Introduction

Cardiovascular disease (CVD) remains a primary cause of both morbidity and mortality among patients with chronic kidney disease (CKD), particularly those in end-stage renal disease. Individuals on dialysis experience substantially higher risks for CVD-related complications compared to the general population, with mortality in younger dialysis patients resembling that of octogenarians without kidney disease [1]. Dyslipidemia is a common contributor to CVD in CKD [2], and glucose absorption from peritoneal dialysis (PD) fluids is known to induce metabolic disruptions such as insulin resistance, weight gain, and lipid imbalances [3-5]. Notably, hypertriglyceridemia is prevalent in PD patients, with incidences reaching 70% [6].

Elevated levels of monounsaturated fatty acids (MUFAs), particularly oleic acid, in erythrocyte membranes have been observed in patients diagnosed with acute coronary syndrome when compared to healthy individuals [7]. Furthermore, higher concentrations of saturated fatty acids (FAs) and oleic acid in erythrocyte membranes appear to be negatively associated with cardiovascular health, potentially increasing the risk of CVD [8-10]. Among dialysis patients, those receiving PD show increased MUFA and oleic acid contents in their erythrocyte membranes compared to those undergoing hemodialysis [11]. In stroke patients, serum oleic acid concentrations have been found to positively correlate with triglyceride levels [12], suggesting that hypertriglyceridemia may significantly influence CVD outcomes in PD patients. Therefore, the development of PD solutions that help reduce triglyceride levels could be critical for the effective management of these individuals.

Although several investigations have explored how icodextrin influences triglyceride levels in PD patients, the results have been inconsistent. While some studies indicate a lack of correlation between icodextrin use and triglyceride levels, others report a notable association [13,14]. These conflicting results may stem from methodological differences, such as the use of nonrandomized study designs or the inclusion of triglyceride levels only as secondary outcomes. Consequently, the current study aims to assess and compare the effectiveness of glucose-based and icodextrin-based PD solutions in managing triglyceride and oleic acid levels in PD patients.

Methods

Ethical statements: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Boards (IRBs) of Dong-A University (IRB No. 14-088) and HBS Han Seo Hospital (IRB No. CTS-14-003) and with the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from all participants. The patient records and information were anonymized and de-identified prior to analysis.

1. Study design and participants

A multicenter, open-label, randomized crossover trial was conducted from January 2017 to March 2019 and was registered at ClinicalTrials.gov (Identifier: NCT02166359). A total of 22 PD patients were enrolled from two hospitals (19 patients from Dong-A University Hospital and three patients from BHS Han Seo Hospital), with 15 patients completing the full study cycle.

The inclusion criteria were as follows: (1) participants aged 20–80 years; (2) participants who had undergone PD for >3 months; (3) participants who had received either 2.5% or 4.25% glucose-based PD solutions for >4 hours; (4) participants who had not received an icodextrin-based PD solution within the last 3 months prior to enrollment; and (5) those who consented to participate in this clinical trial.

The exclusion criteria were as follows: (1) patients allergic to starch polymers; (2) patients with glycogen storage disease; (3) patients with either a maltose or isomaltose intolerance; (4) patients with either active alcohol or substance abuse; (5) pregnant or breastfeeding patients undergoing PD; (6) patients who had been recently prescribed lipid-lowering medications, including statins, omega-3 FAs, or sevelamer hydrochloride within 12 weeks prior to study enrollment; (7) patients with triglyceride levels >500 mg/dL or <100 mg/dL; (8) patients with albumin levels <3.0 g/dL; (9) patients undergoing automated PD; (10) patients who had received icodextrin PD solutions within 12 weeks prior to study enrollment; and (11) patients who had experienced an episode of peritonitis and active systemic infection within 4 weeks prior to study enrollment.

