NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(2):494-498; doi:10.1093/ndt/gfi197
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Dialysis and Transplantation
Beneficial effects of icodextrin on plasma level of adipocytokines in peritoneal dialysis patients
1 Department of Internal Medicine, Iwata City Hospital, Iwata, Japan, 2 Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan and 3 First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
Correspondence and offprint requests to: Ryuichi Furuya, MD, PhD, Renal Division, Department of Internal Medicine, Iwata City Hospital, 512-3 Ohkubo, Iwata, 438-8550, Japan. Email: r-furuya{at}isis.ocn.ne.jp
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Abstract |
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Objective. Leptin and adiponectin, well-recognized adipocytokines, are reported to contribute to the pathogenesis of atherosclerosis. The aim of this study was to elucidate the effects of icodextrin-based dialysis solution on adipocytokine metabolism.
Methods. In 12 non-diabetic anuric patients on peritoneal dialysis, dialysis solution was changed from glucose-based dialysis solution to icodextrin-based dialysis solution for 6 months. Plasma levels of leptin, adiponectin, lipids (total cholesterol, HDL-cholesterol and triglyceride), insulin, blood glucose and insulin sensitivity index by the homeostasis model assessment (HOMA-IR) were compared before and after the use of the icodextrin solution.
Results. Plasma leptin level was decreased from 15.6 (2.5–69.0) to 7.3 (2.9–45.9) ng/ml (P = 0.018) and plasma adiponectin level increased from 11.6 (6.2–19.6) to 17.6 (7.8–33.0) µg/ml (P = 0.002). A reduction in plasma insulin level from 33.1 (13.8–54.1) to 19.1 (5.8–37.3) µU/ml (P = 0.009) and HOMA-IR from 8.22 (3.68–15.09) to 5.15 (1.40–13.78) (P = 0.015) was observed. While plasma total cholesterol level remained similar, HDL-cholesterol level increased, from 36.0 (22–45) to 43.5 (30–69) mg/dl (P = 0.008) and the triglyceride level decreased, from 174.0 (140–250) to 116.5 (81–207) mg/dl (P = 0.012).
Conclusion. Icodextrin-based dialysis solution improves abnormal adipocytokine metabolism, dyslipidaemia and insulin resistance, which are known to be associated with atherosclerosis. These results suggest that the use of icodextrin-based dialysis solution might be useful in preventing atherosclerosis in PD patients. Long-term effects of icodextrin-based dialysis solution on the atherosclerosis in peritoneal dialysis patients should be tested.
Keywords: adiponectin; dyslipidaemia; icodextrin; insulin resistance; leptin; peritoneal dialysis
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Introduction |
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Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality in peritoneal dialysis (PD) patients [1]. Aside from classic risk factors such as hyperlipidaemia, hyperinsulinaemia, insulin resistance and hypertension, recent studies have demonstrated that adipocytokines, such as leptin and adiponectin, play important roles in the development of atherosclerosis. Leptin is linked to coronary atherosclerosis [2]. In fact, plasma leptin level has been identified as an independent risk factor for coronary heart disease [3]. Conversely, adiponectin is reported to suppress the development of atherosclerosis [4]. Low plasma adiponectin level has been observed in patients with coronary atherosclerosis [5]. Importantly, both adipocytokines, adiponectin and leptin, are reported to be in increased levels in PD patients [6,7].
Recently, icodextrin-based dialysis solution was developed. The reduced dose of glucose load may improve the abnormal metabolism in PD patients. Actually, plasma insulin levels have been reported to be reduced by using icodextrin-based dialysis solution [8]. Beneficial effects of icodextrin-based dialysis solution on lipid profile were also reported in PD patients [9]. Since the relationships between plasma levels of leptin or adiponectin and glucose [10,11] or lipid [6,12] metabolisms are reported, it is assumed that the use of icodextrin-based dialysis solution affects plasma levels of adiponectin and other cardiovascular risk factors.
In order to clarify the effects of icodextrin-based dialysis solution on cardiovascular risk factors in anuric PD patients, we evaluated the effects of icodextrin-based dialysis solution on plasma levels of adipocytokines, insulin, and insulin sensitivity in non-diabetic anuric PD patients.
