**2. Etiology of depression in HD patients**

HD treatments alter the psychological well-being and personality of HD patients. These changes are a result of the continual stressful situations they are exposed to three times per week, as well as the many changes they must adapt to in their personal, social, and professional lives, the need to alter their lifestyle habits, their dependence on HD treatment and medical personnel, their loss of their jobs and social positions, their decreased financial situation, their dietary regimen, their sexual dysfunction, their access to dialysis-related issues, and their anxiety about mortality [14].

Dysphoria (depressed mood) and anhedonia (limited capacity for enjoyment) are characteristics of depression. It has a significant influence on people's social lives, including how interpersonal relationships are affected and how social roles are formed, as well as how neurocognitive abilities are affected. One of the primary emotional problems for which individuals seek treatment is depression. Additionally, depression is the primary cause of suicide fatalities [15].

Depression caused by dialysis has a complex etiology that is influenced by medical, psychological, and social processes. Increased cytokine levels and potential genetic susceptibility are two biological explanations. The loss of a job, sentiments of loss and lack of control, and disrupted family and social connections are examples of psychological and social variables. Fatigue is another factor that contributes to depression in HD patients. Fatigue is a subjective sensation that is defined by weakness, exhaustion, and lack of energy. On HD, between 60% and 97% of patients report feeling tired occasionally, and this has a detrimental effect on quality of life [16].

According to research on the behavioral causes of depression, increasing ESRDrelated self-care demands, such as frequent doctor and hospital visits, dietary restrictions, more medication, and at-home monitoring of blood sugar, blood pressure, and weight, might cause despair. Patients with ESRD have been shown to isolate themselves from friends and family and experience financial hardships, both of which have been linked to depression. These patients typically encounter physical symptoms that are connected to uremia, dialysis, and medicines, and these symptoms have been linked to depression. It's still not known if these symptoms lead to depression or if sadness leads to somatic symptoms. Depression may increase the likelihood that people would engage in unhealthy risk-taking behaviors including smoking, staying inactive, and gaining weight [17].

A bidirectional relationship between inflammation and depression in chronic disease was substantiated by the biological mechanisms of depression. This connection is especially important for ESRD patients with high inflammatory markers. Depression has been linked to an increase in inflammation, which can hasten atherosclerosis and result in cardiovascular problems. Depression is also linked to changes in serotonin levels and autonomic nervous system activity, as well as an increase in platelet aggregation and changes in cortisol and norepinephrine production, all of which can result in stroke and cardiovascular events. The brain's ability to regulate mood may

### *Effect of Intra-Dialytic Physical Exercise on Depression in Hemodialysis Patients DOI: http://dx.doi.org/10.5772/intechopen.113360*

be directly impacted by cerebral vascular disease. For instance, certain post-stroke lesions in the frontal lobe, left anterior, and left basal ganglia have been linked to depression. By causing more inflammation, cerebral vascular disease may potentially indirectly alter mood. Depression has been linked to medication noncompliance, poor food choices, and missed dialysis in ESRD patients (**Figure 4**) [17].

In individuals with depression, several studies have discovered large increases in the levels of the pro-inflammatory cytokines IL-6 and tumor necrosis factor alpha (TNF-α) in the blood. Patients who received repeated injections of recombinant cytokines for the treatment of cancer, viral infections, or autoimmune illnesses showed depressive behaviors and mood changes, such as melancholy, depressed mood, and suicide thoughts. As a result, there seems to be a two-way interaction between depression and inflammation. In other words, both the inflammatory response and the onset of depressed symptoms have the potential to trigger inflammation [19].

**Figure 4.** *A conceptual model of the bio-psychosocial links in ESRD [18].*

According to the inflammatory theory of depression, cytokine production is dysregulated and immunological responses are too active. TNF-α, IL-1β, and IL-10 levels were all considerably greater in depressed patients, but IL-8 levels were significantly lower. The abnormal expression of inflammatory cytokines in depressed individuals implies that inflammation is triggered by depression. The pathophysiology of depression may be influenced by immunological disorders. Chronic stress has been linked to hypothalamic-pituitary-adrenal (HPA) axis dysfunction, which reduces serotonin synthesis [20].

The forms of vascular access were related to ESRD patients' survival after HD. Due to its decreased mortality and hospitalization rate, arteriovenous fistula (AVF), arteriovenous graft (AVG), and central venous catheter (CVC) are the most desired and suggested vascular access types. The use of CVC was linked to an increased risk of infection, which eventually led to a higher fatality rate. Despite this mounting evidence, CVC is still the method of choice for starting dialysis for more than half of incident HD patients. One of the modifiable variables for depression and health-related quality of life in dialysis patients appears to be the kind of vascular access [21].

