self-reported questionnaires shortly after dialysis sessions.

Statistical analyses
Data are presented as means ± standard deviation (SD) or medians and interquartile range (IQR), as appropriate. A p-value of less than 0.05 was considered significant. Differences among the four groups of renal dialysis were analyzed using one-way analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis test, as appropriate. Differences were considered significant when the F-value was less than 0.05. The associations between each clinical parameter were calculated using Spearman's correlation coefficient (rho). Independent factors affecting fatigue were assessed using a logistic regression model. In these analyses, the objective variables were dichotomous variables, including POMS score � 10, VAS score � 48, and our original scale of fatigue score � 3. The changes in our original scale of fatigue between dialysis and dialysis-free day were evaluated using a paired t-test. The cut-off values of the POMS and VAS scores were based on receiver operating characteristic analysis, in which fatigue was defined as our original scale of fatigue score � 3. On multivariate analysis, several confounding factors reported to be associated with fatigue in dialyzed patients, including age, sex, dialysis duration, state of employment, the presence of cardiovascular disease and diabetes, body mass index (BMI), hemoglobin (Hb), and serum albumin, were included. Additionally, confounding factor that had shown an appreciable association (P<0.1) with a measure of fatigue were also included in the multivariate analysis. Of them, dialysis duration was markedly skewed and was therefore log-transformed to normalize its distribution. Additionally, independent factors affecting fatigue were assessed using a multiple regression model with the same confounding factors. In these analyses, POMS, VAS, and our original scale of fatigue were treated as continuous variables, and the POMS score was log-transformed to normalize its distribution. Sensitivity analyses including 122 patients without depression (BDI-II score < 14) were performed. Data were statistically analyzed using STATA version 16.0 (STATA Corporation, College Station, TX, USA). Table 1 shows the patients' demographic and biochemical characteristics. The age of the patients was 61 ± 11 years, and males predominated (69.1%). Diabetic patients accounted for 27.3%. Age, sex, prevalence of diabetes, and BMI were not significantly different among the four groups. The duration of dialysis was longer in the HD and online HDF groups (129 (42-259), 153 (96-228), 25 , and 58 (35-74) months for HD, online HDF, PD, and combined therapy, respectively). Hb was higher in patients receiving combined therapy. Serum creatinine was higher in patients receiving online HDF and combined therapy. Urea nitrogen was higher in patients receiving online HDF. Serum albumin was lower in patients receiving PD and combined therapy. CRP and β2 microglobulin levels showed no significant differences among the four groups. All participants read and responded to the questionnaires themselves. According to the results of the self-reported questionnaire, 104 (53.9%) patients were employed. The percentage of employment was not significantly different among the four groups. Of the 104 patients at work, 92 (88.5%) patients felt that the fatigue affected their work to mild (n = 48, 47.1%), moderate (n = 28, 26.9%), and severe (n = 16, 15.4%) degrees, whereas 10 (9.6%) patients felt that the fatigue did not affect their work. Of the 90 unemployed patients, 75 (83.3%) patients felt that the fatigue affected their daily life to mild (n = 28, 31.1%), moderate (n = 32, 35.6%), and severe (n = 15, 16.7%) degrees, whereas 10 (11.1%) patients felt that the fatigue did not affect their daily life. However, 22 (24.4%) patients wished to work.

