INTRODUCTION
Patients with chronic kidney disease (CKD) experience severe nephron damage, metabolite retention, and water-electrolyte and acid-base status imbalances, with complications affecting multiple organ systems. Hemodialysis is a crucial approach for delaying CKD progression[1]. However, even regular maintenance hemodialysis (MHD) involves various complications and may cause significant patient distress. Notably, the prevalences of anxiety and depression are quite high in this population, severely compromising their quality of life (QoL)[2-4]. Recently, research results by Ye et al[5] demonstrated that approximately half of the patients with CKD exhibited varying degrees of anxiety, depression, and elevated self-perceived burden (negative self-evaluation arising from symptom-related guilt), with all having significant negative correlations with resilience. Their study suggests that low resilience could exacerbate anxiety-depression and self-perceived burden in CKD patients, it provides robust evidence for the association between psychological resilience and negative emotions. However, the mechanism through which these factors interact with CKD progression remains unclear. In this editorial, we explore the psychophysiological interplay in CKD outcomes, evaluating current evidence and hypothesizing mechanistic pathways. This has significant practical implications for developing intervention strategies to improve CKD prognosis, enhance patients’ QoL, and achieve better clinical outcomes.
INTERRELATIONSHIP BETWEEN DEPRESSION, ANXIETY, AND RESILIENCE IN PATIENTS WITH CKD AND THEIR EFFECTS ON QOL AND PROGNOSIS
Depression and anxiety in patients undergoing MHD show significant associations with higher cognitive distortions, lower resilience, and poorer QoL. Lower resilience is an independent risk factor for reduced QoL[6]. Depressive symptoms correlate with decreased self-efficacy and resilience, impairing patients’ activities of daily living and overall QoL[7]. In patients undergoing dialysis for CKD, diminished QoL is significantly associated with multiple factors, including depressive symptoms, complications (e.g., recurrent infections and anemia), chronic pain, and post-dialysis fatigue[8]. Studies reveal that treatment adherence is positively correlated with resilience[9] and sleep quality scores in patients with CKD[10]. These findings suggest that patients with lower resilience tend to have poorer treatment compliance and more frequent sleep disturbances. Resilience showed significant positive correlations with disease awareness, self-efficacy, and self-esteem and a negative correlation with age in patients undergoing MHD. This implies that older patients undergoing MHD may have particularly impaired resilience[11]. Notably, in patients undergoing MHD, anxiety is a significant independent determinant and depression is a crucial independent influencing factor for lower QoL[12]. A study involving 707 patients undergoing MHD and with depressive symptoms reported that depressive symptoms predict mortality, with significantly increased death risk for those with Patient Health Questionnaire 9 scores ≥ 10[13]. A large-scale study (12712 cases) on the long-term prognosis of CKD patients comorbid with depression (2006 to 2019) revealed that the coexistence of CKD and depression is associated with adverse outcomes, including recurrent hospitalization, CKD progression, adverse cardiovascular events, and all-cause mortality[14], demonstrating that negative emotions impact survival outcomes. A survey of 1017 outpatient dialysis facilities revealed that lower psychological assessment scale scores were significantly associated with higher mortality[15]. A particularly concerning finding indicates that among patients undergoing MHD and depressive symptoms, 16.5% exhibited suicidal ideation, and 1.9% had concrete suicide plans[16]. All-cause mortality risk increases nearly 30-fold in CKD initiating hemodialysis during the first year of treatment[17]. The coronavirus disease 2019 pandemic exacerbated psychological distress and sleep disturbances in patients with CKD, correlating with diminished QoL[18,19]. The underestimated interplay between these factors appears to bidirectionally influence negative emotions and QoL, disease outcomes.
PSYCHOLOGICAL AND PHYSIOLOGICAL INTERACTION MECHANISMS OF ANXIETY-DEPRESSION OF PATIENTS WITH CKD
Studies show that patients with CKD have significantly higher depression, anxiety, and fatigue scores than healthy controls, along with elevated serum markers of neuronal injury (neurofilament light chain, myelin basic protein, and nestin) and inflammation [C-reactive protein (CRP) and interleukin-10 (IL-10)]. These neuronal damage markers strongly correlate with neuropsychiatric symptom severity[20]. CKD-related neuroinflammation may exacerbate anxiety, depression, and cognitive dysfunction via pro-inflammatory cytokines (IL-1β, tumor necrosis factor-α, and C-C motif chemokine ligand 2) crossing the blood-brain barrier[21].
