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J Clinic Care Skill 2025, 6(1): 47-55 |
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Ethics code: IR.YUMS.REC.1399.199
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Received: 2025/01/21 | Accepted: 2025/03/15 | Published: 2025/03/18
Received: 2025/01/21 | Accepted: 2025/03/15 | Published: 2025/03/18
How to cite this article
Gholami D, Abbasi Larki R, Manzuri L, Taheri T, Asfaram A, Sadeghi Mansourkhani H et al . Effect of Oral L-Carnitine and Omega-3 on Lipid Profiles, Sleep Quality, and Quality of Life in Hemodialysis Patients. J Clinic Care Skill 2025; 6 (1) :47-55
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D. Gholami1, R. Abbasi Larki1, L. Manzuri2, T. Taheri3, A. Asfaram4, H. Sadeghi Mansourkhani *4, A. Dehghan5
1- Department of Nephrology, Faculty of Medical School, Yasuj University of Medical Sciences, Yasuj, Iran
2- Social Determinants of Health Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
3- Department of Medical-Surgical Nursing, Faculty of Nursing, Yasuj University of Medical Science, Yasuj, Iran
4- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
5- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
2- Social Determinants of Health Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
3- Department of Medical-Surgical Nursing, Faculty of Nursing, Yasuj University of Medical Science, Yasuj, Iran
4- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
5- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
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Introduction
Chronic kidney disease (CKD) is characterized by irreversible damage to kidney cells, as indicated by a glomerular filtration rate (GFR) of less than 60 ml/min per 1.73 square meters of body surface area for 3 months or more [1]. Previous studies have estimated the prevalence of CKD in the general population of Iran to be between 5% and 15%, with some regions reporting rates as high as 23% [2]. CKD imposes significant costs on the healthcare system and leads to long-term physical and mental complications [3]. In end-stage renal disease (ESRD), kidney function is no longer sufficient to sustain life over the long term. Treatment options for patients with end-stage kidney disease include dialysis, kidney transplantation, or conservative care (also known as palliative or non-dialysis care) [4].
Dyslipidemia holds significant clinical importance among CKD patients [5]. An increasing number of studies have investigated the association between blood lipid profiles and renal function. Renal dysfunction alters the level, composition, and quality of blood lipids, resulting in a more atherogenic profile [6]. However, evidence from epidemiological studies has been inconsistent, making it difficult to demonstrate a causal relationship [7-9].
In cases of acute infection or inflammation, C-reactive protein (CRP) can be secreted within four to ten hours following inflammatory stimulation, peaking at 48 hours, with a short half-life of 19 hours. Conversely, persistently high levels of CRP may lead to chronic inflammation, as observed in patients with CKD or ESRD [10]. Nevertheless, the significance of a decrease in CRP concerning hard endpoints such as all-cause mortality and cardiovascular complications remains to be clarified [11].
The prevalence of sleep disorders in dialysis patients ranges from 40% to 98%, which is five to ten times higher than in the general population. Sleep disorders include sleep-related breathing disorders, circadian rhythm sleep-wake disorders, central hypersomnia disorders, parasomnias, and sleep-related movement disorders [12]. Several mechanisms can lead to disturbances in sleep quality among dialysis patients, including anemia, fluid and toxic accumulation in the body, pain, itching, and psychological issues such as depression [13]. Furthermore, sleep disorders may be associated with symptoms like fatigue and decreased energy, as well as the overall burden of kidney disease and its treatment. Patients often experience daytime sleepiness, drowsiness, and lethargy, which can impair self-management tasks [12]. Additionally, sleep is an important indicator of health, with its primary function being to promote mental and physical recovery. Poor sleep may reduce a person’s immunity, lead to endocrine disorders, and contribute to more negative emotions, ultimately having a detrimental impact on the patient’s activity and quality of sleep during the daytime [14]. Moreover, the health-related quality of life (HRQOL) in patients with CKD is significantly affected, regardless of the stage of CKD [15].
Quality of life (QOL) is defined as an individual’s perception of themselves within the context of their value system and culture, in relation to their goals, expectations, standards, and concerns in daily life [16]. The QOL of hemodialysis patients decreases due to changes in their habits and daily routines, frequent medication and treatment, water restrictions, absenteeism from work, limitations in nutrition and physical activity, disruptions in social and family life, sexual problems, and spiritual distress. Consequently, the patient’s physical, mental, and emotional health and well-being are compromised, leading to a deterioration in their overall QOL [17].
Dialysis patients are susceptible to carnitine deficiency due to protein restriction, decreased L-carnitine production resulting from renal dysfunction, and increased excretion through dialysis. Carnitine is an amino acid derived from the word “carnus,” meaning meat, and is present in almost every cell in the body [18]. L-carnitine is an amine known for its role in transferring long-chain fatty acids from the cytoplasm into the mitochondrial matrix for oxidation [19]. Acyl-CoAs act as restraining factors for several enzymes involved in intermediary metabolism. The conversion of Acyl-CoA into acylcarnitine is an essential system for removing toxic acyl groups [20]. Therefore, concentrations of L-carnitine in plasma and target organs may exert beneficial effects on several metabolic parameters that have derangements of a common origin (e.g., dyslipidemia), which are frequently present in ESRD patients undergoing dialysis [21]. Carnitine deficiency may lead to reduced availability of fatty acids as an energy source, fat accumulation, muscle weakness, cardiomyopathy, heart failure, and anemia. Adequate levels of L-carnitine can help increase energy and promote longevity [18]. Studies have shown conflicting results regarding the effects of L-carnitine supplementation in hemodialysis patients. Some researchers believe that L-carnitine has beneficial effects in reducing erythropoietin (EPO) hyporesponsiveness, alleviating post-dialysis muscle cramps, and improving serum lipid profiles, while others do not support these claims [22]. However, Semeniuk et al. and Emami Naini et al. indicate no significant improvement in the QOL of hemodialysis patients following L-carnitine supplementation [23, 24]. According to Miyagawa et al., L-carnitine does not improve sleep quality in patients with narcolepsy [25]. Conversely, Estaji et al. showed that oral L-carnitine supplementation can improve sleep quality in hemodialysis patients [26].