Results
The scores of the three assessments for fatigue including POMS, VAS, and our original scale of fatigue were significantly inter-related (rho = 0.58, P<0.01; rho = 0.47, P<0.01, and rho = 0.42, P<0.01 between POMS and VAS, POMS and our original scale for fatigue, and VAS and our original scale for fatigue, respectively). The scores on the POMS and VAS were not significantly different among the four groups, whereas those of our original scale of fatigue were higher in patients receiving combined therapy with PD and HD ( Table 1, Fig 1). In the analysis using our original scale of fatigue, the prevalence of fatigue, defined as Grades 3, 4 and 5, was significantly lower on dialysis-free days than on dialysis days in patients on HD and online HDF (50.0% vs. 84.6%; P<0.01 and 32.4% vs. 66.2%; P<0.01 for patients on HD and online HDF, respectively). Similarly, the severity of fatigue, indicated by the scores of this scale, was significantly lower on dialysis-free days than on dialysis days (2.6±0.8 vs. 3.3±0.9; P<0.01 and 2.3±0.7 vs. 2.9±1.1; P<0.01 for patients on HD and online HDF, respectively). Table 2 shows multiple logistic regression models for the results of the three tests, and the modality of dialysis did not affect the presence of fatigue. Instead, employed patients had a significantly lower risk of the presence of fatigue on the VAS and our original scale of fatigue. In addition, BMI, age and the use of erythropoiesis-stimulating agents were associated with the presence of fatigue on the POMS, VAS score and our original scale for fatigue, respectively. The results of the multiple regression model, with analysis using the findings of the three tests as continuous variables, were very similar ( Table 3). The modality of dialysis did not affect the severity of fatigue. Instead, employed patients had a significantly lower severity of fatigue on the VAS and our original scale of fatigue. BMI was associated with the severity of fatigue on the POMS score, whereas serum creatinine was associated with the severity of fatigue on the POMS and VAS scores.
Sensitivity analyses including 122 patients without depression (BDI-II score < 14) were performed. The results of the logistic regression models ( Table 4) and those of the multiple regression models (Table 5) were very similar.

Discussion
In this cross-sectional study, the prevalence and the severity of fatigue were not significantly different among patients receiving different dialysis modalities (HD, online HDF, PD, and combined therapy with PD and HD). There was a particular focus on the effect of the presence of depression in the present study because fatigue and depression are closely interrelated, and depression may manifest as feelings of tiredness and lack of energy [1,5]. The fatigue profile  was examined in 122 patients without depression in a sensitivity analysis, and the prevalence and the severity of fatigue were not significantly different among patients receiving different dialysis modalities. Additionally, the prevalence of fatigue by our original scale was significantly lower on dialysis-free days than on dialysis days in patients on HD and online HDF.
There have been several studies comparing the severity of fatigue between HD and PD patients. Zazzeroni et al. [11] conducted a systematic review and meta-analysis including 7 studies and 1857 dialyzed patients, of whom 1165 were undergoing HD and 692 were undergoing PD, and they found that the scores of the energy/fatigue subscales were not different between the two groups. Jhamb et al. [2] reported that the SF-36 vitality scales at baseline and 1-year after dialysis initiation were not significantly different between incident HD and PD patients. In the present study, there were no significant differences in the fatigue scales between HD and PD, and the results were consistent with those prior reports.
To the best of our knowledge, this was the first study to examine fatigue in patients receiving online HDF or combined therapy with PD and HD. Online HDF, where replacement fluid is prepared by further purifying dialysate fluid instead of manufacturer-provided solutions, has made HDF more practical and more cost-effective, and high-volume online HDF could potentially improve symptoms, reduce morbidity, and may even improve survival [18]. The number of patients treated with online HDF has been increasing after the 2012 revision to the medical reimbursement system, and it has reached 70000, approximately 30% of all dialysis patients at the end of 2017 in Japan [19]. Suwabe et al. [13] conducted a systematic review and meta-analysis to compare QOL between patients receiving online HDF and HD and concluded that online HDF was associated with a non-significant decrease in the fatigue score compared to HD. Of note, online HDF with post dilution was performed in all of the studies, whereas more than 95% of patients used predilution online HDF in Japan because of the lower blood flow rate and lower serum albumin levels [19]. Because the predilution method is considered advantageous due to the availability of a large volume of substitution solution and lower albumin leakage than the post-dilution method, it could have a good effect on the prevention of fatigue. Although a PD first policy is recommended in order to maximize the advantages of PD therapy including excellent comparable survival, lower cost and improved QOL [20,21], its long-term continuation is difficult because of a decrease in residual renal function and deterioration of the peritoneal membrane. Combined therapy with PD and HD was introduced in Japan in the 1990s and became popular as the preferred dialysis modality of Japan. The combined therapy, generally in the form of 5-6 days of PD and one HD session per week, is the treatment option for PD patients with inadequate dialysis and/or fluid overload instead of a complete shift to HD alone, and approximately 1900 patients (20% of all patients on PD) are receiving this therapy in Japan [22,23]. This unique modality is expected to reduce fatigue compared to direct transfer to HD because of a decrease in the number of HD sessions.
