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Efficacy and safety of a 7.5% icodextrin peritoneal dialysis solution in patients treated with automated peritoneal dialysis
Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Patients Treated With Automated Peritoneal Dialysis Joerg Plum, MD, Stella Gentile, RPh, Christian Verger, MD, Reinhart Brunkhorst, MD, Udo Bahner, MD, Bernadette Faller, MD, Jacky Peeters, MD, Philippe Freida, MD, Dick G. Struijk, MD, Raymond T. Krediet, MD, Bernd Grabensee, MD, Anders Tranaeus, MD, PhD, and Jose´ C. Divino Filho, MD ● In a randomized, prospective, multicenter study, we compared the safety, efficacy, and metabolic effects of a 7.5% icodextrin solution (Extraneal) with a 2.27% glucose solution for long dwell exchanges in patients undergoing automated peritoneal dialysis. Thirty-nine stable patients on automated peritoneal dialysis were randomized to receive either icodextrin (n ⴝ 20) or glucose 2.27% solution (n ⴝ 19). The study included a 2-week baseline period followed by a 12-week icodextrin treatment phase and a 2-week follow-up period when switching back to glucose. The average net ultrafiltration during the long dwell period was 278 ⴞ 43 mL/d for the icodextrin group and ⴚ138 ⴞ 81 mL/d for the control group (P < 0.001). The higher ultrafiltration volume with icodextrin was associated with higher creatinine (2.59 ⴞ 0.09 mL/min versus 2.16 ⴞ 0.11 mL/min) and urea (2.67 ⴞ 0.09 mL/min versus 2.28 ⴞ 0.12 mL/min) peritoneal clearances for the long dwell (both P < 0.001). Ultrafiltration rate per mass of carbohydrate absorbed was ⴙ5.2 ⴞ 1.2 L/min/g in the icodextrin group and ⴚ5.5 ⴞ 2.8 L/min/g in the glucose group (P < 0.001). In the icodextrin group, there was a decrease in serum sodium and chloride compared with baseline (P < 0.01). Total dialysate sodium removal increased in the icodextrin group from 226.7 mEq to 269.6 mEq (week 12, P < 0.001). Serum ␣-amylase activity decreased from 103 U/L to 16 U/L (P < 0.001). The total icodextrin plasma levels reached a steady-state concentration of 6,187 ⴞ 399 mg/L after 1 week of treatment. Urine volume and residual renal function were not specifically affected by icodextrin compared with glucose. None of the laboratory changes resulted in any reported clinically meaningful side effect. Icodextrin produced increased, sustained ultrafiltration during the long dwell period, increasing (convective) peritoneal clearance and sodium removal in automated peritoneal dialysis patients. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Icodextrin; automated peritoneal dialysis; ultrafiltration; sodium; metabolic effects.
L
OSS OF ULTRAFILTRATION capacity over time is well described in patients undergoing long-term peritoneal dialysis. The reported frequency of loss of ultrafiltration in peritoneal dialysis patients necessitating a transfer to hemodialysis has been reported to vary between 17.7% and 24%.1,2 The cumulative risk of developing From the Department of Nephrology and Rheumatology, Heinrich-Heine-University, Du¨sseldorf, Germany; Unite´ de Dialyse Ce´vitone´ale, Hospital Rene´ Dubos, Pontoise, France; the Department of Nephrology, Klinikum, Hannover, Germany; the Department of Nephrology, Medical University, Wu¨rzburg, Germany; Service de Nephrologie et de Dialyse, Hospital Louis Pasteur, Colmar, France; the Department of Nephrology, A.Z. K.U.L. Gasthuisberg, Leuven, Belgium; Service de Nephrologie et de Dialyse, Hospital Louis Pasteur, Cherbourg, France; the Department of Nephrology, Academic Medical Center, Amsterdam, The Netherlands; and the Renal Division, Baxter S.A., Brussels, Belgium. Received June 4, 2001; accepted in revised form October 19, 2001. Address reprint requests to Joerg Plum, MD, Department of Nephrology and Rheumatology, Heinrich-Heine University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/3904-0025$35.00/0 doi:10.1053/ajkd.2002.32009 862
permanent ultrafiltration loss has been reported to be 3% after 1 year, 10% after 3 years, and 31% after 6 years of continuous ambulatory peritoneal dialysis (CAPD) treatment.3 The most common reason for inadequate ultrafiltration seems to be related to a rapid disappearance of the osmotic gradient, resulting from a high glucose transport rate across the peritoneal membrane.4 Such socalled high transporters generally have relatively good low-molecular-weight solute clearance but decreased ultrafiltration,5 resulting in insufficient fluid and sodium removal, which is likely to affect clinical outcomes.6 Icodextrin is a glucose polymer with an average molecular weight of 17,000 D, which acts as a colloid osmotic agent. Compared with glucose based peritoneal dialysis solutions, icodextrin has many advantages, including the ability to provide a sustained, positive net ultrafiltration for at least 16 hours, making it particularly useful for the long dwell exchange in CAPD and APD patients. It has been shown that in patients with ultrafiltration failure, icodextrin can extend the time on peritoneal dialysis.7 In CAPD patients, the ultrafiltration potential of icodextrin is similar to that achieved by a 3.86% glucose solution for the night dwell.8 In
