Factors Associated with Fatigue in Chronic Kidney Disease Patients Undergoing Hemodialysis: A Systematic Review Faktor yang Berhubungan dengan Kelelahan pada Pasien Gagal Ginjal Kronik yang Menjalani Hemodialisis: Sistematika Review

Fatigue is the primary complaint most frequently reported by patients on hemodialysis. The importance of knowing the factors related to fatigue is a strategy that can be carried out by health workers in optimally applying interventions to reduce patient fatigue problems. This systematic review aimed to determine the factors associated with fatigue in patients undergoing hemodialysis. The systematic review method began by identifying research articles in the Pubmed, ProQuest, Ebsco, and ScienceDirect databases in 2011–2020. Review protocol was using PRISMA. Based on the results of the analysis, it was obtained 23 articles that discussed demographic factors, physiological factors, socioeconomic factors, situational factors, and psychological factors that could be associated with fatigue in hemodialysis patients. There is much to learn about fatigue in patients undergoing hemodialysis, including causative factors, assessment of severity, and effective management of fatigue so that it can be used as a benchmark for determining appropriate interventions.


INTRODUCTION
The number of patients undergoing hemodialysis due to chronic kidney disease in 2010 increased by 2.62 million people worldwide, and it is predicted that it will double by 2030 (1). Data Report of the China Kidney Disease Network (CKNET) shows that in China the prevalence of hemodialysis increased rapidly by around 553,000 in 2015 (2). According to data from the Portuguese Nephrology Society, in 2015 there were 18,928 chronic kidney disease patients in Portugal, with 11,514 of them were enrolled in the dialysis program (3).
Although hemodialysis can help patients with kidney problems, long-term hemodialysis therapy can lead to complications and affect physical, psychological, social, spiritual, and emotional aspects that the individual cannot control (4,5). Hemodialysis patients come with various problems such as sleep disorders, neurological problems, physiological problems, poor quality of life, anxiety, depression symptoms, and fatigue (6). The results of research conducted by Ali & Taha (7) and Bossola et al (8) found that fatigue is one of the main complaints most often reported by patients with hemodialysis with a percentage of 78% to 83.8% .
The fatigue experienced by patients undergoing hemodialysis can be due to several factors. According to the theory of unpleasant symptoms put forward by Lenz et al (9), fatigue can be influenced by physiological factors, psychological factors, and situational factors. Meanwhile, according to Artom et al (10) and Jham et al (11), demographic factors and socioeconomic factors can also contribute to the development of fatigue, thus when describing the factors that can affect fatigue -they include demography, physiology, socioeconomic, situational, and psychological. These factors can also contribute to further complications of fatigue.
Further complications of fatigue in patients on hemodialysis have been associated with poor quality of life and lower survival rates due to decreased physical and psychological activity (12,13). Research by Abd El-Nasser Ali (14) and Vasilopoulou et al (15) found that hemodialysis patients who have significant problems with fatigue and depression can also affect the poor quality of life. Poor quality of life in hemodialysis patients can increase cardiovascular and suicide risks, therefore this will become a big problem if not given proper management (13,16,17).
The importance of knowing the factors associated with fatigue is one of the strategies that can be used by health professionals in understanding and optimally applying interventions to reduce patient problems. Appropriate intervention can help patients manage fatigue thus it is important for improving the quality of life of patients with dialysis (12). However, the factors associated with fatigue in hemodialysis patients are still not comprehensively discussed, so this article aimed to determine the factors associated with fatigue in patients undergoing hemodialysis.

Design
The design of this study was a systematic review that discussed the factors that cause fatigue in chronic kidney disease patients undergoing hemodialysis. The evaluation used in this study was the PRISMA checklist as a component to select the studies that have been found so that they could be adjusted to the objectives of this systematic review.

Literature Search Strategy
Study adapted to PRISMA guidelines. A data-based literature search was carried out in June 2020 and the articles selected were articles of reputable journals. Publication from 2011-2020 were include in this study. The literature has been systematically reviewed for empirical evidence regarding factors associated with fatigue in chronic kidney disease patients undergoing hemodialysis. Search using the Pubmed, ProQuest, EBSCO, and ScienceDirect databases used a combination of the keywords of chronic kidney disease, fatigue, and hemodialysis with the Boolean AND, OR, and NOT search methods to get related articles that match the objectives of the systematic review.