Omega-3 is a long-chain n-3 polyunsaturated fatty acid (n-3 PUFA) found in fish oil, which is a good source of this nutrient. It can improve lipid metabolism, blood pressure, heart rate, inflammation, and oxidative stress [27]. Lin et al. and Shen et al. revealed that Omega-3 or fish oil supplementation in patients undergoing hemodialysis significantly decreases total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) while increasing high-density lipoprotein (HDL) [28, 29]. Moreover, Musazadeh et al. [30] and Emami Naini et al. [24] have shown an improvement in lipid profiles following L-carnitine supplementation. However, according to Karimi et al., there is no significant change in the lipid profiles of patients undergoing hemodialysis [31].
Zhang et al. have indicated that using fish oil during hemodialysis improves the QOL in patients [32]. Additionally, Moeinzadeh et al. found that omega-3 supplementation improves inflammatory factors and QOL in hemodialysis patients [20]. The positive effects of omega-3 supplementation on sleep have also been noted. Dai & Liu, in their systematic review and meta-analysis, have reported conflicting results regarding the effect of omega-3 long-chain polyunsaturated fatty acids on sleep quality in children and adults [33].
There are conflicting reports in the literature regarding the impact of omega-3 and L-carnitine supplementation on lipid profiles, QOL, and sleep quality in hemodialysis patients. Additionally, the combined effects of L-carnitine and omega-3 may provide greater benefits for the outcomes in question. Therefore, this study aimed to assess the effects of oral administration of L-carnitine and omega-3, either alone or in combination, on lipid profiles, sleep quality, and QOL in individuals undergoing hemodialysis.
Materials and Methods
Design and Participants
The current double-blind randomized trial was done on hemodialysis patients referred to the nephrology clinics of Shahid Beheshti and Shahid Jalili Hospitals in Yasuj, Iran, in 2021.
Participants, sampling, and sample size calculation
The sample size was calculated based on the formula for comparing two means, using the mean QOL score from the study by Emami Naini et al. [24]. The mean QOL score in the L-carnitine group was 51.0±18.5, while that of the placebo group was 3±14. With α set at 0.05 and β set at 80%, the required sample size for each group was determined to be 21.53, rounded up to 25 patients per group, accounting for attrition [25]. Consequently, 75 eligible patients were recruited using a convenience sampling method. The patients were randomly assigned to three groups (n=25 patients per group) using quadruple blocks through block randomization (Figure 1).
Inclusion criteria included being over 18 years old and undergoing hemodialysis more than twice a week for at least three months. Exclusion criteria included patients requiring more than the prescribed dose of L-carnitine or omega-3, patients who did not agree to participate in the study, patients with plans for kidney transplantation, and those with a history of allergy to L-carnitine or omega-3. The study was subsequently registered in the Iranian Clinical Trial Registry (IRCT20201027049166N1).
Intervention
Three intervention groups participated in the study; intervention group 1 (L-carnitine), intervention group 2 (omega-3), and intervention group 3 (L-carnitine + omega-3).
L-carnitine group: Participants received one 250mg L-carnitine tablet (Poursina Pharmaceutical Company), taken twice a day for three months.
Omega-3 group: Participants received a 1000mg omega-3 capsule (GMV Pharmaceutical Company), taken once daily for three months.
L-carnitine plus omega-3 group: Individuals received 250mg of L-carnitine twice a day and 1000mg of Omega-3 daily for three months.
Each n-3 FA capsule contains 1000 mg of fish oil (which includes a minimum of 13% eicosapentaenoic acid (EPA) and a minimum of 9% docosahexaenoic acid (DHA)), as well as wheat germ oil (linoleic acid 52%-59%; Omega-3 Plus; SEDCO, Giza, Egypt). Participants were regularly followed up to ensure compliance with the medications taken [21, 24].
Figure 1. Schematic flow diagram of the study
Outcomes
The primary outcomes were the lipid profile (LDL, HDL, TC, TG), sleep quality, and kidney disease QOL, which were measured at baseline and after the intervention. Secondary outcomes included CRP and the subscales of sleep quality, such as sleep latency, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction.
Measurements and data collection
Laboratory investigations
Laboratory parameters, including serum TG, TC, HDL, LDL, and CRP levels, were measured both before and after the administration of omega-3 and L-carnitine supplementation.
At baseline and at the end of the three-month intervention, 5ml of blood was collected from each patient after a 12-hour fasting period before hemodialysis. Blood samples were centrifuged at 3000rpm for 15 minutes to obtain serum and were then separated into small aliquots, which were frozen at -80°C until analysis. Lipid parameters, including TG, TC, HDL, and LDL levels, were measured using the colorimetric method (spectrophotometry) and commercial diagnostic kits (Pars Azmoon Co, Tehran, Iran). The levels of inflammatory markers CRP (qualitative), TG, TC, HDL, and LDL were measured using a Pars Azmoon company kit, following the kit instructions and utilizing a Cobas analyzer.
Data collection tools
The Kidney Disease Quality of Life Short Form, version 1.3 (KDQOL-SF), developed for individuals with ESRD undergoing dialysis, was used to assess QOL as described by Hayes et al. [34].
