Advances in Peritoneal Dialysis, Vol. 29, 2013

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1 Advances in Peritoneal Dialysis, Vol. 29, 2013 Takeyuki Hiramatsu, 1 Takahiro Hayasaki, 1 Akinori Hobo, 1 Shinji Furuta, 1 Koki Kabu, 2 Yukio Tonozuka, 2 Yoshiyasu Iida 1 Icodextrin Eliminates Phosphate and Ameliorates Cardiac Hypertrophy and Valvular Calcification in Patients with End-Stage Renal Disease and Diabetes Mellitus Undergoing Peritoneal Dialysis Among end-stage renal disease (ESRD) patients, cardiovascular disease is a common comorbidity and one of most important factors affecting clinical prognosis. Calcium deposition has been reported to correlate with plasma phosphate. Icodextrin (Ico) based peritoneal dialysis (PD) has many advantages over glucose (Glu) based PD. We aimed to identify factors that suppress arteriosclerosis and valvular disease in patients with ESRD and diabetes mellitus (DM) undergoing Icobased PD. In this retrospective study, we evaluated the effects of Ico-based PD (n = 20) on phosphate elimination and cardiovascular disease progression in patients with ESRD and DM, and we compared the results with those for Glu-based PD (n = 20). Left ventricular mass index (LVMI) and aortic valve calcification (AVC) score were significantly decreased and daily phosphate elimination was significantly increased in the Ico group compared with the Glu group. Furthermore, mean daily phosphate elimination was significantly and negatively correlated with the amelioration in LVMI and AVC score. Our study suggests that, compared with glucose, icodextrin has the ability to eliminate more phosphate from the body, indicating that phosphate elimination From: 1 Department of Nephrology, Aichi Welfare Cooperative Agricultural Konan-Kosei Hospital, Aichi, and 2 Baxter Ltd., Tokyo, Japan. might potentially be a means of controlling cardiovascular disease in PD patients with DM. Key words Icodextrin, phosphate, left ventricular mass index, calcification Introduction Cardiovascular disease is one of the most important factors affecting outcome in peritoneal dialysis (PD) patients. Peritoneal dialysis patients with diabetes mellitus (DM) as a complication are reported to frequently be affected by cardiac hypertrophy and valvular calcification caused by uremia (1 4). Because disturbed mineral metabolism, including hyperphosphatemia, has been suggested to play a major role in vascular and valvular calcification (5), current therapeutic strategies for vascular and valvular calcification in end-stage renal disease (ESRD) patients are directed toward controlling hyperphosphatemia. For effective management of phosphate, the use of calcium-containing or non-calcium-containing phosphate binders has been indicated, but little information is available about dialysis solutions that effectively treat hyperphosphatemia with subsequent cardiovascular disease amelioration in PD patients. We therefore undertook a retrospective study to compare the effect of icodextrin (Ico) based PD with glucose (Glu) based PD on cardiovascular disease progression in patients with DM.