Inclusion and Exclusion Criteria
The determination of inclusion and exclusion criteria was adjusted based on PICOS (population, intervention, comparators, outcomes, and study design). The inclusion criteria in this systematic review were studies that focus on the population undergoing hemodialysis, studies that discuss factors associated with fatigue or interventions that can affect fatigue in chronic kidney disease patients undergoing hemodialysis, studies that explain the outcomes of factors that can influence fatigue and studies that focus on cross-sectional, randomized controlled clinical trial, prospective cohort study, dan non randomized control trial. While the exclusion criteria were studies that focus on populations other than chronic kidney disease patients, studies that had no association with causes of fatigue in patients undergoing hemodialysis, and studies that include articles review.

Data Extraction
Extraction of data and information was in the form of authors, research objectives, population selection, research design, data analysis techniques, educational content, samples, year of publication, and language used from each study so that the correct study will be extracted according to the research objectives.

Characteristics of the Studies
The results of a review of 23 articles in this study are related to factors associated with fatigue in chronic kidney disease patients undergoing hemodialysis (

Study Selection
Based on the results of literature searches through publications in four databases and using keywords, the researchers found 3575 articles that matched the keywords. Then the articles were checked for duplication and it was found 759 duplicated articles so they were excluded, and the remaining was 2816 articles. The researchers then conducted a screening based on the title and abstract of the study and obtained 82 articles that fit the objective of this study; these 82 articles were then screened in full text. The feasibility assessment of 82 articles based on the text as a whole and conformity to the eligibility criteria obtained 23 articles that can be used in this systematic review. The results of the study articles selection can be illustrated in the Flow Diagram using the PRISMA selection process below:

Demographic Factors
Based on the results of the study, it was found that demographic factors such as age that is more than 50 years, female gender, married status, lower education are associated with higher levels of fatigue in patients (18)(19)(20)(21).
Then, other factors such as black race and unemployed status have higher rates associated with the problem of fatigue (18,19). However, there is not enough evidence and research controversy remains to describe the association of these factors with fatigue in patients undergoing hemodialysis. Several studies did not find a relationship between age, gender, marital status, occupation, race, and education with the level of fatigue in h e m o d i a l ys i s p at i e nt s w i t h a p -va l u e > 0 . 0 5 (8,17,19,22,23). However, other studies found a relationship between gender, marital status, occupation, and education with the level of fatigue with a p-value <0.05 (18,21,24).

Physiological Factors
The results of the analysis showed that patients who had sleep disorders (7), HB levels of <10 mg/dl (21), an average BUN of 44.1 mg/dl (25), mean hematocrit of 35%, mean albumin of 3.9 g/dl, mean creatinine of 9.7 mg/dl, mean calcium of 9.1 mg/dl (8)

Socioeconomic Factors
In general, several studies found that low physical activity (18), smokers and ex-smokers (19), living in urban areas (23), low family income (24), and families with nuclear family structures and difficult economic status (17)

Situational Factors
In situational factors, it was found that the length of time in undergoing hemodialysis with an average of above 6 years, has comorbid diseases (8,18,26)

Psychological Factors
The psychological factors most commonly found in cases of fatigue are depression and anxiety. Moderate to severe depression levels were found to be in line with the incidence of fatigue (7,27). Meanwhile, the higher the anxiety score, the higher the symptoms of fatigue (20,24).
There is a study that found that there is no relationship between depression (p-value 0.07) and fatigue. However, other studies found there is a relationship between anxiety and depression (p-value <0.05) (20,29) with fatigue.