The KDQOL-SF is a standardized self-report tool comprising 11 subscales and 43 items. It includes a part of the SF-36 to measure general QOL, which consists of 36 items along with additional items that assess the dimensions of CKD. The SF-36 section encompasses eight dimensions, including physical function (ten questions), role limitations due to physical problems (four questions), role limitations caused by emotional problems (three questions), social function (two questions), emotional well-being (five questions), pain (two questions), fatigue and energy (four questions), general health perception (five questions), and the overall health.
The second part of the KDQOL-SF is the Kidney Disease Component Summary (KDCS), which is divided into 11 subscales, including symptoms/problems (12 questions), the impact of kidney disease on life (eight questions), the burden of kidney disease responsibility (four questions), job status (two questions), cognitive function (three questions), quality of social interaction (three questions), sexual function (two questions), sleep (four questions), social support (two questions), encouragement from dialysis staff (two questions), and patient satisfaction (one question). The score for each dimension ranges from 0 to 100, with higher scores indicating a better QOL. Each dimension receives a score between 0 and 100 based on the individual’s scoring status [35]. The validation of this questionnaire in Iran was conducted using the forward-backward translation method, as assessed by Fardinmehr et al. Furthermore, the validity and reliability of the Persian version were confirmed [36]. It takes about 20-30 minutes to complete this questionnaire independently. If the patient does not wish to complete the questionnaire on their own, the researcher is permitted to interview the patient, following the recommendations of the non-profit center promoting public policy through research and analysis, as well as the QOL working group for kidney patients.
The Pittsburgh Sleep Quality Questionnaire (PSQI), developed by Buysse et al. [37], was used to assess sleep quality. It includes 19 items with a total score range of 0-21 and consists of seven subscales, including subjective sleep quality, sleep latency, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The scoring for the questionnaire is based on a four-item Likert scale (zero-three score). Internal consistency is indicated by an α of 0.83, and test-retest reliability is demonstrated with an r of 0.83, confirming the validity and reliability of the questionnaire. In the Iranian version, its validity and reliability were confirmed with a score of 0.77 [38].
Statistical analysis
The Kolmogorov-Smirnov test was used to assess the normality of the data distribution. The Chi-square test was employed to compare relative or absolute frequencies. An independent sample t-test was used to compare the ages of males among study groups. One-way analysis of variance (ANOVA) was conducted for data with a normal distribution, while the Kruskal-Wallis test was utilized for analyzing nonparametric data. All statistical analyses were performed using version 20 of SPSS software (SPSS, Chicago, IL), with p<0.05 considered statistically significant.
Findings
Seventy-four patients completed the experiments; 25 patients in intervention group 1, 25 patients in group 2, and 24 patients in group 3.
The average age was 61.56±13.37 years, and 68.6% of the participants were male. The average age of subjects in group 1 was 59.52±11.39, in group 2 was 60.84±15.10, and in group 3 was 64.45±13.43 years (p=0.41). There were no significant differences in age, sex, marital status, occupation, education, and duration of CKD among the study groups (p>0.05; Table 1).
Table 1. Frequency of demographic characteristics of the participants
There was no statistically significant difference in lipid profiles (LDL, HDL, TC, TG) and CRP levels among the three intervention groups before and after the study (p>0.05). The serum levels of TG and LDL decreased to some extent after the administration of omega-3 (1000 mg per day) and L-carnitine (500 mg per day), as well as their combination (1000 mg omega-3 per day and 500 mg L-carnitine per day) in the three intervention groups, although these changes were not statistically significant. Additionally, there was no statistically significant difference in CRP levels in each of the groups after the intervention compared to before (p>0.05; Table 2).
Table 2. Effect of omega-3 and L-carnitine, and their combination on mean profile lipids and CRP levels in hemodialysis subjects
The administration of omega-3 (1000 mg per day) and L-carnitine (500 mg per day), as well as their combination, for three months significantly improved the total score of sleep quality (p<0.05).
Moreover, there was a significant difference in all subscales of sleep quality, including subjective sleep quality, habitual sleep efficiency, daytime dysfunction, and sleep latency, in patients treated with omega-3 (1000 mg) and L-carnitine (500 mg; p < 0.05). However, the other subscales of sleep quality did not show significant changes with treatment using omega-3 and L-carnitine at the indicated doses (p>0.05; Table 3).
Table 3. Effect of omega-3 and L-carnitine and their combination on mean quality of sleep and its subscales in hemodialysis patients
There was no statistically significant difference in the general HRQOL score (SF-36) after the administration of omega-3 (1000 mg per day) and L-carnitine (500 mg per day), as well as their combination, for three months (p=0.059). The QOL score (KDQOL-SF) indicated an improvement in hemodialysis patients after three months of treatment with omega-3 (1000 mg per day), L-carnitine (500 mg per day), and their combination, although the enhancement was not statistically significant (Table 4).
Table 4. Effect of omega-3 and L-carnitine and their combination on mean general health-related quality of life and quality of life kidney disease in hemodialysis patients
Discussion
The present study was conducted to determine the effects of oral administration of L-carnitine and omega-3, both separately and in combination, on lipid profiles, sleep quality, and QOL in hemodialysis patients.
Omega-3, L-carnitine, and the combination of both supplements did not change the plasma levels of TC and HDL. However, they did reduce the levels of LDL and TG, although these changes were not statistically significant. The effects of L-carnitine and omega-3 on lipid profiles have been reported as a controversial subject in previous studies. Lin et al. found that supplementation with omega-3 reduces levels of CHO, LDL, and TG while increasing HDL levels in patients undergoing hemodialysis. However, similar to the present study, at the end of month three, the TC, LDL, and TG indices decrease compared to the first and second months but almost returned to initial levels [28]. Additionally, Shen et al. indicated that fish oil-based polyunsaturated fatty acid (PUFA) supplementation (Omega-3Q10) significantly decreases TC and LDL after 12 months, while HDL increased [29].
