Carnitine is a water-soluble amino acid derivative with a molecular weight of 161 Da, and it has an important role in fatty acid metabolism in skeletal muscle (1–3). Seventy-five percent of the human body requirement for carnitine is obtained from the diet such as red meat, while the remaining 25% is biosynthesized in the kidneys and liver (4, 5). Carnitine exists in different forms in serum including free carnitine and acyl carnitine (6, 7). Total carnitine is the sum of free carnitine and acyl carnitine (6, 7). Free carnitine is converted to acyl carnitine by binding acyl residues, and it can transfer acyl residues into mitochondria for use as an energy source (1, 2). However, excess and harmful acyl residues are also discharged as acyl carnitines (1, 2). Therefore, to maintain homeostasis of energy metabolism, the different forms of carnitine must be properly balanced.

Low serum free carnitine and/or high acyl carnitine/free carnitine ratio generally result in diagnosis of carnitine deficiency (8). In the healthy population, the frequency of carnitine deficiency is very low because carnitine is supplied satisfactorily through diet and renal and hepatic biosynthesis (4, 5). However, carnitine deficiency is frequently observed in patients undergoing hemodialysis (4, 9, 10). Possible mechanisms for the deficiency include dietary restrictions attributed to renal failure, decreased biosynthesis, and exposure to dialysate (11, 12). Previous studies have reported a loss of more than 60% of free carnitine in one hemodialysis session (13). Additionally, a Japanese research group recently reported that hemodiafiltration contributed more to carnitine loss than hemodialysis (hemodialysis 64% ± 4% vs. hemodiafiltration 75% ± 7%) (10). Typically, carnitine deficiency is associated with various symptoms such as erythropoietin-resistant anemia, muscle weakness, cardiac dysfunction, and intradialytic hypotension (14). Additionally, recent studies have suggested an association between carnitine deficiency and conditions such as glucose metabolism disorders and liver dysfunction (15–18). National Kidney Foundation guidelines recommend carnitine supplementation for patients with carnitine deficiency undergoing hemodialysis (14).

However, at this time, only a few reports have investigated carnitine deficiency in patients undergoing peritoneal dialysis (PD) (19–21). Clinicians should note that the National Kidney Foundation guidelines are not sufficiently supported by reports of carnitine deficiency in patients undergoing PD (14). Under these circumstances, we previously reported a high prevalence of carnitine deficiency in patients undergoing PD in a cross-sectional study (21). Additionally, we found a significant association between the acyl carnitine/free carnitine ratio and the erythropoietin resistance index (ERI) in this population (21). The ERI is an indicator for the severity of erythropoietin-resistant anemia (22, 23), and it is associated with the mortality rate in patients undergoing dialysis (23). Therefore, carnitine deficiency is considered to be an important pathological condition in patients undergoing hemodialysis and in patients undergoing PD. The utility of carnitine supplementation in the patients undergoing PD remains unclear because, to date, it has not been fully investigated. Therefore, in the present study, we retrospectively investigated the effects of carnitine supplementation in patients with carnitine deficiency who were undergoing PD.

In this study, 4–6 months of oral carnitine supplementation (mean dose: 9.1 ± 3.3 mg/kg/day) in patients undergoing PD increased total carnitine, free carnitine, and acylcarnitine levels, and did not affect the acyl carnitine/free carnitine ratio. Although carnitine supplementation did not decrease the mean ERI value, the ERI change rate was significantly decreased. In the control group, the mean ERI value was not changed after 6 months of follow-up and the ERI change rate was significantly increased. These results suggest that erythropoietin resistance in patients who are undergoing PD may be improved by oral carnitine supplementation. The difference in the baseline ERI between the two groups (13.7 ± 4.7 vs. 6.9 ± 2.6 [IU/kg/(g/dL)/week], P < 0.01) may be because we preferentially administered carnitine to patients with severe erythropoietin resistance in accordance with the guidelines (14). Although this short-term observational study had a small sample size, the results are important because few similar studies have been conducted (19, 20). In Japan, carnitine measurement was covered by public medical insurance starting in February 2018, and we expect that the details on carnitine deficiency in patients who are undergoing PD will be gradually clarified in the future.