2 10 Icodextrin, Phosphate, and Cardiac Hypertrophy in Diabetic Patients on PD Methods Patients and study protocol We retrospectively analyzed 40 ESRD patients with incident DM [mean age: 61.1 ± 1.7 years (range: years); DM duration: 9.73 ± 9.95 years (range: 2 35 years)]. Initially, all patients received 4 bags of 1.36% Glu-based dialysate daily. Thereafter, patients were divided into a Glu group (n = 20) and an Ico group (n = 20). In the latter group, patients initially received 3 bags of 1.36% glucose; 1 bag of 7.5% icodextrin was added 7 14 days after PD initiation because of manifestation of overt edema or insufficient ultrafiltration volume (<500 ml daily). Laboratory parameters were evaluated at the start of PD and every 6 months for 24 months after PD initiation (Table I). Weekly Kt/V urea was calculated from a 24-hour collection of dialysate and urine at baseline (0 months) and at 24 months after PD initiation. Echocardiography Echocardiography was performed at the start of PD and every 6 months for 24 months thereafter. All echocardiography results were analyzed by a single experienced cardiologist who was blinded to all clinical details, and the data were rechecked by other cardiologists. The parameters included in the analysis were left ventricular mass and left ventricular mass index (LVMI) as indicators of eccentric left ventricular hypertrophy (LVH), which were calculated according to the formulae given by Devereux and Reicheck (6). Aortic valve calcification (AVC) and mitral valve calcification scores were also analyzed every 6 months for 24 months after PD initiation. Valve calcification was scored as follows: 0, no calcification; 1, calcification in 1 valve; 2, calcification in 2 or more valves. Based on the extent of change in AVC score, the patients were classified into 3 groups: Improved: total score of 90% or less compared with baseline No change: total score of more than 90% but 110% or less compared with baseline Worsened: total score of more than 110% compared with baseline Statistical analysis Repeated-measures analysis of variance was used to evaluate differences in the data obtained at various time points. Data are expressed as mean ± standard deviation. Correlations between LVMI and phosphate elimination were evaluated using the Pearson product moment correlation coefficient. Because age, sex, and glucose metabolism were considered possible confounders in the analysis of the relationship between LVH and phosphate elimination, adjustments for those variables were made during the statistical analysis. A p value less than 0.05 was considered statistically significant. Statistical analyses were performed using the SPSS statistical software (version 18 for Windows: SPSS, Chicago, IL, U.S.A.). Results At 18 and 24 months, LVMI was significantly ameliorated in the Ico group (126.4 ± 43.0 g/m 2 and ± 36.0 g/m 2 respectively); however, in the Glu group, LVMI gradually increased from 6 months onward, becoming significantly higher than that in the Ico group at 24 months [155.2 ± 38.0 g/m 2, p < 0.005; Figure 1(A) and Table I]. In the Ico group, the AVC score declined significantly at 12, 18, and 24 months compared with baseline (0.200 ± 0.523, p < 0.05; ± 0.308, p < 0.05; and ± 0.308, p < respectively vs ± 0.894). On the other hand, the AVC score significantly increased after 12 months in the Glu group [Figure 1(B)]. During the study period, the degree of phosphate elimination remained constant in the Ico group; however, it gradually declined and reached statistical significance at 6 months in the Glu group (Figure 2). We observed a strong negative correlation between average phosphate elimination and LVH expressed as the end-to-initial ratio of left ventricular mass index (LVMI 2 /LVMI 0 ) at baseline and at 24 months after peritoneal dialysis initiation, and analyzed using the Pearson product moment correlation coefficient: r = [Figure 3(A)]. Furthermore, when patients were categorized into the improved, not changed, and worsened groups as described in the Methods section, daily phosphate elimination was significantly lower in the worsened group than in the other two groups [323.7 ± 50.7 mg vs ± 34.6 mg in the improved group, p < 0.001, and ± 30.2 mg in the no-change group, p < 0.005; Figure 3(C)]. Discussion This study demonstrates that phosphate elimination is associated with LVH progression and valvular

3 Hiramatsu et al. 11 table i Characteristics of patients a at baseline and 24 months after peritoneal dialysis initiation, by treatment group Baseline 24 Months Variable Glucose Icodextrin p Value Glucose Icodextrin p Value C-Reactive protein (mg/dl) 0.171± ± ± ± HbA1c (%) 6.19± ± ± ± Blood urea nitrogen (mg/dl) 55.3± ± ± ± Creatinine (mg/dl) 7.78± ± ± ± β 2 -Microglobulin (mg/dl) 18.9± ± ± ± Calcium (mg/dl) 8.29± ± ± ± Phosphate (mg/dl) 5.93± ± ± ± Intact PTH (pg/ml) 276.1± ± ± ± ANP (pg/ml) 84.4± ± ± ± BNP (pg/ml) 158.1± ± ± ± D/P creatinine 0.550± ± ± ± Kt/V 2.02± ± ± ± Urine volume (ml/day) ± ± ± ± Ultrafiltration (ml/day) ± ± ± ± Blood pressure (mmhg) Systolic 143.4± ± ± ± Diastolic 85.5± ± ± ± LVMI (g/m 2 ) 139.3± ± ± ± Phosphate elimination (mg/day) Dialytic 420.7± ± ± ± Urinary 153.5± ± ± ± Glucose absorption (g/day) 49.4± ± ± ± a All values are mean ± standard deviation. PTH = parathyroid hormone; ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; LVMI = left ventricular mass index. calcification; it is therefore a good predictor of the pathologic condition of PD patients with DM. Cardiac hypertrophy, especially LVH, is caused by several conditions associated with the uremic state, such as hypertension, anemia, acidosis, hyperphosphatemia, and fluid overload (7 9). Office systolic and diastolic blood pressure were not significantly different in the Ico and Glu groups, suggesting that the amelioration in LVH in the Ico group was not associated with correction of the office-recorded blood pressure. Rather, total ultrafiltration was significantly higher at 2 years in Ico group, suggesting that the decrease in LVMI was caused by improvement in fluid control especially third-compartment water. That hypothesis is consistent with a previous report showing that Ico produced higher ultrafiltration as the extracellular fluid volume increased (10). In the present study, daily phosphate elimination remained constant in the Ico group, but it gradually declined in the Glu group. Elimination of Na + into effluent was also higher in the Ico group than in the Glu group, but we observed no difference between the groups in K + and Ca 2+ elimination into dialysate, suggesting that higher phosphate elimination was not related merely to an increase in water removal. There might be another reason that Ico removed more phosphate: It has been reported that valvular calcification is associated with peritoneal membrane transport