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Methods |
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Patients
Twelve anuric non-diabetic patients (7 men and 5 women) with chronic renal failure undergoing peritoneal dialysis at Iwata City Hospital participated in this study. The protocol was approved by the local ethics committee and written informed consent was obtained from each patient. The patient characteristics are shown in Table 1. The median age of the patients was 57.0 years, and the median time on peritoneal dialysis was 51.0 months. The cause of chronic renal failure was glomerulonephritis in all patients. Nine patients were prescribed antihypertensive agents and two patients hydroxyl-methylglutaryl coenzyme A inhibitor. The doses of these drugs were not changed during this study period.
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Before the start of this study, peritoneal dialysis had been carried out using standard glucose-based dialysis solution with glucose concentrations of 1.36 or 2.27% (Dianeal, Baxter Healthcare, Miyazaki, Japan). Of the 12 patients, 9 received regular continuous ambulatory peritoneal dialysis (CAPD), where 1.5 or 2.0 L dialysis solution was exchanged 4 to 5 times a day and 3 were prescribed continuous cycling peritoneal dialysis (CCPD) receiving 8 L dialysis solution exchanged with a cycler during night time and 2 L dialysis solution was exchanged twice during day time. The median calculated glucose load was 186.3 g/day.
Study design
Dialysis fluid was changed from glucose-based solution to 7.5% icodextrin-based dialysis solution (Extraneal, Baxter Healthcare) for 6 months in all patients. The 7.5% icodextrin-based dialysis solution was used during night time in nine CAPD patients (dwell time: 10 h) and during day time in three CCPD patients (dwell time: 10 h). Other dialysis conditions, including the glucose concentration of the dialysis exchanges, were not changed during the study periods.
Blood samples and wasted dialysate were obtained before and 6 months after the start of icodextrin-based dialysis solution. We collected blood samples at noon before lunch. All samples were stored at –80°C until analysis.
A standard peritoneal equilibration test was also performed before and 6 month after the start of treatment with icodextrin-based dialysis solution.
Analytic procedures and calculations
Body mass index (BMI) was calculated as follows:
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Blood urea nitrogen (BUN), creatinine, total cholesterol, HDL-cholesterol and triglyceride were measured by standard laboratory technique using automatic analysers. CRP was measured by the latex agglutination method. Blood glucose was measured by glucose-DH method, and plasma insulin by enzyme immuno assay (EIA). Plasma concentrations of leptin and adiponectin were measured using Human Leptin Assay Kit (IBL Co., Ltd., Gunma, Japan) and Human Adiponectin ELISA Kit (Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan), respectively.
Insulin resistance was evaluated using homeostatic model assessment (HOMA-IR) as follows:
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The leptin to adiponectin ratio was calculated as an atherogenic index [13].
Statistical analysis
Each value is expressed as median (range). Two paired variables were analysed by Wilcoxon signed rank test. P-values less than 0.05 were considered statistically significant. All statistical calculations were performed with StatView 5.0 (SAS Institute, Inc., Cary, NC, USA).
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Results |
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During the study periods, no significant change was observed in serum levels of urea nitrogen and creatinine, Kt/V and total creatinine clearance (Ccr). Icodextrin-based dialysis solution significantly increased the ultrafiltration, but did not affect dialysate–plasma creatinine ratio (D/PCr) (Table 2).
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PD using icodextrin-based dialysis solution significantly increased the plasma level of adiponectin from 11.6 (6.2–19.6) to 17.6 (7.8–33.0) µg/ml (P = 0.002), and significantly decreased the plasma level of leptin from 15.6 (2.5–69.0) to 7.3 (2.5–45.9) ng/ml (P = 0.018), respectively (Figure 1). The leptin-to-adiponectin ratio was decreased significantly from 1.113 (0.192–9.035) to 0.330 (0.114–3.655) (P = 0.002). PD using icodextrin-based dialysis solution also significantly decreased the plasma levels of insulin and triglyceride and HOMA-IR (Table 3). In contrast, plasma HDL-cholesterol level was increased by using icodextrin-based dialysis solution. Icodextrin-based dialysis solution did not affect body weight, BMI, blood pressure, total Ccr, blood glucose and serum total cholesterol. We also did not notice any significant changes in the general condition of patients, including their blood pressure, during 6 months of study period. So we did not change the content and the dosage of anti-hypertensive agents.