However, in the current study, there was no significant difference in the fatigue scales between patients receiving online HDF and combined therapy with PD and HD. While dialysis modalities were not associated with fatigue in dialysis patients in the present study, several influential factors were identified by multivariate analysis, such as age, BMI, creatinine, and employment status. The present findings were consistent with a prior report that showed employment status to be strongly associated with fatigue and depression in HD patients [24][25][26]. In the present study, more than 80% of patients felt that the fatigue affected their work or daily life, including those who were unemployed, but wished to work. Thus, it is possible that fatigue may have a negative impact patients' will to work. Interestingly, the prevalence of fatigue, defined as Grades 3, 4 and 5 in our original scale of fatigue, and the severity of fatigue, indicated by the scores of this scale, were significantly lower on dialysis-free days than on dialysis days in patients on HD and online HDF. Thus, these daily fluctuations in fatigue in relation to HD and online HDF session warrant further investigations. The POMS, VAS, and our original scale of fatigue were used to evaluate fatigue in the present study. Although the 36-item Short-Form general health survey (SF-36), especially its vitality scale is frequently used in this area [2,3], the POMS was used instead for two reasons. First, it includes the fatigue scale. Second, it is widely used in clinical practice and covered by the public medical insurance system in Japan. The scales of fatigue might differ by several sociodemographic factors such as age, sex, and race. The median scores of the fatigue subscale of the POMS scores in a Polish study including 115 dialysis patients were around 5 to 11, lower than in the present study [27], whereas this score at baseline of a randomized, controlled trial including 15 HD patients in the U.S.A. was similar to the present study [28]. The associations between the scores of these three scales were significant but weak. Additionally, the effects of several confounding factors, such as age, BMI, employment status and serum creatinine, on the presence or severity of fatigue differed depending on the scales. These discrepancies indicate the fact that different measures could yield different results. However, the presence or the severity of fatigue assessed using all scales did not differ significantly among patients receiving different dialysis modalities.
There were some limitations in this study. First, the cross-sectional, observational nature of the study allowed the identification of associations, but not causal relationships between fatigue and clinical variables, including dialysis modality. Additionally, the effect of residual confounding factors including adequacy or frequency of dialysis and residual renal function, could not assessed. Second, assessment of inflammation, an important factor related to fatigue, was difficult, because of missing values and lower levels, including below the detectable level, of CRP. Third, selection bias, especially physicians' preference, for choice of dialysis modalities was considerable, because this study was not a randomized, controlled study, but an observational study. Fourth, although the results of our original scale of fatigue were significantly associated with those of the POMS and VAS, convergent and discriminant validity, test-retest reliability, or social desirability could not be clarified using this study design. Fifth, the details of the screening process at each center were not known. Further selection bias may have been introduced by recruiting predominantly patients who were able to read and respond to the questionnaires themselves, thereby compromising the generalizability of the study. Sixth, since patients receiving combined therapy with PD and HD answered all self-reported questionnaires not on the HD session days but at regular outpatient visits, the impact of HD on the questionnaire scores was unclear, because the timing of assessment related to HD sessions differed among patients in this group. Seventh, sample size was small, which may be the reason for not detecting a statistically significant difference in fatigue levels across modalities.

Conclusions
The results indicated that the type of dialysis modality, including HD, online HDF, PD and combined therapy with PD and HD did not appear to be associated with the prevalence or severity of fatigue of patients on dialysis. In patients undergoing HD or online HDF, fatigue levels were significantly lower on dialysis-free days. Further research to explore the differences in pathophysiology of fatigue between dialysis modalities may be warranted.
Supporting information S1 Data. Original data set. (ZIP)