Ten and 12 participants were assigned to the icodextrin-based PD solution group and glucose-based PD solution group, respectively. Participants assigned to the glucose group initially received PD treatment with 2.5% or 4.25% glucose-based PD solutions over a 12-week period. This was followed by another 12 weeks using the same glucose-based PD solutions as part of a designated washout phase. In the final 12 weeks, the glucose-based PD solutions were replaced with icodextrin-based PD solutions (Fig. 1).

For individuals who had been administered both concentrations of glucose-based PD solutions, the 4.25% glucose-based PD solution was substituted with icodextrin, typically maintained for 8 to 16 hours daily. The duration and concentration of glucose-based PD solutions were either sustained or lowered, depending on clinical judgment.

Conversely, the icodextrin-based PD solution group commenced PD therapy with icodextrin-based PD solutions during the first 12 weeks. These were then switched to glucose-based PD solutions (2.5% or 4.25%) for the next 12 weeks, serving as the washout phase. The glucose-based PD solutions were continuously administered for the remaining 12 weeks. Since dialysis could not be halted, the washout was conducted using glucose-based PD solutions instead. In summary, both groups received glucose-based PD solutions treatment for a total of 24 weeks (including washout), while icodextrin-based PD solutions were administered for 12 weeks per group. Data from this 24-week period were used to evaluate and compare clinical outcomes.

Following the 36-week study duration, treatment regimens were either maintained or modified to include icodextrin-based PD solutions, depending on patient needs. In cases of edema, attending physicians prescribed additional high glucose-based PD solutions.

The primary outcome was to assess differences in triglyceride levels following glucose- or icodextrin-based PD solutions treatment at the 12- and 24-week marks. Additionally, changes in erythrocyte membrane FA composition—including oleic acid—were examined and compared between the two treatment groups at 12 and 24 weeks.

2. Biochemical evaluation

Blood specimens were collected, properly handled, and cooled before being stored at −70 °C until testing. Measurements were taken for serum hemoglobin, glucose levels, blood urea nitrogen, creatinine, albumin, cystatin C, C-reactive protein, total cholesterol, triglycerides, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and apolipoproteins A and B (apo A and B). These evaluations were conducted at 0, 3, 6, and 9 months. Insulin resistance was assessed using the homeostatic model (HOMA-IR), calculated as HOMA-IR=fasting insulin (μIU/mL)×fasting glucose (mg/dL)/450 [15]. Additionally, ultrafiltration volume was recorded during each evaluation period.

3. Gas chromatography analysis

FA content in erythrocyte membranes was quantified using gas chromatography at the beginning of the study and after 24 weeks, following previously established methodologies [16,17]. To assess the proportion of eicosapentaenoic acid and docosahexaenoic acid in these membranes, the omega-3 index was applied [18]. FA values were reported as percentages by weight relative to total FA composition.

4. Statistical analysis

A total of 20 subjects per group was estimated to be necessary to detect a mean triglyceride difference of 20±36.3 mg/dL, achieving an 80% statistical power with a two-tailed alpha level of 0.05 and factoring in an anticipated 30% dropout rate [19].

Continuous data were expressed as mean±standard deviation, while categorical variables were represented as frequencies. For nonnormally distributed data, the Wilcoxon-Mann-Whitney U test was applied; categorical comparisons were conducted using the chi-squared test. All analyses were executed using PASW Statistics ver. 18.0 (IBM Corp.), with statistical significance defined as p<0.05.

5. Dropout of participants

From the icodextrin-based PD solution group, two participants withdrew their consent, one participant refused to continue participating in this clinical trial, and the blood sample of another participant was lost. From the glucose-based PD solution group, three participants refused to continue participating in this clinical trial. Thus, 22 participants were enrolled, and 15 participants completed the study.

Results

1. Characteristics of the participants

A total of 22 individuals were enrolled in the study, with 15 successfully completing the trial. The mean age of these participants was 63.6 years, with a standard deviation of 9.5 years. Their PD duration had a mean of 10.8 months, with a deviation of 5.9 months. Detailed baseline data can be found in Table 1. Specifically, the glucose-based PD solution group had a mean age of 66.1±10.6 years, while those in the icodextrin-based PD solution group had a mean age of 60.5±7.4 years.