4 12 Icodextrin, Phosphate, and Cardiac Hypertrophy in Diabetic Patients on PD (a) (B) * * Glu 50 Ico 0 (month) LVMI (g/m 2 ) Calcification of Aortic Valve B ** ** * (month) *** * * figure 1 Change in (A) left ventricular mass index (LVMI) and (B) aortic valve calcification score every 6 months for 24 months after peritoneal dialysis initiation. * p < compared with baseline; ** p < 0.01 compared with baseline; *** p <0.005 compared with baseline. Glu = glucose; Ico = icodextrin. (a) figure 2 Change in daily phosphate elimination into effluent every 6 months for 24 months after peritoneal dialysis initiation. * p < 0.05 compared with baseline; ** p < 0.01 compared with baseline. Glu = glucose; Ico = icodextrin. (B) status, residual renal function, and inflammation (11). Amelioration of the AVC score in the Ico group compared with the Glu group in the present study seems to be attributable mainly to better phosphate control, because at 2 years, we observed no significant differences in urine volume, dialysate-to-plasma ratio of creatinine, and C-reactive protein. However, our study was not a randomized multicenter trial, but a single-center trial with a small sample and inter-group bias (such as the groups having only patients with DM and similar membrane permeability characteristics). Further studies are required to clarify our observations figure 3 (A) Correlation between mean phosphate elimination and the end-to-initial ratio of left ventricular mass index (LVMI 2 / LVMI 0 ) before and at 24 months after peritoneal dialysis initiation. (B) Mean phosphate elimination in the study patients, classified by aortic valve calcification (AVC) score (improved, no change, worsened). * p < 0.01 compared with baseline, ** p < compared with baseline.

5 Hiramatsu et al. 13 and to investigate whether our observations also apply to patients without DM. Conclusions The present study suggests that Ico not only induces greater fluid removal and improves residual renal function, but that it also ameliorates cardiac hypertrophy and valvular calcification in PD patients with DM and high peritoneal membrane transport. Disclosures The authors declare no financial conflicts of interest in relation to this study. References 1 Wang AY, Wang M, Woo J, et al. A novel association between residual renal function and left ventricular hypertrophy in peritoneal dialysis patients. Kidney Int 2002;62: Wang AY, Lam CW, Wang M, Chan IH, Lui SF, Sanderson JE. Is valvular calcification a part of the missing link between residual renal kidney function and cardiac hypertrophy in peritoneal dialysis patients? Clin J Am Soc Nephrol 2009;4: Wang AY, Wang M, Woo J, et al. Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 2003;14: Wang AY, Woo J, Wang M, et al. Association of inflammation and malnutrition with cardiac valve calcification in continuous ambulatory peritoneal dialysis patients. J Am Soc Nephrol 2001;12: Goodman WG, Goldin J, Kuizon BD, et al. Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342: Devereux RB, Reicheck N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55: Moon KH, Song IS, Yang WS, et al. Hypoalbuminemia as a risk factor for progressive left-ventricular hypertrophy in hemodialysis patients. Am J Nephrol 2000;20: Jokiniitty JM, Tuomisto MT, Majahalme SK, Kähönen MA, Turjanmaa VM. Pulse pressure responses to psychological tasks improve the prediction of left ventricular mass: 10 years of follow-up. J Hypertens 2003;21: Qi H, Xu C, Yan H, Ma J. Comparison of icodextrin and glucose solutions for long dwell exchange in peritoneal dialysis: a meta-analysis of randomized controlled trials. Perit Dial Int 2011;31: Kurata C, Wakabayashi Y, Shouda S, et al. Enhanced cardiac clearance of iodine-123 MIBG in chronic renal failure. J Nucl Med 1995;36: Paniagua R, Ventura MD, Avila Díaz M, et al. Icodextrin improves metabolic and fluid management in high and high-average transport diabetic patients. Perit Dial Int 2009;29: Wang AY, Lam CW, Wang M, et al. Increased circulating inflammatory proteins predict a worse prognosis with valvular calcification in end-stage renal disease: a prospective cohort study. Am J Nephrol 2008;28: Corresponding author: Takeyuki Hiramatsu, md, Department of Nephrology, Aichi Welfare Cooperative Agricultural Konan- Kosei Hospital, 137 Omatsubara, Takaya-cho, Konan-city, Aichi , Japan. t-hiramatsu@konan.jaaikosei.or.jp