Like the present study, Karimi et al. found in a meta-analysis that L-carnitine supplementation does not significantly improve the serum lipid profile, including TC and HDL levels [31]. However, a meta-analysis by Musazadeh et al. reported that L-carnitine supplementation at a dose of more than 2g per day can improve the lipid profile of HDL, TC, LDL, and TG [30]. L-carnitine is an amine known to transfer long-chain fatty acids from the cytoplasm into the mitochondrial matrix for oxidation [19], and its expected reduction may be due to sample size or low doses of supplementation. Emami Naini et al. showed that in dyslipidemic ESRD patients undergoing continuous hemodialysis, oral L-carnitine supplementation can reduce TG and increase HDL levels, indicating that L-carnitine consumption had beneficial effects on lipid profiles. Moreover, L-carnitine at a dose of 1g per day for 16 weeks in patients on hemodialysis decreases TG and increases HDL levels; however, there is no improvement in the levels of TC and LDL [24].
Additionally, according to Chen et al., L-carnitine significantly decreases LDL and CRP levels. However, there are no significant differences in TG, HDL, and TC levels [39].
Inflammation is a prominent feature of CKD, which affects 10-15% of the population worldwide. Moreover, inflammation is an established risk factor for early mortality and acts as a catalyst for the development of other complications, such as cardiovascular disease [40]. Our findings were consistent with those of De Lima et al., evaluating the impacts of omega-3 fatty acid supplementation on inflammatory parameters in patients with CKD undergoing hemodialysis treatment [41]. Additionally, Lin et al. found that supplementation with omega-3 reduces plasma levels of CRP in hemodialysis patients [28].
The administration of L-carnitine and omega-3 did not reduce CRP levels. In contrast to our findings, Keshani et al. [42] and Rastgoo et al. [43] reported that L-carnitine supplementation significantly decreases CRP. Furthermore, in the study by Sahebkar, there is a significant decrease in CRP levels after receiving L-carnitine supplementation [44]. Additionally, Haghighatdoost et al. revealed that CRP decreases significantly in the L-carnitine group after the intervention [45]. The lack of a remarkable impact of omega-3 and L-carnitine on CRP levels may be due to chronic inflammation, which is often too severe for supplements to counteract. Additional factors, such as insufficient dosage or duration of treatment, drug interactions, and individual variability in patient responses due to differences in disease severity, comorbidities, and nutritional status, may also contribute. Together, these factors elucidate why these supplements may not significantly decrease CRP levels in dialysis patients in the present study.
The total score of sleep quality improved after taking L-carnitine and omega-3 alone or in combination. In this context, Estaji et al. found that a 500mg L-carnitine supplement taken twice a day for 12 weeks improves sleep quality in hemodialysis patients [26]. Furthermore, Heydarbaki et al. reported that omega-3 improves the sleep quality of patients with uremic pruritus undergoing hemodialysis [46].
There was no statistically significant difference in the general HRQOL score after treatment with omega-3 and L-carnitine. However, the QOLin kidney disease and quality of sleep significantly improved in the omega-3 and omega-3 plus L-carnitine groups. In this regard, Dashti-Khavidaki et al. reported that in hemodialysis patients, omega-3 fatty acids (180mg eicosatetraenoic acid and 120mg docosahexaenoic acid in each capsule) taken daily for four months improves HRQOL and reduces depression [21]. Moreover, Zhang et al. have shown significant improvement in subscales of QOL, including energy/fatigue and physical role during hemodialysis, after receiving fish oil, as assessed using the KDQLQ-SF [32].
L-carnitine only improved the quality of sleep in hemodialysis patients. Contrary to the results of the present study, Semeniuk et al. indicated that L-carnitine (20mg/kg) does not significantly change QOL, muscle cramping, hemoglobin levels, or intradialytic hypotension in hemodialysis patients [23]. Moreover, according to Emami Naini et al., the QOL of patients on hemodialysis does not improve after receiving L-carnitine [24]. Additionally, as Miyagawa et al. stated, there is no significant improvement in the QOL of patients with narcolepsy in the intervention group after receiving L-carnitine compared to the placebo group [25]. One possible explanation for the discrepancies between previous studies and the present work may be attributed to differences in L-carnitine dosage, the comorbidity of the disease, and sample size.
The study had some limitations, such as a small sample size, a low dose of supplements, and the absence of a control group without intervention, which may affect the validity of the data. However, further research with larger sample sizes and higher doses of the indicated supplements is recommended to confirm these findings.
Conclusion
Omega-3 and a combination of omega-3 and L-carnitine improve the QOL and quality of sleep in patients undergoing hemodialysis.
Acknowledgments: The results of this trial are part of an MD thesis by Alireza Dehghan. We gratefully acknowledge the Vice Chancellor for Research at Yasuj University of Medical Sciences for their support.
Ethical Permissions: All methods were performed under the relevant guidelines and regulations outlined by the Declaration of Helsinki. Approval from the Ethics Committee of Yasuj University of Medical Sciences was obtained (IR.YUMS.REC.1399.199) on 2021-02-24. Before the intervention, written informed consent was obtained from all patients, and they were informed of their right to withdraw from the study at any time. We also received written informed consent from the patient caregivers, whether parents or primary guardians. Moreover, the confidentiality and privacy of the participants were ensured.
Conflicts of Interests: The authors declared no conflicts of interests.