American Journal of Kidney Diseases, Vol 39, No 4 (April), 2002: pp 862-871
EFFICACY AND SAFETY OF ICODEXTRIN IN APD
APD, a positive effect on ultrafiltration and convective small solute clearance also has been reported.9,10 Some metabolic side effects (eg, hyponatremia, decreased plasma amylase activity) may arise by the accumulation of icodextrin and its degradation products in the plasma.10,11 The use of APD as the initial mode of renal replacement therapy has been increasing continuously. Social reasons, such as patient employment and lifestyle, and medical indications, such as the need for higher clearance rates and the compensation of ultrafiltration loss by shorter dwell times, represent important arguments for this development. Up to now, benefits with regard to ultrafiltration in APD have been shown in two open studies with a limited number of patients.9,10 Metabolic side effects and icodextrin kinetics in APD have not been studied prospectively in a large number of patients so far. In this controlled, randomized, prospective European multicenter study, we investigated solute transport, fluid balance, and metabolic changes in APD patients treated with icodextrin for the long dwell over 3 months. METHODS
Study Design This prospective, randomized, open-label, parallel-group, active-controlled study was performed according to Good Clinical Practice standards. The study started in January 1997 and was completed in February 1998. A total of 39 patients were enrolled to give an evaluable patient group of 32 or more patients. The study included a 2-week baseline period followed by a 12-week treatment period and a subsequent 2-week follow-up period (Fig 1). Patients meeting the
Fig 1.
Study design.
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selection criteria entered the baseline period. During the baseline period, all patients used the 2.27% glucose concentration (Dianeal PD4) for the long dwell day exchange. At the end of the baseline period, 20 patients were randomized into the icodextrin (Extraneal) test group, and 19 patients were assigned to the control group (Dianeal 2.27%). During the follow-up period, all patients used the 2.27% glucose solution for the long dwell day exchange. The physician was free to change the dialysis regimen according to overnight dialysate volume and glucose concentration if clinically necessary. Concomitant medications (eg, antihypertensives, lipid-lowering drugs) were allowed to be adapted according to clinical requirements but did not change significantly in either group. Residual renal function was monitored at baseline and during treatment by averaging creatinine and urea clearance from a 24-hour urine collection period.
Subjects Men and women undergoing APD were recruited from the investigators’ patient populations at eight hospitals. The inclusion criteria were patients who had been treated with APD for at least 90 days before the screening visit and whose standard prescription included a long dwell daytime exchange of 14 ⫾ 2 hours with 2 L of 2.27% glucose PD4 and excluded any dry period. Of the 39 patients randomized, 33 patients completed the study (16 control patients, 17 icodextrin patients). Six patients discontinued the study because of unrelated serious adverse events or because of renal transplantation. There was one death during the study as a result of ventricular fibrillation, which was assessed as unrelated to treatment. Chronic glomerulonephritis was the most common cause of renal failure. None of the demographic variables was significantly different between the groups. The two groups were similar with regard to past medical history. There were four diabetic patients, all type 1 (two in the control group and two in the icodextrin group) enrolled in the study (Table 1). Patients did not differ according to their peritoneal transport properties. The mass transfer area coefficient of
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PLUM ET AL Table 1.