DISCUSSION
Demographic factors such as age that is more than 50 years, lower education, female gender, and married status are associated with have high levels of fatigue (17,24). However, there is still inconclusive and insufficient evidence because there are still differences in research findings. Regarding age, there are many convincing findings that found the increase of age will contribute to fatigue (17,18,21). This is because patients with older age experience decreased physical function, especially in the kidneys, which is a triggering factor for fatigue. Regarding gender, most studies have found no association with fatigue, this may be due to the large sample size from several studies and the unbalanced distribution between women and men so that this needs to be further proven. Varied results are found in educational status and marital status, so further exploration is needed to obtain consistent results. There was no effect of giving physical exercise in the first and second months on fatigue in hemodialysis patients There was effect of physical exercise at the third month on fatigue in hemodialysis Physiological factors associated with disturbed levels of hemoglobin, BUN, hematocrit, creatinine, IL-6, and BMI levels are associated with factors of fatigue (8,19,25). However, some research findings are still different related to factors related to fatigue. The state of anemia is related to fatigue in general due to a lack of oxygen supply that enters the cells, which is a trigger to fatigue. Individuals with chronic kidney disease have a target of maintaining hemoglobin levels of 10 to 11.5 g/dL (38). Increased levels of BUN and creatinine can affect fatigue due to accumulated body metabolic waste which can trigger a state of malaise (39). Increased IL-6 is also associated with fatigue but research by Bossola et al (40) found that there was no significant relationship between IL-6 levels and fatigue, however, in general serum IL-6 levels were proven to increase in patients with fatigue. The lack of statistical significance can be attributed to the small sample size. Meanwhile, BMI is associated with excess body weight that triggers fatigue in chronic kidney disease patients undergoing hemodialysis (39).
The socioeconomic factors most often associated with fatigue are low physical activity and a history of smoking and alcohol consumption (17,18,22,29). Most of the studies found that decreased physical activity is closely related to fatigue. Several studies found the effect of physical activity on reducing levels of fatigue in patients undergoing hemodialysis (34,36). Physical activity can be associated with increased blood flow to the muscles, increasing the number of capillaries and increasing the area and surface of the capillaries so as to reduce fatigue in patients. Then related to a history of smoking and alcohol consumption in general, there are higher numbers of patients experiencing fatigue. However, there is no strong evidence yet and there are still differences from some of the research results, thus it remains to be explored further (17,22).
In situational factors, there are several studies that reveal that the length of time in undergoing hemodialysis with more than 5 years, has comorbid diseases and complications such as cardiovascular disease and diabetes mellitus, has more frequency of hemodialysis, and has disease complications (8,18,21,24,26) have a higher incidence of fatigue in patients on hemodialysis. However, the mechanism mentioned from several studies related to situational factors with the incidence of fatigue is still unclear, so this still needs to be further proven. In general, hemodialysis patients report higher levels of fatigue when they have been on hemodialysis for a long time which is associated with intradialysis hypotension, whereas patients who have comorbid disease will add more burden and stress to the individual. Patients with stage 4 and 5 of kidney disease who suffer from hypertension and diabetes mellitus have a higher rate of fatigue than patients who do not have comorbidities (39).
The most common psychological factors found in research are depression and anxiety (20,24,33). Most of the studies found that there is a relationship between psychological factors and fatigue, although there were still differences in the results of the research which might be due to the relatively small sample factor. In general, depression and anxiety are associated with peripheral activation of immune-inflammatory pathways that can contribute to neurological inflammation and ongoing neuroprogressive changes including decreased neuroplasticity, neurogenesis, increased neurodegeneration, and reduced expression of neurotransmitters (e.g., serotonin, noradrenaline). Therefore, It has been shown that activated immune-inflammatory pathways such as interleukin-6 (IL-6) can contribute to the fatigue experienced by individuals with chronic kidney disease (27,41).
The implication that can be learned from the factors that cause fatigue in patients undergoing hemodialysis is to facilitate health practitioners to manage fatigue, especially those associated with the most dominant causative factor. Besides, health practitioners can identify the patient population undergoing hemodialysis who have the most potential to experience fatigue which can result in a decrease in quality of life and increase the risk of death to make sure that prevention can be carried out more quickly so as not to cause more complex problems.
The study's findings concluded that there were several factors contributing to fatigue, but there were still some discrepancies between the findings, which may be attributed to variations in respondent characteristics, sample size, and study design methods, necessitating further research to determine the causative factors of fatigue. There is much to learn about fatigue in patients undergoing hemodialysis, including causal factors, assessment of severity, and effective management of fatigue so it is important to study fatigue-related issues more specifically to apply to patients. Further identification of fatigue can be used as a benchmark to determine appropriate interventions that can be provided by health workers to produce fatigue management following the dominant causative factors that can be applied to patients undergoing hemodialysis.