Authors' Contribution: Gholami D (First Author), Main Researcher/Methodologist/Introduction Writer/Discussion Writer (20%); Abbasi Larki R (Second Author), Methodologist/Introduction Writer/Discussion Writer (15%); Manzuri L (Third Author), Methodologist/Assistant Researcher/Introduction Writer/Statistical Analyst (15%); Taheri T (Fourth Author), Assistant Researcher/Introduction Writer (10%); Asfaram A (Fifth Author), Introduction Writer/Methodologist/Discussion Writer (10%); Sadeghi Mansourkhani H (Sixth Author), Main Researcher/Methodologist/Introduction Writer/Discussion Writer (20%); Dehghan A (Seventh Author), Assistant Researcher/Introduction Writer (10%)
Funding/Support: This study was supported by the Yasuj University of Medical Sciences.
Chronic kidney disease (CKD) is characterized by irreversible damage to kidney cells, as indicated by a glomerular filtration rate (GFR) of less than 60 ml/min per 1.73 square meters of body surface area for 3 months or more [1]. Previous studies have estimated the prevalence of CKD in the general population of Iran to be between 5% and 15%, with some regions reporting rates as high as 23% [2]. CKD imposes significant costs on the healthcare system and leads to long-term physical and mental complications [3]. In end-stage renal disease (ESRD), kidney function is no longer sufficient to sustain life over the long term. Treatment options for patients with end-stage kidney disease include dialysis, kidney transplantation, or conservative care (also known as palliative or non-dialysis care) [4].
Dyslipidemia holds significant clinical importance among CKD patients [5]. An increasing number of studies have investigated the association between blood lipid profiles and renal function. Renal dysfunction alters the level, composition, and quality of blood lipids, resulting in a more atherogenic profile [6]. However, evidence from epidemiological studies has been inconsistent, making it difficult to demonstrate a causal relationship [7-9].
In cases of acute infection or inflammation, C-reactive protein (CRP) can be secreted within four to ten hours following inflammatory stimulation, peaking at 48 hours, with a short half-life of 19 hours. Conversely, persistently high levels of CRP may lead to chronic inflammation, as observed in patients with CKD or ESRD [10]. Nevertheless, the significance of a decrease in CRP concerning hard endpoints such as all-cause mortality and cardiovascular complications remains to be clarified [11].
The prevalence of sleep disorders in dialysis patients ranges from 40% to 98%, which is five to ten times higher than in the general population. Sleep disorders include sleep-related breathing disorders, circadian rhythm sleep-wake disorders, central hypersomnia disorders, parasomnias, and sleep-related movement disorders [12]. Several mechanisms can lead to disturbances in sleep quality among dialysis patients, including anemia, fluid and toxic accumulation in the body, pain, itching, and psychological issues such as depression [13]. Furthermore, sleep disorders may be associated with symptoms like fatigue and decreased energy, as well as the overall burden of kidney disease and its treatment. Patients often experience daytime sleepiness, drowsiness, and lethargy, which can impair self-management tasks [12]. Additionally, sleep is an important indicator of health, with its primary function being to promote mental and physical recovery. Poor sleep may reduce a person’s immunity, lead to endocrine disorders, and contribute to more negative emotions, ultimately having a detrimental impact on the patient’s activity and quality of sleep during the daytime [14]. Moreover, the health-related quality of life (HRQOL) in patients with CKD is significantly affected, regardless of the stage of CKD [15].
Quality of life (QOL) is defined as an individual’s perception of themselves within the context of their value system and culture, in relation to their goals, expectations, standards, and concerns in daily life [16]. The QOL of hemodialysis patients decreases due to changes in their habits and daily routines, frequent medication and treatment, water restrictions, absenteeism from work, limitations in nutrition and physical activity, disruptions in social and family life, sexual problems, and spiritual distress. Consequently, the patient’s physical, mental, and emotional health and well-being are compromised, leading to a deterioration in their overall QOL [17].
Dialysis patients are susceptible to carnitine deficiency due to protein restriction, decreased L-carnitine production resulting from renal dysfunction, and increased excretion through dialysis. Carnitine is an amino acid derived from the word “carnus,” meaning meat, and is present in almost every cell in the body [18]. L-carnitine is an amine known for its role in transferring long-chain fatty acids from the cytoplasm into the mitochondrial matrix for oxidation [19]. Acyl-CoAs act as restraining factors for several enzymes involved in intermediary metabolism. The conversion of Acyl-CoA into acylcarnitine is an essential system for removing toxic acyl groups [20]. Therefore, concentrations of L-carnitine in plasma and target organs may exert beneficial effects on several metabolic parameters that have derangements of a common origin (e.g., dyslipidemia), which are frequently present in ESRD patients undergoing dialysis [21]. Carnitine deficiency may lead to reduced availability of fatty acids as an energy source, fat accumulation, muscle weakness, cardiomyopathy, heart failure, and anemia. Adequate levels of L-carnitine can help increase energy and promote longevity [18]. Studies have shown conflicting results regarding the effects of L-carnitine supplementation in hemodialysis patients. Some researchers believe that L-carnitine has beneficial effects in reducing erythropoietin (EPO) hyporesponsiveness, alleviating post-dialysis muscle cramps, and improving serum lipid profiles, while others do not support these claims [22]. However, Semeniuk et al. and Emami Naini et al. indicate no significant improvement in the QOL of hemodialysis patients following L-carnitine supplementation [23, 24]. According to Miyagawa et al., L-carnitine does not improve sleep quality in patients with narcolepsy [25]. Conversely, Estaji et al. showed that oral L-carnitine supplementation can improve sleep quality in hemodialysis patients [26].