2. Analyses of the changes in the biochemical parameters

At baseline, there were no statistically significant differences observed between the glucose- and icodextrin-based PD solution groups in terms of clinical and laboratory metrics. Following a 3-month exposure to icodextrin-based PD solutions, no significant reductions were noted in total cholesterol, HDL-, and LDL-cholesterol levels (Table 2). While triglyceride levels decreased during this period, the change did not reach statistical significance (p=0.093) (Fig. 2).

In contrast, after 3 months of treatment with glucose-based PD solutions, triglyceride levels exhibited an increasing trend. Insulin levels showed a statistically significant rise, accompanied by an elevation in HOMA-IR values.

Prolonged exposure to glucose-based PD solutions over 6 months resulted in increases in triglyceride (p=0.041) and LDL-cholesterol levels. Apo B levels also demonstrated a statistically significant rise at the 6-month mark.

3. Alterations in fatty acid composition of erythrocyte membranes

Following a 3-month treatment period using icodextrin-based PD solution, a significant elevation in lignoceric acid levels was observed. However, the oleic acid levels remained statistically unchanged compared to baseline measurements (Table 3).

After 6 months of continued exposure to glucose-based PD solutions, notable increases were detected in the levels of MUFA, oleic acid (p=0.009), and alpha-linolenic acid when compared to baseline values (Fig. 3). In contrast, a significant reduction in arachidonic acid levels in erythrocyte membranes were identified.

Discussion

In this study, triglyceride levels demonstrated a declining pattern following a 3-month treatment with icodextrin-based PD solutions. In contrast, an identical exposure period to glucose-based PD solutions led to an upward trend in triglyceride levels. These contrasting outcomes indicate that prolonged exposure to different PD solutions exerts distinct effects on triglyceride and LDL-cholesterol levels. The favorable metabolic trends observed with icodextrin are fundamentally rooted in its unique physiochemical and biocompatibility advantages over conventional glucose-based PD solutions. As a high molecular weight starch polymer, icodextrin generates ultrafiltration primarily through colloid osmosis, which is slower and more sustained than the osmotic effect of dextrose. Crucially, its large size significantly limits peritoneal glucose absorption, thereby reducing the total systemic caloric load derived from the dialysate. This core action alleviates the metabolic burden. It prevents the hyperglycemia and subsequent hyperinsulinemia that characterizes glucose-based PD solutions, thereby improving insulin resistance. Lower insulin levels reduce the substrate availability for hepatic lipogenesis, directly suppressing very LDL and triglyceride production [15]. By improving fluid management and potentially reducing extracellular volume, icodextrin may control volume overload, which is often intertwined with metabolic disturbances [10,20]. Supporting this, earlier studies have shown that in newly initiated PD patients, icodextrin use was linked to reduced all-cause and cardiovascular mortality [10,14,21,22]. The suppression of atherogenic lipids and FA accumulation observed in our study, although not statistically robust over 12 weeks, aligns with the protective effects demonstrated in these larger, long-term clinical outcome studies. This suggests that the early metabolic shifts we observed may contribute to improved long-term outcomes in PD patients.

Following a 3-month period of treatment using icodextrin-based PD solutions, erythrocyte membrane oleic acid levels exhibited the trends of reduction, which did not reach statistical significance. In comparison, patients in the glucose-based PD solutions showed a slight, nonsignificant increase in oleic acid levels at week 12, with a marked and statistically significant elevation by week 24—underscoring the need for extended follow-up studies beyond the 12-week timeframe. Furthermore, levels of apo B in the glucose-based PD solution group began trending upward at the 12-week point and became significantly elevated by week 24. These observations are consistent with earlier research by Sniderman et al. [21], which examined individuals with diabetes mellitus undergoing PD. Their results demonstrated that apo B levels significantly decreased in the icodextrin-based PD solution group at both 3 and 6 months, while the glucose-based PD solution group experienced notable increases over the same duration. Taken together, these outcomes suggest that icodextrin-based PD solutions may offer meaningful improvements in lipid parameters compared to glucose-based PD solutions. Accordingly, a dual approach that incorporates both glucose- and icodextrin-based PD solutions may prove beneficial.