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Discussion |
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In this study, we demonstrated that the change of dialysis fluid from glucose-based to icodextrin-based dialysis solution in anuric PD patients improved abnormal adipocytokine metabolism, dyslipidaemia and insulin resistance, which are known to be associated with atherosclerosis. Icodextrin-based dialysis solution induced an increase in adiponectin and HDL-cholesterol and a decrease in leptin and triglyceride levels as well as in HOMA-IR.
In this study, we evaluated the factors that affect plasma adipocytokines, such as renal function, blood glucose, insulin, insulin sensitivity, body weight and BMI. Plasma adiponectin levels are reported to correlate inversely with GFR in patients without renal replacement therapy [14] and with residual renal function in PD patients [6]. Since all patients selected to receive icodextrin-based dialysis solution in this study were anuric during the study period, the elevation of plasma adiponectin level cannot be ascribed to the changes in residual renal function. Body weight reduction is reported to increase plasma adiponectin level [11,15]. For example, Yang et al. [15] reported a 46% increase in plasma adiponectin on a 21% reduction in body mass index. In the present study, a 50% increase in plasma adiponectin level was associated with no significant change of the body mass index, indicating that the icodextrin-based dialysis solution-induced increase in plasma adiponectin level was not mediated by body weight reduction. In the present study, the icodextrin-based dialysis solution-induced increase in plasma adiponectin was associated with a decrease in plasma insulin. Since insulin reduced the level of adiponectin mRNA in a dose- and time-dependent manner [16], it is likely that the elevation of plasma adiponectin level was secondary to the decline of plasma insulin level. It is possible that icodextrin-based dialysis solution reduced the plasma insulin through the lower glucose load and better glycaemic control.
The continuous glucose load during PD induces chronic hyperinsulinaemia, which in turn stimulates leptin mRNA and results in increasing plasma leptin level [17]. As the reduction in plasma insulin level and HOMA-IR in our study were observed in patients treated with icodextrin-based dialysis solution, it is likely that the decrease in plasma leptin was secondary to decreased plasma insulin level and enhanced insulin sensitivity. Though leptin was reported to be removed through peritoneal clearance, only 2–3% of leptin produced daily is cleared through peritoneum and peritoneal elimination of leptin is reported to play a minor role in determining the plasma leptin level [18]. However, we cannot exclude the possibility that an increase in peritoneal clearance could have contributed to the decrease in plasma leptin level in some degree, since the use of icodextrin-based dialysis solution is known to increase the peritoneal clearance of leptin [19]. We found no changes in body weight or BMI in the present study, suggesting a minor change of body fat volume. However, we cannot exclude the possibility that icodextrin-based dialysis solution decreased plasma leptin level through the reduction of body fat, since fat content could be changed without alterations in body weight or BMI [20].
High plasma leptin level and low plasma adiponectin level have been observed in patients with coronary atherosclerosis [3,5]. Furthermore, the leptin-to-adiponectin ratio is more strongly correlated with pulse wave velocity (PWV) than leptin or adiponectin levels alone [13]. In the current study, a significant reduction of leptin-to-adiponectin ratio was noted in patients treated with icodextrin-based dialysis solution, indicating that the use of icodextrin-based solution may reduce the risk of atherosclerosis.
In summary, icodextrin-based dialysis solution decreased plasma leptin and increased plasma adiponectin level in addition to improvements in insulin resistance and dyslipidaemia, suggesting that icodextrin-based dialysis solution may be useful in preventing atherosclerosis in PD patients. Long-term effects of icodextrin-based dialysis solution on the atherosclerosis in PD patients should be tested.
Conflict of interest statement. None declared.
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Accepted in revised form: 9. 9.05
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