Pain is one of the most common symptoms among patients with End Stage Renal Disease (ESRD), and often goes unrecognized or inadequately managed in hemodialysis patients. More than 50% of patients undergoing hemodialysis suffer from pain, with 75% of them being treated ineffectively due to healthcare professionals' lack of awareness of this symptom. Therefore, pain management in this population is a complex and challenging task for healthcare providers. The most prevalent pain syndromes in hemodialysis patients include musculoskeletal disorders, metabolic neuropathies, in addition to typical intradialytic pain.

The aim of this study is to assess the presence and characteristics of chronic pain in patients with ESRD undergoing hemodialysis to determine whether it is relevant to include the management of chronic pain in the holistic treatment (physical activity, nutrition, and psychological support) already being implemented in various studies for these patients.

Chronic Kidney Disease (CKD) has an estimated prevalence ranging from 13.4% to 10.6% across stages 1 to 5. These data indicate that CKD is recognized as a major global health issue, with high healthcare costs. Its incidence increases with age, with individuals over 65 years old comprising 40% of CKD patients. Gender differences exist, with males being more affected, although females exhibit greater frailty and severity. This population often presents high comorbidity with other conditions such as diabetes, hypertension, and cardiovascular diseases, along with malnutrition, sedentary lifestyles, poor health-related quality of life, low functional capacity, frailty, high levels of dependency, and, recently evidenced, pain. All of these factors are associated with increased mortality risk, exceeding 15% annually. Cardiovascular disease is the leading cause of death in patients with advanced CKD and a significant risk factor for peripheral arterial disease and lower limb amputation.

Chronic pain imposes a significant personal and economic burden, affecting over 30% of people worldwide. Unlike acute pain, which serves a protective function, chronic pain may be better considered as a disease itself, with both physical and psychological implications. There has been a growing acceptance of the biopsychosocial model in addressing patients with chronic pain, understanding pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage," according to the International Association for the Study of Pain (IASP). This perspective considers pain not only as a purely nociceptive experience but also as a personal experience involving both biological and emotional/psychological components.

Pain is one of the most common symptoms among patients with end-stage CKD, often going unrecognized or inadequately managed. Barriers to proper pain management include limited awareness of the problem, inadequate medical education, and common misconceptions about the inevitability of pain in older adults and HD patients. More than 50% of hemodialysis patients suffer from pain, with 75% of them receiving ineffective treatment due to healthcare professionals' lack of awareness of this symptom. Therefore, pain management in this population is a complex and challenging task. The most prevalent pain syndromes in hemodialysis patients include musculoskeletal disorders, metabolic neuropathies, and typical intradialytic puncture pain.

Patients with chronic pain from musculoskeletal disorders have been shown to exhibit high levels of catastrophizing, fear of movement, anxiety, depression, sleep disturbances, and elevated salivary cortisol levels due to the stress caused by chronic pain and the prevalence of musculoskeletal disorders as potential causes of pain in CKD patients.

Hormonal alterations at the hypothalamic-pituitary axis (HPA) level are frequently observed with worsening renal function. Traditionally, these alterations have been understood as a consequence of renal insufficiency. However, recent evidence suggests the involvement of such hormonal disorders in the genesis of CKD. The HPA axis controls stress responses through a negative feedback mechanism. If chronic pain is considered a stressor, a reciprocal response is triggered, with increased pain activating physiological mechanisms responding to stress, such as elevated cortisol, thereby increasing perceived pain. Chronic pain induces a chronic increase in cortisol and other central mediators of the HPA axis. Cortisol is one of the physiological indices used to quantify stress, with salivary cortisol levels reflecting HPA axis activity and quantifiable non-invasively through saliva samples using ELISA methods. Currently, physiological stress assessment is easily performed by measuring cortisol levels in saliva samples.

There is a gap in the literature regarding this topic as it has not been studied whether patients with advanced-stage CKD undergoing hemodialysis present the same characteristics of chronic pain as other pathologies, such as musculoskeletal disorders.

Methodology Study Type: A cross-sectional observational study will be conducted. Since no previous studies exist, a study with n: 20 will be conducted, and based on this data, the sample size calculation will be performed. Randomization and blinding will not be performed, and no intervention is planned.

Variables

The following measurement variables will be used in this study:

Biomarkers:

• Salivary Cortisol: Physiological stress assessment will be performed simply by measuring cortisol levels in a saliva sample and subsequently analyzed using the ELISA method.

The following questionnaires will be used to measure health condition variables:

• Sleep Quality: The validated Spanish version of the Pittsburgh Sleep Quality Index will be used.
• Stress: The validated Spanish version of the Perceived Stress Questionnaire will be used.
• Disease Self-Management: The self-efficacy questionnaire will be used.

The following questionnaire and physical variable measurement will be used to measure variables related to chronic pain:

• Chronic Pain Severity Scale: The validated Spanish version of the Chronic Pain Severity Scale will be used.
• Pressure Pain Thresholds (PPT): This variable is used to assess if the patient presents symptoms compatible with central sensitization. Pressure will be applied with an algometer at two bilateral points, the second rib and knee. Each measured subject will be instructed to say 'stop' when the pressure sensation becomes the first sensation of pain. Each measurement will be repeated three times with 10 seconds of rest between them.

The following questionnaire will be used to measure headache-related variables:

• HIT-6: The validated Spanish version of the Headache Impact Test-6 questionnaire will be used.

The following questionnaires will be used to measure behavioral variables:

• Catastrophizing: The validated Spanish version of the Pain Catastrophizing Scale will be used.
• Anxiety and Depression: The validated Spanish version of the Hospital Anxiety and Depression Scale (HADS) will be used.

Inclusion Criteria:

• Patients with End-Stage Renal Disease (ESRD)
• Have been on hemodialysis treatment for at least 3 months and are medically stable.
• Able to walk a few steps, even if they require walking aids such as canes or walkers.

Exclusion Criteria:

• Myocardial infarction in the past 6 weeks.
• Unstable angina during exercise or at rest.
• Amputation of lower limbs above the knee without prosthetics.
• Cerebrovascular disease such as stroke or transient ischemic attacks in the last 6 months or with significant sequelae affecting lower limb mobility.
• Musculoskeletal or respiratory disorders that worsen with exercise.
• Inability to perform study tests/questionnaires.

Patients selected by Nephrologists in different Hemodialysis units collaborating in the current project, which includes holistic treatment through non-immersive virtual reality both at the dialysis center and at home, will be invited to participate in this study. Patients from different Hemodialysis units (Hospital de Manises and with approval from the Clinical Research Ethics Committee (CEIC) at the Consorcio Sanitario de Terrassa) and patients who are part of the renal patient association ALCER España (Association for the Fight against Kidney Diseases) will also be selected.

Data will be shared under request