Patients with elevated triglyceride levels tend to display higher levels of insulin resistance than those with normal triglyceride concentrations [7]. In our study, although insulin resistance did not show statistically significant changes, insulin levels in the glucose-based PD solution group increased at week 12—indicating that glucose-containing PD solutions may stimulate insulin secretion indirectly. A separate investigation by Babazono et al. [3] found that individuals with an initial glycated hemoglobin (HbA1c) level of ≥6.5% experienced a significant reduction in HbA1c when treated with icodextrin-based PD solutions. Additionally, their findings reported improved lipid profiles. Patients presenting with triglyceride levels above 150 mg/dL saw significant reductions by month 3, whereas those with normal baseline levels showed improvement only by month 9. Notably, that study included more than twice the number of participants compared to ours, yet triglyceride reduction was evident at 9 months among those receiving icodextrin treatment [23]. Overall, the current study reinforces the notion that icodextrin may counteract multiple metabolic disturbances caused by glucose components in PD therapy.

This study presents certain limitations. The relatively small sample size may have influenced statistical power and interpretability. While the icodextrin-based PD solution group demonstrated a favorable declining trend in triglyceride levels, this result failed to reach statistical significance. To explore this statistical limitation, a post-hoc power analysis was performed. Based on the observed effect size and the final sample size for the paired t-test, the calculated statistical power was only 46.5%. This value is substantially below the generally accepted standard of 80% for detecting the observed effect. The nonsignificant p-value is likely attributable to insufficient statistical power rather than the absence of a true metabolic benefit. This highlights the need for larger and appropriately powered studies to confirm the potential long-term benefits of icodextrin on lipid profiles in PD patients. Another limitation is the relatively short 12 weeks duration of icodextrin exposure. Metabolic shifts are often time-dependent and may require more prolonged exposure to become fully manifest [3,14]. Due to the nature of PD, treatment could not be halted, necessitating the use of glucose-based PD solutions as a temporary washout period substitute. This nonideal measure introduced a potential risk of a carryover effect on the subsequent treatment period. However, the potential for a carryover effect was statistically assessed by analyzing the sum of the primary outcome values for both periods between the two groups using an independent t-test. No statistically significant carryover effect was detected for any of the primary outcomes, including serum triglycerides, confirming the validity of the sequential analysis. The observed declining trend in triglycerides after following 12 weeks of icodextrin use may substantially underestimate its long-term metabolic benefits. Lastly, our study did not check for the concurrent use of insulin, oral hypoglycemic agents, or lipid-lowering agents and dietary habits. Larger-scale, long-term studies—either retrospective or prospective—are essential to draw more conclusive insights.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: WSA. Data curation: JN, SML, SHS. Formal analysis: SML, SHS. Investigation: JN, SML, SHS, WSA. Methodology: SML, WSA. Supervision: JKK, WSA. Writing-original draft: JN, SML, WSA. Writing-review & editing: SHS, JKK, WSA. All authors read and approved the final manuscript.

Fig. 1.

Study flow chart. PD, peritoneal dialysis.

Fig. 2.

Changes in triglyceride levels from baseline to 12 weeks during exposure to icodextrin-based peritoneal dialysis solutions.

Fig. 3.

Changes in erythrocyte membrane oleic acid contents from baseline to 12 weeks and 24 weeks during exposure to glucose- and icodextrin-based peritoneal dialysis (PD) solutions. ^*p-value <0.05 (mean values are significantly different from baseline).

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References

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