Patients’ Demographics and Anthropometric Data at Baseline
No. enrolled patients Age (y) Male Female White Asian Height (cm) Weight (kg) Blood pressure, sitting (systolic/diastolic, mm Hg) Time on dialysis (mo) Time since PD started (mo) Time since APD started (mo) Residual renal function (average) (creatinine/urea clearance, mL/min) 24-h dialysate volume (L) Long dwell time (h) Infused volume for long dwell (L) Underlying renal disease Diabetic nephropathy Glomerulonephritis Polycystic kidney disease Hypertensive nephropathy Interstitial nephritis Autoimmune disease Obstructive nephropathy Other
Glucose Group
Icodextrin Group
19 45.4 (26-75) 13 6 19 0 170 ⫾ 9 71.1 ⫾ 13.3 131 ⫾ 25/81 ⫾ 16 43.6 (5-235) 25.0 16.0 (2-57)
20 46.1 (27-74) 17 3 19 1 173 ⫾ 10 73.3 ⫾ 7.3 139 ⫾ 19/89 ⫾ 13 26.8 (4-85) 23.4 14.1 (2-30)
2.4 ⫾ 0.6 19.61 ⫾ 3.68 13.5 ⫾ 1.3 1.964 ⫾ 0.047
2.4 ⫾ 0.6 18.10 ⫾ 4.10 13.5 ⫾ 0.9 1.933 ⫾ 0.073
2 7 2 0 1 2 0 5
2 9 1 1 0 1 1 5
NOTE. Values are numbers or mean ⫾ SD. Abbreviations: PD, peritoneal dialysis; APD, automated peritoneal dialysis.
creatinine (MTAC) measured at baseline was 10.8 ⫾ 0.8 mL/min 䡠 1.73 m2 in the icodextrin group and 10.7 ⫾ 0.7 mL/min 䡠 1.73 m2 in the glucose control group (Table 1).
Procedures During the entire study, the dwell time for the daytime exchange was standardized to 14 ⫾ 2 hours. The overall mean long dwell time was 13.4 ⫾ 1.2 hours. The control and the test solutions used were supplied by Baxter S.A. (Brussels, Belgium) and provided in 2-L single bags. The HomeChoice cycler system (Baxter Healthcare, Deerfield, IL) was used for the administration of the night exchanges and the long dwell day exchange in both groups. The overall mean infused volume was 1,914 ⫾ 78 mL. Patients were asked to complete daily records of the solution administered. At the five regular home visits, the nursing staff checked the patient’s compliance. These visits took place in the evening, at the end of the long dwell day exchange. In addition, the patients visited the hospital five times for additional blood sampling and physical examination. A standard peritoneal equilibration test (PET) (using glucose 2.27%) was carried out once in each study phase (baseline and treatment phase, week 12). The PET was performed after the long dwell of at least 8 hours with the long dwell solution currently used. MTAC for creatinine was calculated using the Vonesh formula.12 During the 12-week
treatment phase, the visits were performed at weeks 1, 6, and 12. Complete physical examinations were performed at baseline, at the end of the treatment period, and at the final follow-up visit.
Laboratory Methods Serum biochemistry measurements for urea, creatinine, and sodium were performed by routine methods. Blood glucose levels were determined using a hexokinase-based assay. There was no interference from icodextrin and its metabolites with this method. Serum amylase levels were analyzed by an enzymatic colorimetric test with 4,6ethylidene (G7)-p-nitrophenyl (G1)-a,D-maltoheptaoside (ethylidene-G7PNP) as substrate. Total icodextrin and metabolites in plasma and dialysate were analyzed by highperformance anion-exchange chromatography with pulsed amperometric detection.13
Statistical Analysis The primary efficacy variable was net ultrafiltration for the long dwell, and the smallest clinically meaningful difference between the test and control solutions was predefined as 250 mL. All study results are expressed as mean values ⫾ SE. Changes from baseline were compared within the groups and between the groups. Repeated measures analysis of
EFFICACY AND SAFETY OF ICODEXTRIN IN APD
covariance, analysis of covariance, Pearson’s chi-square test, Fisher’s exact test, and Student paired t-test were used to analyze the data. Statistical significance was defined as P ⱕ 0.05, apart from laboratory safety variables.