Meta-analyses reveal that patients with CKD with comorbid depression exhibit higher pro-inflammatory cytokines (CRP, IL-6, tumor necrosis factor-α) and lower anti-inflammatory IL-10 than non-depressed counterparts[22]. Serum endotoxin and IL-6 Levels closely correlate with depressive and fatigue symptoms, with endotoxin and depression independently predicting fatigue[23]. CKD patients frequently exhibit insulin resistance, muscle wasting, malnutrition, and chronic low-grade inflammation, along with dysregulated brain-derived neurotrophic factor (BDNF). BDNF abnormalities are implicated in insulin resistance, muscle atrophy, depression, oxidative stress, and inflammation, highlighting its central role in CKD’s mind-body interface[24]. Interventional and autonomic evidence further supports this link. A 10-day noise management intervention improved sleep quality, anxiety, blood pressure, heart rate, cortisol levels, and QoL in patients with CKD[25]. These patients also show reduced heart rate variability (HRV), which correlates with disease progression[26] and independently predicts 8-year mortality in MHD patients[27]. Notably, HRV abnormalities are associated with chronic stress, sleep disturbance, and depression[28]. Thus, depression and anxiety in CKD may worsen outcomes via neuroimmune dysregulation (pro-/anti-inflammatory imbalance), hypothalamic-pituitary-adrenal axis dysfunction (cortical alterations), autonomic dysfunction (reduced HRV), and neuro-immune-endocrine network disruption (BDNF changes). This bidirectional psychophysiological interaction may create a vicious cycle in which poor health exacerbates mood disorders, further deteriorating QoL and prognosis (Figure 1). These mechanisms likely contribute to CKD’s adverse clinical trajectory.
Figure 1 Bidirectional association between psychological factors and clinical outcomes in chronic kidney disease.
HRV: Heart rate variability; HPA: Hypothalamic-pituitary-adrenal; BDNF: Brain-derived neurotrophic factor; CKD: Chronic kidney disease; QoL: Quality of life.
NON-PHARMACOLOGICAL INTERVENTIONS FOR ANXIETY, DEPRESSION, AND RESILIENCE IN PATIENTS WITH CKD
Psychological interventions
The degree of acceptance of the need for long-term MHD is positively correlated with QoL. Accepting the reality of the disease is an important independent determinant of higher QoL[29]. Therefore, resisting the reality of illness negatively impacts QoL. In contrast, accepting it and adapting to the unchangeable fact of severe kidney disease are proactive psychological strategies for facing these health challenges. For example, life skills training interventions (focusing on goal setting, cognitive restructuring, acceptance/gratitude/mindfulness, and personal strengths) can improve anxiety, depression, QoL, illness perception, self-efficacy, self-management skills, benefit finding, and resilience in patients undergoing high-flux hemodialysis (HFHD)[30]. Psychoeducational interventions incorporating coping method, goal setting, and relaxation techniques demonstrated benefits such as improved QoL and reduced anxiety/depression in patients undergoing MHD in short- (< 1 month) and medium-term (1-3 months)[31]. Narrative nursing care with enhanced psychological elements improves treatment safety, reduces anxiety/depression, and enhances QoL in patients with CKD undergoing HFHD[32]. Evidence-based psychological therapies such as cognitive behavioral therapy (CBT) are effective for treating depression in patients with CKD[33,34]. CBT combined with resilience training proved superior to CBT alone in enhancing resilience, alleviating anxiety/depression symptoms, and improving QoL in patients undergoing MHD[35]. A controlled study on mindfulness meditation combined with progressive muscle relaxation training in patients undergoing MHD showed that the intervention group demonstrated significant improvements in exercise capacity, physical function, general health, energy, symptom/problem checklist, sleep, pain, cognitive function, emotional well-being, and QoL scores after 12 weeks[36,37]. After 12 weeks of mindfulness-based CBT, patients undergoing HFHD had significantly improved QoL, depression, anxiety, perceived stress, and serum creatinine levels[38]. Psychosocial interventions (including counseling, support groups, CBT, relaxation techniques, education, and social support) effectively reduce depression severity and improve QoL in patients with CKD[39]. Music therapy effectively alleviates depressive symptoms and enhances QoL in patients undergoing MHD, particularly in terms of functional capacity, pain management, mental health, vitality, and overall health status[40]. These findings suggest that psychological interventions positively influence mental health and physical outcomes, in patients undergoing MHD.