Omega-3 is a long-chain n-3 polyunsaturated fatty acid (n-3 PUFA) found in fish oil, which is a good source of this nutrient. It can improve lipid metabolism, blood pressure, heart rate, inflammation, and oxidative stress [27]. Lin et al. and Shen et al. revealed that Omega-3 or fish oil supplementation in patients undergoing hemodialysis significantly decreases total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) while increasing high-density lipoprotein (HDL) [28, 29]. Moreover, Musazadeh et al. [30] and Emami Naini et al. [24] have shown an improvement in lipid profiles following L-carnitine supplementation. However, according to Karimi et al., there is no significant change in the lipid profiles of patients undergoing hemodialysis [31].
Zhang et al. have indicated that using fish oil during hemodialysis improves the QOL in patients [32]. Additionally, Moeinzadeh et al. found that omega-3 supplementation improves inflammatory factors and QOL in hemodialysis patients [20]. The positive effects of omega-3 supplementation on sleep have also been noted. Dai & Liu, in their systematic review and meta-analysis, have reported conflicting results regarding the effect of omega-3 long-chain polyunsaturated fatty acids on sleep quality in children and adults [33].
There are conflicting reports in the literature regarding the impact of omega-3 and L-carnitine supplementation on lipid profiles, QOL, and sleep quality in hemodialysis patients. Additionally, the combined effects of L-carnitine and omega-3 may provide greater benefits for the outcomes in question. Therefore, this study aimed to assess the effects of oral administration of L-carnitine and omega-3, either alone or in combination, on lipid profiles, sleep quality, and QOL in individuals undergoing hemodialysis.
Materials and Methods
Design and Participants
The current double-blind randomized trial was done on hemodialysis patients referred to the nephrology clinics of Shahid Beheshti and Shahid Jalili Hospitals in Yasuj, Iran, in 2021.
Participants, sampling, and sample size calculation
The sample size was calculated based on the formula for comparing two means, using the mean QOL score from the study by Emami Naini et al. [24]. The mean QOL score in the L-carnitine group was 51.0±18.5, while that of the placebo group was 3±14. With α set at 0.05 and β set at 80%, the required sample size for each group was determined to be 21.53, rounded up to 25 patients per group, accounting for attrition [25]. Consequently, 75 eligible patients were recruited using a convenience sampling method. The patients were randomly assigned to three groups (n=25 patients per group) using quadruple blocks through block randomization (Figure 1).
Inclusion criteria included being over 18 years old and undergoing hemodialysis more than twice a week for at least three months. Exclusion criteria included patients requiring more than the prescribed dose of L-carnitine or omega-3, patients who did not agree to participate in the study, patients with plans for kidney transplantation, and those with a history of allergy to L-carnitine or omega-3. The study was subsequently registered in the Iranian Clinical Trial Registry (IRCT20201027049166N1).
Intervention
Three intervention groups participated in the study; intervention group 1 (L-carnitine), intervention group 2 (omega-3), and intervention group 3 (L-carnitine + omega-3).
L-carnitine group: Participants received one 250mg L-carnitine tablet (Poursina Pharmaceutical Company), taken twice a day for three months.
Omega-3 group: Participants received a 1000mg omega-3 capsule (GMV Pharmaceutical Company), taken once daily for three months.
L-carnitine plus omega-3 group: Individuals received 250mg of L-carnitine twice a day and 1000mg of Omega-3 daily for three months.
Each n-3 FA capsule contains 1000 mg of fish oil (which includes a minimum of 13% eicosapentaenoic acid (EPA) and a minimum of 9% docosahexaenoic acid (DHA)), as well as wheat germ oil (linoleic acid 52%-59%; Omega-3 Plus; SEDCO, Giza, Egypt). Participants were regularly followed up to ensure compliance with the medications taken [21, 24].
Figure 1. Schematic flow diagram of the study
Outcomes
The primary outcomes were the lipid profile (LDL, HDL, TC, TG), sleep quality, and kidney disease QOL, which were measured at baseline and after the intervention. Secondary outcomes included CRP and the subscales of sleep quality, such as sleep latency, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction.
Measurements and data collection
Laboratory investigations
Laboratory parameters, including serum TG, TC, HDL, LDL, and CRP levels, were measured both before and after the administration of omega-3 and L-carnitine supplementation.
At baseline and at the end of the three-month intervention, 5ml of blood was collected from each patient after a 12-hour fasting period before hemodialysis. Blood samples were centrifuged at 3000rpm for 15 minutes to obtain serum and were then separated into small aliquots, which were frozen at -80°C until analysis. Lipid parameters, including TG, TC, HDL, and LDL levels, were measured using the colorimetric method (spectrophotometry) and commercial diagnostic kits (Pars Azmoon Co, Tehran, Iran). The levels of inflammatory markers CRP (qualitative), TG, TC, HDL, and LDL were measured using a Pars Azmoon company kit, following the kit instructions and utilizing a Cobas analyzer.
Data collection tools
The Kidney Disease Quality of Life Short Form, version 1.3 (KDQOL-SF), developed for individuals with ESRD undergoing dialysis, was used to assess QOL as described by Hayes et al. [34].
The KDQOL-SF is a standardized self-report tool comprising 11 subscales and 43 items. It includes a part of the SF-36 to measure general QOL, which consists of 36 items along with additional items that assess the dimensions of CKD. The SF-36 section encompasses eight dimensions, including physical function (ten questions), role limitations due to physical problems (four questions), role limitations caused by emotional problems (three questions), social function (two questions), emotional well-being (five questions), pain (two questions), fatigue and energy (four questions), general health perception (five questions), and the overall health.