RESULTS
Ultrafiltration APD patients using the 7.5% icodextrin solution during the long dwell exchanges showed superior long dwell net ultrafiltration compared with patients using the 2.27% glucose. The mean changes from baseline within the icodextrin group were highly significant during the treatment phase (P ⬍ 0.001), whereas no change in ultrafiltration was registered in the control group at each visit (Fig 2). All patients but one experienced negative ultrafiltration at baseline, and all showed a positive ultrafiltration when using the icodextrin solution. The average long dwell net ultrafiltration registered during the treatment period was 278 ⫾ 43 mL/d in the icodextrin group and ⫺138 ⫾ 81 mL/d in the glucose group. The overall difference in net ultrafiltration between the two patient groups was greater than the postulated difference of 250 mL. In the icodextrin group, mean overnight glucose concentration used was 1.93 ⫾ 0.49%, and total dialysate volume was 18.10 ⫾ 4.10 L at baseline. On treatment with icodextrin, the prescription concerning mean overnight glucose concentration (1.98 ⫾ 0.48%) and total
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dialysate volume did not change (18.6 ⫾ 0.5 L). There also was no significant change in the prescription of the control group. Change in Blood Pressure, Body Weight, and Residual Renal Function Although some patients experienced reduction in body weight, reduction in edema, and improved blood pressure when using icodextrin, no statistically significant differences were observed in blood pressure and the number of prescribed antihypertensive drugs between the groups. At the end of the treatment phase and after switching back to glucose, there was a small increase in systolic blood pressure in the icodextrin group compared with baseline. Body weight decreased slightly, but this trend became significant only after 6 weeks of icodextrin treatment (⫺0.5 kg versus ⫹0.9 kg in the glucose group; P ⬍ 0.05). Residual renal function (average of creatinine and urea clearance) was 2.4 ⫾ 0.6 mL/min 䡠 1.73 m2 in the icodextrin group during baseline period and 2.9 ⫾ 0.8 mL/min 䡠 1.73 m2 after 12 weeks of icodextrin treatment (difference not significant). These values did not differ from the control group, which were 2.4 ⫾ 0.6 mL/min 䡠 1.73 m2 and 1.7 ⫾ 0.6 mL/min 䡠 1.73 m2 (difference not significant). Peritoneal Small Solute Clearance The increased long dwell net ultrafiltration observed with the icodextrin solution was associated with higher peritoneal clearances of creatinine and urea. The average peritoneal creatinine clearance measured during the long dwell period was 2.59 ⫾ 0.09 mL/min for the icodextrin group and 2.16 ⫾ 0.11 mL/min for the glucose group (P ⬍ 0.001) (Fig 3). The average urea clearance measured during the long dwell period was 2.67 ⫾ 0.09 mL/min and 2.28 ⫾ 0.12 mL/min (P ⬍ 0.001). The increase of solute removal by enhanced ultrafiltration accounted for an increase of weekly creatinine clearance of 2 to 4 L in 90% of the patients.
Fig 2. Mean net ultrafiltration during the long dwell period in patients randomized to glucose or icodextrin. *Significant differences from baseline within the icodextrin group (*P < 0.001). #Significant differences between the groups (#P < 0.001). (■) Glucose 2.27% group; (䊐) icodextrin group (receiving icodextrin on week 1 to 12 and glucose at baseline and follow-up).
Peritoneal Equilibration Test Standard PET performed in both study groups at baseline and at the end of the treatment phase did not show any significant changes with regard to the dialysate/plasma (D/P) ratio and MTAC of
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Fig 3. Mean peritoneal creatinine clearance from the long dwell period in patients on either glucose or icodextrin. *Significant differences from baseline within the icodextrin group (*P < 0.001). #Significant differences between the groups (#P < 0.001). (●) Glucose 2.27%; (E) icodextrin.
