Acupuncture for Symptom Burden and Quality of Life in Patients With End-Stage Kidney Disease

• Acupuncture (Other): Body acupuncture will be administered using sterile, single-use needles, with needles retained for 30 minutes. The standardized core acupuncture points will include bilateral LI4, ST36, SP6, LV3, KI3, and BL23. Up to two additional points (KI7, KI10, KI6, CV4, or CV6) may be selected according to the participant's clinical presentation and Traditional Chinese Medicine assessment, and up to two local trigger points may be used for musculoskeletal pain when indicated. Mild deqi will be elicited at the main acupuncture points, avoiding vigorous needle manipulation. Auricular acupuncture with sterile semi-permanent needles may also be used for 3-4 days. Treatment will consist of 2-3 sessions per week, for up to 24 sessions over 8-12 weeks. Acupuncture points on the limb with an arteriovenous fistula or graft and areas near the vascular access will be avoided.
• Sham Acupuncture (Other): Sham acupuncture will be administered at non-acupuncture points located away from recognized acupuncture points and major neurovascular structures. Needles will be inserted superficially (1-2 mm), without elicitation of deqi, needle manipulation, or electrical stimulation. The sham procedure will mimic the active acupuncture intervention with respect to treatment setting, participant positioning, session duration, and treatment frequency in order to maintain participant masking. Participants will continue to receive their usual care without modification.

Primary outcomes

• Change in health-related quality of life assessed by KDQOL-36 domain scores [Baseline, week 6, week 12, and week 24]: Health-related quality of life will be assessed using the Kidney Disease Quality of Life 36-item questionnaire (KDQOL-36). The instrument includes the SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS), as well as three kidney disease-specific domains: Symptoms and Problems, Effects of Kidney Disease, and Burden of Kidney Disease. Scores are transformed to a 0-100 scale, with higher scores indicating better health-related quality of life. The KDQOL-36 will be administered at baseline, at week 6, at the end of the 12-week intervention, and at the 12-week post-intervention follow-up (24 weeks). Changes over time will be compared between the acupuncture and sham acupuncture groups.

Secondary outcomes

• Change in handgrip strength [Baseline, week 6, week 12, and week 24]: Handgrip strength will be measured as an objective assessment of functional capacity. Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in individual symptom scores assessed by the ESAS-r [Baseline, week 6, week 12, and week 24]: Symptom burden will be assessed using the revised Edmonton Symptom Assessment System (ESAS-r). The intensity of each symptom will be rated separately on a numerical scale from 0 to 10, with higher scores indicating greater symptom intensity. Changes in individual symptom scores over time will be compared between the acupuncture and sham acupuncture groups.
• Change in Pittsburgh Sleep Quality Index (PSQI) global score [Baseline, week 6, week 12, and week 24]: Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI). The PSQI global score ranges from 0 to 21, with higher scores indicating poorer sleep quality. The validated Greek version will be used. Changes in global scores over time will be compared between the acupuncture and sham acupuncture groups.
• Change in Brief Pain Inventory (BPI) pain interference score [Baseline, week 6, week 12, and week 24]: The impact of pain on daily functioning will be assessed using the pain interference subscale of the Brief Pain Inventory (BPI). The pain interference score ranges from 0 to 10, with higher scores indicating greater interference of pain with daily activities. Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in pressure pain threshold assessed by algometry [Baseline, week 6, week 12, and week 24]: Pressure pain threshold will be measured using an algometer as an exploratory assessment of mechanical pain sensitivity. Higher pressure pain threshold values indicate lower mechanical pain sensitivity. Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in 5-D Itch Scale total score [Baseline, week 6, week 12, and week 24]: Pruritus will be assessed using the 5-D Itch Scale, which evaluates five dimensions: duration, degree, direction, disability, and distribution. The total score ranges from 5 to 25, with higher scores indicating greater pruritus burden. The validated Greek version will be used. Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in circulating beta-endorphin concentration [Baseline, week 6, week 12, and week 24]: Circulating beta-endorphin levels will be measured in peripheral blood samples collected at four predefined time points: baseline (T0), week 6 (T1), week 12 (T2), and week 24 (T3). Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in circulating Substance P concentration [Baseline, week 6, week 12, and week 24]: Circulating Substance P concentration will be measured in peripheral blood samples collected at four predefined time points: baseline (T0), week 6 (T1), week 12 (T2), and week 24 (T3). Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in circulating calcitonin gene-related peptide (CGRP) concentration [Baseline, week 6, week 12, and week 24]: Circulating calcitonin gene-related peptide (CGRP) concentration will be measured in peripheral blood samples collected at four predefined time points: baseline (T0), week 6 (T1), week 12 (T2), and week 24 (T3). Changes over time will be compared between the acupuncture and sham acupuncture groups.
• Change in serum proteomic/peptidomic profile [Baseline and end of intervention (up to 12 weeks)]: Exploratory serum proteomic/peptidomic analyses will be performed before and after the treatment cycle to investigate changes in the serum proteomic/peptidomic profile following the intervention.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥18 years.
2. Diagnosis of end-stage kidney disease (ESKD) requiring chronic kidney replacement therapy:

   * Hemodialysis for ≥3 months and/or
   * Peritoneal dialysis for ≥3 months.
3. Stable treatment regimen (dialysis frequency/duration and analgesic therapy) for at least 4 weeks prior to enrollment.
4. Adequate understanding of the Greek language and ability to understand and provide written informed consent.

Exclusion Criteria:

1. Active infection, decompensated heart failure (NYHA class IV), recent acute coronary syndrome (ACS), or any other serious acute illness that could interfere with study participation.
2. Severe thrombocytopenia (platelet count <50,000/μL) or coagulation disorders (e.g., INR >1.5 or other known coagulation disorder) constituting a contraindication to acupuncture.
3. Current or recent (within the previous 3 months) use of high-dose systemic opioids (>100 mg morphine milligram equivalents \[MME\]) or initiation/significant modification of antidepressant or antiepileptic medication used for analgesia within 4 weeks prior to enrollment.
4. Regular acupuncture treatment within the previous 6 months.
5. Pregnancy, cognitive impairment, or severe psychiatric illness that may interfere with the valid completion of study questionnaires.

• Zhong Z, Sun MM, He M, Huang HP, Hu GY, Ma SQ, Zheng HZ, Li MY, Yao L, Cong DY, Wang HF. Proteomics and its application in the research of acupuncture: An updated review. Heliyon. 2024 Jun 18;10(12):e33233. doi: 10.1016/j.heliyon.2024.e33233. eCollection 2024 Jun 30. PMID 39022010
• Fletcher BR, Damery S, Aiyegbusi OL, Anderson N, Calvert M, Cockwell P, Ferguson J, Horton M, Paap MCS, Sidey-Gibbons C, Slade A, Turner N, Kyte D. Symptom burden and health-related quality of life in chronic kidney disease: A global systematic review and meta-analysis. PLoS Med. 2022 Apr 6;19(4):e1003954. doi: 10.1371/journal.pmed.1003954. eCollection 2022 Apr. PMID 35385471
• Correia de Carvalho M, Pereira Machado J, Laranjeira M, Nunes de Azevedo J, Azevedo P. Effect of Acupuncture on Functional Capacity and Health-Related Quality of Life of Hemodialysis Patients: Study Protocol for a Randomized Controlled Trial. Healthcare (Basel). 2022 Oct 17;10(10):2050. doi: 10.3390/healthcare10102050. PMID 36292497
• Liu S, Zhang F, Bai Y, Huang L, Zhong Y, Li Y. Therapeutic effects of acupuncture therapy for kidney function and common symptoms in patients with chronic kidney disease: a systematic review and meta-analysis. Ren Fail. 2024 Dec;46(1):2301504. doi: 10.1080/0886022X.2023.2301504. Epub 2024 Jan 8. PMID 38189090
• Correia de Carvalho M, Nunes de Azevedo J, Azevedo P, Pires C, Laranjeira M, Machado JP. Effect of Acupuncture on Functional Capacity in Patients Undergoing Hemodialysis: A Patient-Assessor Blinded Randomized Controlled Trial. Healthcare (Basel). 2022 Oct 5;10(10):1947. doi: 10.3390/healthcare10101947. PMID 36292394