The second part of the KDQOL-SF is the Kidney Disease Component Summary (KDCS), which is divided into 11 subscales, including symptoms/problems (12 questions), the impact of kidney disease on life (eight questions), the burden of kidney disease responsibility (four questions), job status (two questions), cognitive function (three questions), quality of social interaction (three questions), sexual function (two questions), sleep (four questions), social support (two questions), encouragement from dialysis staff (two questions), and patient satisfaction (one question). The score for each dimension ranges from 0 to 100, with higher scores indicating a better QOL. Each dimension receives a score between 0 and 100 based on the individual’s scoring status [35]. The validation of this questionnaire in Iran was conducted using the forward-backward translation method, as assessed by Fardinmehr et al. Furthermore, the validity and reliability of the Persian version were confirmed [36]. It takes about 20-30 minutes to complete this questionnaire independently. If the patient does not wish to complete the questionnaire on their own, the researcher is permitted to interview the patient, following the recommendations of the non-profit center promoting public policy through research and analysis, as well as the QOL working group for kidney patients.
The Pittsburgh Sleep Quality Questionnaire (PSQI), developed by Buysse et al. [37], was used to assess sleep quality. It includes 19 items with a total score range of 0-21 and consists of seven subscales, including subjective sleep quality, sleep latency, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The scoring for the questionnaire is based on a four-item Likert scale (zero-three score). Internal consistency is indicated by an α of 0.83, and test-retest reliability is demonstrated with an r of 0.83, confirming the validity and reliability of the questionnaire. In the Iranian version, its validity and reliability were confirmed with a score of 0.77 [38].
Statistical analysis
The Kolmogorov-Smirnov test was used to assess the normality of the data distribution. The Chi-square test was employed to compare relative or absolute frequencies. An independent sample t-test was used to compare the ages of males among study groups. One-way analysis of variance (ANOVA) was conducted for data with a normal distribution, while the Kruskal-Wallis test was utilized for analyzing nonparametric data. All statistical analyses were performed using version 20 of SPSS software (SPSS, Chicago, IL), with p<0.05 considered statistically significant.
Findings
Seventy-four patients completed the experiments; 25 patients in intervention group 1, 25 patients in group 2, and 24 patients in group 3.
The average age was 61.56±13.37 years, and 68.6% of the participants were male. The average age of subjects in group 1 was 59.52±11.39, in group 2 was 60.84±15.10, and in group 3 was 64.45±13.43 years (p=0.41). There were no significant differences in age, sex, marital status, occupation, education, and duration of CKD among the study groups (p>0.05; Table 1).
Table 1. Frequency of demographic characteristics of the participants
There was no statistically significant difference in lipid profiles (LDL, HDL, TC, TG) and CRP levels among the three intervention groups before and after the study (p>0.05). The serum levels of TG and LDL decreased to some extent after the administration of omega-3 (1000 mg per day) and L-carnitine (500 mg per day), as well as their combination (1000 mg omega-3 per day and 500 mg L-carnitine per day) in the three intervention groups, although these changes were not statistically significant. Additionally, there was no statistically significant difference in CRP levels in each of the groups after the intervention compared to before (p>0.05; Table 2).
Table 2. Effect of omega-3 and L-carnitine, and their combination on mean profile lipids and CRP levels in hemodialysis subjects
The administration of omega-3 (1000 mg per day) and L-carnitine (500 mg per day), as well as their combination, for three months significantly improved the total score of sleep quality (p<0.05).
Moreover, there was a significant difference in all subscales of sleep quality, including subjective sleep quality, habitual sleep efficiency, daytime dysfunction, and sleep latency, in patients treated with omega-3 (1000 mg) and L-carnitine (500 mg; p < 0.05). However, the other subscales of sleep quality did not show significant changes with treatment using omega-3 and L-carnitine at the indicated doses (p>0.05; Table 3).
Table 3. Effect of omega-3 and L-carnitine and their combination on mean quality of sleep and its subscales in hemodialysis patients
There was no statistically significant difference in the general HRQOL score (SF-36) after the administration of omega-3 (1000 mg per day) and L-carnitine (500 mg per day), as well as their combination, for three months (p=0.059). The QOL score (KDQOL-SF) indicated an improvement in hemodialysis patients after three months of treatment with omega-3 (1000 mg per day), L-carnitine (500 mg per day), and their combination, although the enhancement was not statistically significant (Table 4).
Table 4. Effect of omega-3 and L-carnitine and their combination on mean general health-related quality of life and quality of life kidney disease in hemodialysis patients
Discussion
The present study was conducted to determine the effects of oral administration of L-carnitine and omega-3, both separately and in combination, on lipid profiles, sleep quality, and QOL in hemodialysis patients.
Omega-3, L-carnitine, and the combination of both supplements did not change the plasma levels of TC and HDL. However, they did reduce the levels of LDL and TG, although these changes were not statistically significant. The effects of L-carnitine and omega-3 on lipid profiles have been reported as a controversial subject in previous studies. Lin et al. found that supplementation with omega-3 reduces levels of CHO, LDL, and TG while increasing HDL levels in patients undergoing hemodialysis. However, similar to the present study, at the end of month three, the TC, LDL, and TG indices decrease compared to the first and second months but almost returned to initial levels [28]. Additionally, Shen et al. indicated that fish oil-based polyunsaturated fatty acid (PUFA) supplementation (Omega-3Q10) significantly decreases TC and LDL after 12 months, while HDL increased [29].
Like the present study, Karimi et al. found in a meta-analysis that L-carnitine supplementation does not significantly improve the serum lipid profile, including TC and HDL levels [31]. However, a meta-analysis by Musazadeh et al. reported that L-carnitine supplementation at a dose of more than 2g per day can improve the lipid profile of HDL, TC, LDL, and TG [30]. L-carnitine is an amine known to transfer long-chain fatty acids from the cytoplasm into the mitochondrial matrix for oxidation [19], and its expected reduction may be due to sample size or low doses of supplementation. Emami Naini et al. showed that in dyslipidemic ESRD patients undergoing continuous hemodialysis, oral L-carnitine supplementation can reduce TG and increase HDL levels, indicating that L-carnitine consumption had beneficial effects on lipid profiles. Moreover, L-carnitine at a dose of 1g per day for 16 weeks in patients on hemodialysis decreases TG and increases HDL levels; however, there is no improvement in the levels of TC and LDL [24].