Exercise therapy and lifestyle interventions
Studies have shown that fatigue tends to be more severe on dialysis days and negatively correlates with physical activity levels on non-dialysis days[41]. Depression severity is positively associated with fatigue, suggesting that physical inactivity and depression may exacerbate fatigue symptoms[41]. Moderate physical exercise is beneficial for patients with CKD. Breathing exercises performed thrice daily (each session lasts 5 minutes: Inhale slowly through the nose for 4 seconds, hold the breath for 7 seconds, then exhale for 8 seconds to release the air) for 30 days significantly reduced depression scores and improved QoL and symptom control in patients undergoing MHD[42]. Clinical benefits of structured exercise programs such as aerobic and resistance training include improvement in depressive symptoms, restless legs syndrome, muscle cramps, and fatigue. Exercise improves inflammation, oxidative stress, vascular function, immune response, and macromolecular metabolism across all stages of CKD, while significantly enhancing patients’ QoL[43-45] and muscle strength and reducing frailty. Personalized exercise plans may lower all-cause and infection-related mortalities, thereby improving long-term prognosis[46-48]. Notable clinical trials, such as a randomized controlled study combining resistance training (training is administered 4 times per week for 24 weeks; during the first week, it begins at 50% of the initial one-repetition maximum, with an increase in the load by 5% monthly) with religious music (Quran recitation), demonstrated significantly greater improvements in 6-minute walk test performance, anxiety, depression, and QoL than exercise alone[49]. Participants completed 36 supervised sessions over 12 weeks (frequency: 3 ×/week). Session structure: 5-minute warm-up (dynamic stretching), 20-minute endurance phase (magnetic-resistance mini-cycle ergometry), and 5-minute cool-down (static stretching). This exercise program caused a measurable QoL improvement and depression reduction in the intervention group, whereas no significant changes were observed in the control group[50]. Comprehensive lifestyle approaches such as nature-based physical activities promote physical and mental well-being by reducing anxiety, fatigue, and stress while enhancing social skills[51]. Collectively, these findings suggest that appropriately personalized physical activity regimens may significantly benefit the overall physical and mental health of patients undergoing MHD.
PHARMACOLOGICAL INTERVENTIONS FOR ANXIETY, DEPRESSION, AND LOW RESILIENCE IN PATIENTS WITH CKD
Antidepressant pharmacotherapy: Efficacy and safety
Depressive symptoms are significantly correlated with low resilience and can impair patients’ activities of daily living and overall QoL[52]. Clinical studies on sertraline [a selective serotonin reuptake inhibitor (SSRI)] demonstrate the following benefits in patients with end-stage renal disease undergoing dialysis: Improved depressive mood, reduced intradialytic refractory syncope and pruritus, lowered hypotensive episode risk, modulated neurotransmitters by enhancing serotonergic transmission and downregulating postsynaptic receptors (attenuating hypovolemic stress responses), and maintained a good safety profile without affecting platelet function[53]. SSRIs also exhibit the following anti-inflammatory effects: Decreased pro-inflammatory cytokines (CRP, IL-1β, IL-6, and IL-12) and increased anti-inflammatory factors (IL-4, transforming growth factor-β1)[54-56]. The European Renal Best Practice guidelines recommend an 8-12-week SSRI trial for moderate-to-severe depression in patients undergoing dialysis and efficacy evaluation at 12 weeks to avoid ineffective medication[57].
Thus, the following safety considerations are recommended. Cardiac risks: Citalopram and escitalopram carry higher QT prolongation risk, potentially increasing sudden cardiac death risks in patients undergoing MHD[58]; comparative safety: Fluoxetine, fluvoxamine, paroxetine, and sertraline show lower cardiac risk, no significant association with 5-year all-cause mortality, cardiovascular events, or CKD progression, and potential 1-year increased risk of hip fractures (post-fall) and upper gastrointestinal bleeding. Long-term adverse outcomes - including all-cause mortality, major adverse cardiovascular events, CKD progression, and suicidal behavior - showed no significant association with SSRI use[59]. In CKD patients with comorbid depression and anxiety, agomelatine and paroxetine significantly improved symptoms and daily living capacity. Notably, agomelatine exhibited superior efficacy in alleviating anxiety and depression, as well as improving sleep quality[60,61]. Comparative studies found melatonin more effective than alprazolam in enhancing sleep quality and reducing insomnia severity[62]. A multinational survey of 112 medical institutions across three countries identified melatonin as the most frequently prescribed first-line treatment for insomnia in CKD patients with comorbid depression, followed by zolpidem and zopiclone[63]. In an eight-week trial comparing zolpidem (10 mg nightly) and acupressure in patients undergoing MHD, the zolpidem group showed significant improvements in pruritus, sleep quality, and QoL, with no serious adverse events in either group[64].