In patients undergoing PD, carnitine deficiency can be explained by several factors. First, patients with kidney disease, including those undergoing PD, must follow dietary restrictions. Therefore, oral intake of carnitine is reduced (11, 12). Second, because carnitine is biosynthesized in the kidney, it tends to be deficient in patients with impaired renal function (11, 12). Third, loss of carnitine in PD fluid is also possible (33). Although a previous study showed that APD contributed more to free carnitine loss than CAPD (34), our previous studies did not show the same results (21). Additionally, the hemodialysis combination (daily PD + hemodialysis once a week) did not affect the carnitine level in our previous study (21).

At present, there are few reports on carnitine supplementation in patients undergoing PD (19, 20). The National Kidney Foundation recommends 9–12 months of carnitine supplementation for dialysis patients. However, this is intended for patients undergoing hemodialysis, not those undergoing PD (14). Japanese guidelines propose oral carnitine supplementation at 10–20 mg/kg in patients undergoing PD, although there are no previous reports that support these guidelines. Therefore, the optimal treatment period, supplementation dose, and monitoring frequency for carnitine deficiency in patients who are undergoing PD have not been established. To avoid unexpected adverse effects, we performed a relatively short-term study (4–6 months) using a relatively small dose (9.1 ± 3.3 mg/kg/day) of carnitine.

We previously reported the importance of the acyl carnitine/free carnitine ratio for diagnosing carnitine deficiency in patients undergoing PD (21). In the current study, ERI decreased following carnitine supplementation with increasing levels of both free carnitine (from 17.4 ± 3.0 to 46.9 ± 14.5 μmol/L) and acyl carnitine (from 31.1 ± 8.6 to 83.1 ± 25.8 μmol/L). The acyl carnitine/free carnitine ratio was not changed by carnitine supplementation. According to these results, increased free carnitine level may be more effectives than corrected balance of acyl carnitine/free carnitine ratio for improving ERI in patients undergoing PD. Future studies with larger sample sizes and longer observational periods are required to further clarify the effects and proper monitoring of carnitine supplementation in patients undergoing PD with carnitine deficiency.

Carnitine is considered to be associated with red blood cell deformability (22, 35, 36). Therefore, carnitine deficiency is considered to be one of the factors that caused the increased ERI (21). To our knowledge, there are only two reports on the effects of carnitine supplementation on erythropoietin-resistant anemia in patients undergoing PD (19, 20). Sotirakopoulos et al. reported that anemia improved in 12 patients undergoing PD who received carnitine supplementation (19). In contrast, Lilien et al. reported that carnitine supplementation did not improve anemia in four pediatric patients undergoing PD (20). The differences between these reports and our report may be explained by oral medication adherence. Poor oral medication adherence is often a serious problem in clinical settings. At our institution, we thoroughly checked the oral medication adherence and confirmed that the patients did not miss a dose. Additionally, the effects of carnitine supplementation on erythropoietin-resistant anemia may be associated with differences in the carnitine supplementation dose, supplementation period, and patient background.

This study had important limitations. First, this was an observational study with a small sample size, and additional large-scale studies are needed. Second, it was conducted at a single facility. Third, carnitine supplementation was only administered orally, and carnitine-containing PD fluid was not considered. Fourth, the results may have been affected by differences in carnitine supplementation dose and period. Fifth, this finding cannot be applied to patients without carnitine deficiency. Large-scale interventional studies are required to clarify the effectiveness of carnitine supplementation in patients who are undergoing PD with carnitine deficiency.

Carnitine supplementation may improve erythropoietin resistance in patients undergoing PD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Saitama Medical Center, Jichi Medical University Ethics Committee (DAI-RIN 15-34). Written informed consent for participation was not required for this study in accordance with the National Legislation and the Institutional requirements.

SK: conceptualization, methodology, software, validation, formal analysis, investigation, resources, visualization, and writing—original draft preparation. SK, KY, TK, HM, KH, SO, and YM: data curation. SK and YM: writing—review and editing. YM: supervision and project administration. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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