Additionally, according to Chen et al., L-carnitine significantly decreases LDL and CRP levels. However, there are no significant differences in TG, HDL, and TC levels [39].
Inflammation is a prominent feature of CKD, which affects 10-15% of the population worldwide. Moreover, inflammation is an established risk factor for early mortality and acts as a catalyst for the development of other complications, such as cardiovascular disease [40]. Our findings were consistent with those of De Lima et al., evaluating the impacts of omega-3 fatty acid supplementation on inflammatory parameters in patients with CKD undergoing hemodialysis treatment [41]. Additionally, Lin et al. found that supplementation with omega-3 reduces plasma levels of CRP in hemodialysis patients [28].
The administration of L-carnitine and omega-3 did not reduce CRP levels. In contrast to our findings, Keshani et al. [42] and Rastgoo et al. [43] reported that L-carnitine supplementation significantly decreases CRP. Furthermore, in the study by Sahebkar, there is a significant decrease in CRP levels after receiving L-carnitine supplementation [44]. Additionally, Haghighatdoost et al. revealed that CRP decreases significantly in the L-carnitine group after the intervention [45]. The lack of a remarkable impact of omega-3 and L-carnitine on CRP levels may be due to chronic inflammation, which is often too severe for supplements to counteract. Additional factors, such as insufficient dosage or duration of treatment, drug interactions, and individual variability in patient responses due to differences in disease severity, comorbidities, and nutritional status, may also contribute. Together, these factors elucidate why these supplements may not significantly decrease CRP levels in dialysis patients in the present study.
The total score of sleep quality improved after taking L-carnitine and omega-3 alone or in combination. In this context, Estaji et al. found that a 500mg L-carnitine supplement taken twice a day for 12 weeks improves sleep quality in hemodialysis patients [26]. Furthermore, Heydarbaki et al. reported that omega-3 improves the sleep quality of patients with uremic pruritus undergoing hemodialysis [46].
There was no statistically significant difference in the general HRQOL score after treatment with omega-3 and L-carnitine. However, the QOLin kidney disease and quality of sleep significantly improved in the omega-3 and omega-3 plus L-carnitine groups. In this regard, Dashti-Khavidaki et al. reported that in hemodialysis patients, omega-3 fatty acids (180mg eicosatetraenoic acid and 120mg docosahexaenoic acid in each capsule) taken daily for four months improves HRQOL and reduces depression [21]. Moreover, Zhang et al. have shown significant improvement in subscales of QOL, including energy/fatigue and physical role during hemodialysis, after receiving fish oil, as assessed using the KDQLQ-SF [32].
L-carnitine only improved the quality of sleep in hemodialysis patients. Contrary to the results of the present study, Semeniuk et al. indicated that L-carnitine (20mg/kg) does not significantly change QOL, muscle cramping, hemoglobin levels, or intradialytic hypotension in hemodialysis patients [23]. Moreover, according to Emami Naini et al., the QOL of patients on hemodialysis does not improve after receiving L-carnitine [24]. Additionally, as Miyagawa et al. stated, there is no significant improvement in the QOL of patients with narcolepsy in the intervention group after receiving L-carnitine compared to the placebo group [25]. One possible explanation for the discrepancies between previous studies and the present work may be attributed to differences in L-carnitine dosage, the comorbidity of the disease, and sample size.
The study had some limitations, such as a small sample size, a low dose of supplements, and the absence of a control group without intervention, which may affect the validity of the data. However, further research with larger sample sizes and higher doses of the indicated supplements is recommended to confirm these findings.
Conclusion
Omega-3 and a combination of omega-3 and L-carnitine improve the QOL and quality of sleep in patients undergoing hemodialysis.
Acknowledgments: The results of this trial are part of an MD thesis by Alireza Dehghan. We gratefully acknowledge the Vice Chancellor for Research at Yasuj University of Medical Sciences for their support.
Ethical Permissions: All methods were performed under the relevant guidelines and regulations outlined by the Declaration of Helsinki. Approval from the Ethics Committee of Yasuj University of Medical Sciences was obtained (IR.YUMS.REC.1399.199) on 2021-02-24. Before the intervention, written informed consent was obtained from all patients, and they were informed of their right to withdraw from the study at any time. We also received written informed consent from the patient caregivers, whether parents or primary guardians. Moreover, the confidentiality and privacy of the participants were ensured.
Conflicts of Interests: The authors declared no conflicts of interests.
Authors' Contribution: Gholami D (First Author), Main Researcher/Methodologist/Introduction Writer/Discussion Writer (20%); Abbasi Larki R (Second Author), Methodologist/Introduction Writer/Discussion Writer (15%); Manzuri L (Third Author), Methodologist/Assistant Researcher/Introduction Writer/Statistical Analyst (15%); Taheri T (Fourth Author), Assistant Researcher/Introduction Writer (10%); Asfaram A (Fifth Author), Introduction Writer/Methodologist/Discussion Writer (10%); Sadeghi Mansourkhani H (Sixth Author), Main Researcher/Methodologist/Introduction Writer/Discussion Writer (20%); Dehghan A (Seventh Author), Assistant Researcher/Introduction Writer (10%)
Funding/Support: This study was supported by the Yasuj University of Medical Sciences.
Keywords:
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