Antidepressants and hypnotics benefit patients undergoing MHD with anxiety, depression, poor resilience, and insomnia. However, given the severely impaired renal function in CKD, their use requires careful assessment of risk - benefit ratios. When the clinical benefits of SSRIs or hypnotics outweigh the risks, individualized treatment regimens should be adopted. Drug selection should consider cardiac status, fracture risk, drug interactions, and allergy history of allergies. Treatment should begin with low doses, gradually and slowly increased, and the cardiac QT interval regularly monitored. Tricyclic antidepressants should generally be avoided, as should the concurrent use of multiple antidepressants or hypnotics. Drugs with significant QT prolongation risk should be minimized, and attention paid to bone mineral density and gastrointestinal symptoms. Non-pharmacological interventions should be integrated to enhance efficacy and reduce adverse drug events.
ADDRESSING ANXIETY, DEPRESSION, AND LOW RESILIENCE IN CKD: CHALLENGES AND MULTIDISCIPLINARY SOLUTIONS
Given the substantial impact of comorbid anxiety, depression, and low resilience in patients with CKD, managing these conditions poses significant challenges. These include diagnostic limitations (nephrologists often lack expertise in mental health assessment), pharmacological risks (renal impairment increases susceptibility to adverse drug reactions), and adherence difficulties (poor patient compliance). These are critical barriers that clinicians must address.
To tackle these challenges, a multidisciplinary approach is essential: (1) Nurses should undergo mental health evaluation training; and (2) They should assist physicians by conducting routine screenings (every 1-2 weeks) using the Patient Health Questionnaire 9 and Generalized Anxiety Disorder 7 scales. Suspected cases require prompt referral to psychiatrists and psychotherapist for diagnosis and treatment. By integrating nephrologists, psychiatrists, psychotherapists, and nurses, personalized care plans can be developed, including pharmacological interventions such as antidepressants or hypnotics. For example, when prescribing sertraline, regular monitoring of estimated glomerular filtration rate, electrolytes (Na+, K+), and electrocardiogram (QTc) intervals is essential (Figure 2).
Figure 2 Intervention flowchart for anxiety/depression in chronic kidney disease.
Nurses can also collaborate with psychotherapists to deliver non-pharmacological interventions, forming a comprehensive, multidimensional care model (Figure 3). Furthermore, digital health technologies may augment traditional approaches, including smart wristbands for continuous monitoring of vital signs (heart rate, blood pressure, oxygen saturation) and virtual reality-assisted relaxation training. Integrating these strategies into CKD management pathways may help disrupt the vicious psychophysiological cycle, thereby achieving synergistic therapeutic outcomes.
Figure 3 Application strategy of sertraline for anxiety/depression in chronic kidney disease.
CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate.
CONCLUSION
Existing studies consistently report a high prevalence of comorbid anxiety and depression in patients with CKD. These negative emotions affect QoL and prognosis through multiple physiological pathways. Their impact may have been previously underestimated, underscoring the need for further investigation and proactive management. Low resilience significantly contributes to the onset and progression of anxiety and depression; however, the psychological and biological mechanisms underlying this relationship remain poorly understood. Most pharmacological and non-pharmacological interventions are based on short-term studies. Such outcomes impose limitations on creating well-rounded interventions to ameliorate QoL and prognosis in CKD populations. Future large-scale, controlled trials are required to assess long-term efficacy and safety. Additionally, research is required to examine cultural and geographical differences in non-pharmacological interventions and to evaluate the cost-effectiveness of comprehensive intervention models. A focus on bidirectional psychosomatic interactions and the development of multidimensional strategies may offer a novel approach to improving QoL and prognosis in patients with CKD.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B, Grade B, Grade C
Novelty: Grade B, Grade B, Grade B, Grade C, Grade C
Creativity or Innovation: Grade B, Grade B, Grade B, Grade C, Grade C
Scientific Significance: Grade A, Grade B, Grade C, Grade C, Grade C
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
P-Reviewer: Shu P, China; Zhan YT, PhD, Academic Fellow, China; Zhu CR, MD, PhD, Chief Physician, Professor, China S-Editor: Wang JJ L-Editor: A P-Editor: Yu HG