In HD patients, uremic pruritus (UP) is a frequent and unsettling issue. Predialysis UP incidence ranges from 15% to 49%, whereas treatment-related UP incidence ranges from 50% to 90%. UP is assumed to have several factors, despite the fact that its pathogenesis is poorly understood. Recent theories contend that UP is caused by modifications to the immune and opioid systems. Increased blood urea nitrogen (BUN), calcium, phosphorus, and 2-microglobulin are risk factors for UP. Additional contributing variables include high ferritin levels, erythropoietin insufficiency, anemia, low transferrin, albumin levels, secondary hyperparathyroidism, elevated calcium, phosphate and magnesium levels, and an increase in chemicals produced by mast cells as histamine. The quality of life, sleep, emotional state, and social interactions of patients are all negatively impacted by UP [22].

Abnormal brain activity in numerous areas, including the prefrontal cortex, is associated with depression. Reduced prefrontal brain activity inhibits the ability to manage unpleasant emotions, which worsens the condition of one's mood [23]. The activity of the amygdala is also elevated during depression [24].

Depression is linked to high cortisol levels that increased during times of stress [25]. Depression is caused by cortisol, which makes the amygdala more active and the prefrontal cortex less active. According to cognitive theories of depression, depressive symptoms are brought on by unfavorable ideas, interpretations, self-evaluations, and expectancies [26].

Cognitive susceptibility and stressful life circumstances can also promote depression [27]. It has long been assumed that a stressful existence might lead to depression, and various studies have confirmed this [28]. Hopelessness theory is another cognitive theory of depression that proposes that a specific type of negative thinking leads to a sense of despair, which ultimately leads to depression [29].

Depression has the potential to negatively impact the medical outcome of ESRD patients through a variety of ways. In dialysis patients, depressive symptoms were linked to poor adherence. Depression has also been linked to changes in immune system function, notably lower cellular immunity and higher cytokine levels. Furthermore, depression has been associated to poor nutritional status and has been demonstrated to precede a decrease in blood albumin levels in ESRD patients (**Figure 5**) [30].

*Effect of Intra-Dialytic Physical Exercise on Depression in Hemodialysis Patients DOI: http://dx.doi.org/10.5772/intechopen.113360*

 **Figure 5.**

 *The impact of depression on medical outcomes [ 30 ].* 

## **3. Epidemiology of depression in HD patients**

 Depression is more common among HD patients, with estimated rates ranging from 23% to 42% in the United States and Europe, and 45.9% in Taiwan. Furthermore, clinical depression and subthreshold depressed symptoms are closely linked to poor treatment adherence, increased mortality, and hospitalization rates [ 31 ].

 ESRD is associated with high rates of both anxiety and depression, with 38% of kidney disease patients reporting anxiety and 27% reporting depression. Since these mood disorders are strongly associated with poor health-related quality of life and adverse outcomes including hospitalization, cardiovascular events, stopping dialysis, and death, it is crucial to detect patients with anxiety and/or depression in the setting of ESRD [ 32 ].

### **4. Depression diagnosis in HD patients**

 Due to the overlapping medical symptoms of uremia and depression, such as weariness, loss of appetite, disturbed sleep, and other symptoms, evaluating depression in ESRD patients can be challenging. These symptoms may also be influenced by other medical comorbidities, including as sleep apnea and vascular issues, which are common in ESRD [ 5 ].

 Screening for depression in people with ESRD is critical. Several studies have been conducted to validate the more commonly used depression screening methods in chronic renal disease patients. The Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Nine-Question Patient Health Questionnaire, and the

Center for Epidemiologic Studies Depression Scale are a few of the tests used to check for depression in patients with ESRD [30].

With a self-reported questionnaire, patients with uremic symptoms may test positive for depression. During a clinical interview, these uremic symptoms can be separated from depressed symptoms. As a result, the clinical interview remains the gold standard for detecting depression in ESRD patients [17].

For more than 40 years, the Hamilton depression scale has been the gold standard for assessing depression. It was created in the late 1950s to evaluate the efficacy of the first generation of antidepressants, and it was first published in 1960. The HDRS is the most often used clinician-administered depression scale. The original version has 17 items (HDRS17) referring to depressive symptoms encountered in the previous week. The rating is clinical, and the administration time is 20–30 minutes. The primary goal is to determine the intensity and change of depression symptoms. A score of 0–7 on the HDRS17 is considered normal (or in clinical remission), but a score of 20 or more (showing at least severe severity) is usually necessary for inclusion into a clinical trial [33].

### **5. Depression treatment in HD patients**

Several research have recently examined the impact of antidepressants on cytokine levels and functions. Antidepressants appear to normalize blood levels of key inflammatory cytokines such as IL1 and IL6, as well as TNF. Antidepressants have been shown in certain clinical investigations to reduce the impact of proinflammatory cytokines by boosting the production of antiinflammatory cytokines. Antidepressants may have immune-modulatory effects by decreasing proinflammatory cytokines and increasing antiinflammatory cytokines [19].

Although evidence demonstrate that antidepressants are helpful and safe, side effects such as sleepiness, diarrhea, nausea, vomiting, ejaculatory dysfunctions, sleeplessness, and headache limited their use. As a result, it is critical to investigate non-pharmaceutical therapies. AE has been shown to be useful in the treatment of depression sufferers and has no negative side effects [34].

Physical exercise improves physical functionality, psychological status, and quality of life in ESRD patients, according to studies that have used it as part of their therapy regimen. Physical activity has been shown to significantly improve ESRD patients' levels of depression, quality of life, physical and mental health [35].

Many recent studies have emphasized the need of nonmedical therapies to address depression in HD patients rather than pharmacological therapy; some of these strategies include psychological, behavioral, modified regimens, supporting efforts by families, hypnotism, muscle relaxation, and meditation. Exercise and physical exercise are indicated as non-pharmacological treatments to treat or assist cure serious depression [36].

### **6. Physical exercise in HD patients**

The participation of physical therapy professionals (physiotherapists and exercise physiologists) improved the efficacy and safety of individually recommended exercise regimens. The engagement of exercise professionals considerably contributes to increasing the "exercise culture" in HD units, which is the only way to build a sustainable excellent practice [37].

#### *Effect of Intra-Dialytic Physical Exercise on Depression in Hemodialysis Patients DOI: http://dx.doi.org/10.5772/intechopen.113360*

A nephrologist, a sports medicine doctor, a physiotherapist, nurses, an exercise physiologist, and even a renal nutritionist may establish an exercise dialysis team as a first step. For dialysis patients to successfully implement physical exercise, the following elements may be suggested:


A team of experts and professionals, including a cardiologist, physiotherapist, exercise physiologist, renal dietitian, and nurse, should be led by a nephrologist. Building an effective exercise team, establishing an exercise culture, and raising physical activity levels all contribute to more comprehensive and current clinical care treatment of ESRD patients [37].

The workout consists of the following phases: (a) Warm-up phase: 5 minutes of low-intensity cycling at a slow tempo. (b) Active phase: The patient cycled for 20–25 minutes at the speed obtained during the warm-up phase, after which the speed was increased in increments of nearly one cycle per second until the participant reached an intensity of stress with a fatigue score of 11–13 points, which corresponds to an exercise of (mild) intensity to (quite hard) on the Borg scale. (c) Cool down phase: Following the speed reduction to low speed, a 5-minute cooling down time followed, much like in the warming up phase. This type of training has the advantage that the quick burst of intense activity causes peripheral adaptations in the leg muscles without risking an overload in central mediation. In order to calculate an effort score between 11 and 13, or what would be considered (moderate) to (very hard) exercise on this scale, the bicycle load was maintained [38].

Patients with ESRD are constantly under oxidative stress due to an imbalance between reactive oxygen generation and inadequate endogenous antioxidant defense systems. As a result, oxidative stress encourages the activation of factors that trigger inflammatory processes in these individuals, resulting in a vicious cycle of oxidative stress and inflammation. This process is linked to an increased risk of developing cardiovascular disease (CVD). Physical workouts have been shown in recent research to lower oxidative stress indicators and boost the antioxidant defense system in HD patients; they may help diminish the inflammatory process in these individuals [39].

IDE has been shown to benefit HD patients. As they deal with the issues associated with ESRD, these people need to be less treated as "patients" and encouraged to take

a more active role in their health. Obstacles must be overcome by medical and health professionals in order to encourage continued improvements in their patients' health and fitness. IDE programming that is well-planned and supervised can be both safe and efficient, with significant potential for enhanced quality of life [12].

Increasing physical activity should be a goal of clinical care management, however there are barriers that prevent physical exercise programs from being widely used in dialysis units. A HD exercise program may be maintained if three important characteristics are present: (a) participation of exercise specialists; (b) genuine commitment of nephrologists and dialysis professionals; and (c) unique patient customization of the exercise program [37].

Exercise training should be medically monitored and guided by an experienced exercise therapist (or physiotherapist) in HD patients. Physical examination, monitoring of heart rate, blood pressure, and rhythm before, during, and after exercise training should all be part of the supervision. A rigorous supervision allows for the verification of individual responses and tolerability, clinical stability, and the rapid identification of signs and symptoms suggesting the need for program adjustment or discontinuation [40].

However, there may be several exercise-related adverse effects such as fatigue, hypotensive episodes, musculoskeletal complications, and rare cardiovascular complications. The dialyzer experiences a significant flow of uremic toxins from the tissue to the vascular compartment during IDE. It results in increased capillary surface area and improved muscle blood flow. The IDE also showed increased compliance and lower drop-out rates in addition to enhanced adoption and adherence [41].

Exercise regimens must be adapted to each patient's physical capabilities and comorbidities. This is the primary method for implementing physical exercise in ESRD patients in a proper and safe manner. Dialysis nurses play an important role in encouraging and assisting patients during intravenous dialysis. This emphasizes the need of incorporating exercise specialists in a dialysis exercise team. To sum up, before suggesting an exercise program, either extra-dialysis or intra-dialysis, or both, a thorough evaluation of general condition, comorbidities, notably cardiovascular, nutritional state, and physical activity ability is essential. A multidisciplinary team of specialists and professionals, including a cardiologist, physiotherapist, exercise physiologists, renal dieticians, and nurses, should be led by nephrologists (**Figure 6**) [37].

**Figure 6.** *The ideal exercise team [37].*