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Serum Biochemistry There was a marked decrease of serum ␣-amylase activity in the patients using icodextrin (P ⬍ 0.001). Values returned to normal in the follow-up period. The decrease was not found to be associated with any clinical adverse event or change in serum glucose concentrations. In patients using icodextrin, there was a transient small decrease in serum aspartate transaminase compared with the glucose group (P ⬍ 0.005). Serum alkaline phosphatase showed a small, but within the normal range, increase during icodextrin treatment. None of these laboratory changes resulted in any reported clinically meaningful side effect (Table 2).
creatinine and urea and the glucose concentration [at time x]/glucose concentration at time 0 in the dialysate (D/D0) ratio of glucose. Ultrafiltration volume during the PET did not differ. The long dwell peritoneal equilibration of urea and creatinine also did not show any differences between the solutions. Albumin D/P ratio at 4 hours measured in the standard PET decreased by 19% from baseline to week 12 in the icodextrin group (P ⬍ 0.02). At week 12, the mean total dialysate albumin loss during the long dwell was 1,692 ⫾ 101 mg for the icodextrin group and 1,878 ⫾ 176 mg for the glucose group, not showing any significant changes from baseline or between the groups. Serum Sodium and Sodium Removal Patients randomized to icodextrin showed a significant decrease in serum sodium and chloride concentrations during the treatment phase compared with baseline, the sodium reduction being about 4 to 7 mEq/L at week 12 (P ⬍ 0.001) (Fig 4A and Table 2). This corresponded to an increase in total dialysate sodium excretion of 43 ⫾ 12 mEq during the long dwell (P ⬍ 0.001) (Fig 4B). The finding of an enhanced dialysate sodium excretion with icodextrin was significant and remained stable throughout the treatment phase. After switching to glucose (follow-up period), serum sodium and sodium dialysate removal in the icodextrin group returned to baseline levels.
Fig 4. Course of serum sodium concentration during the study (A) and total sodium extracted in the dialysate by the long dwell exchange (B) in patients on either glucose or icodextrin. Significant differences from baseline within the icodextrin group (*P < 0.002). Significant differences between the groups (#P < 0.01). (A) (●) Glucose 2.27%; (E) icodextrin. (B) (■) Glucose 2.27%; (䊐) icodextrin.
EFFICACY AND SAFETY OF ICODEXTRIN IN APD Table 2.
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Evaluation of Vital Signs, Peritoneal Solute Equilibration, and Serum and Blood Chemistry in the Study Groups Baseline
Vital signs Body weight (109/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) PET MTACcreat (mL/min) D/Do glucose 4 h (%) Laboratory assays WBC (10 ^ 9/L) Platelets (10 ^ 9/L) Hematocrit (%) Sodium (mEq/L) Chloride (mEq/L) Potassium (mEq/L) Calcium (mEq/L) Phosphorus (mEq/L) Bicarbonate (mEq/L) AST (U/L) ALT (U/L) Alkaline phosphate (U/L) Amylase (U/L) Cholesterol (mg/dL)
Group
Week 2
Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin
71.50 72.20 127.4 138.8 84.1 88.6
Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin
Treatment Period
Week 1
Week 1
72.20 72.40 136.8 138.2 85.0 88.6
Week 6
72.40 71.70* 130.5 138.4 82.1 88.4
10.79 10.74 0.37 0.36 7.58 6.76 246 273 33.9 32.7 136.9 138.7 95.8 96.7 4.47 4.51 9.80 9.64 5.88 5.85 24.9 25.2 22.1 16.2 26.6 18.6 84.9 76.8 102.5 112.9
7.69 7.62 248 260 32.7 30.4 137.1 137.9 95.4 95.6 4.68 4.81 9.56 9.52 6.12 6.39 25.1 25.6 20.5 17.0 25.1 17.0 86.2 80.1 95.2 102.6 230.1 229.7
Follow-up Week 12
71.80 73.30 127.0 146.70* 83.1 92.6
Week 14
71.60 73.90 124.2 145.1* 81.6 91.2
10.88 11.10 0.35 0.36 7.42 7.10 250 271 31.6 30.6 137.3 134.2*† 96.4† 94.0*† 4.51 4.76 9.44 9.28 6.21 6.00 24.5 24.0* 29.9 13.7*† 24.1 15.5* 84.4 92.5 98.9 23.2*†
7.61 6.94 247 268 33.4 30.1 136.4 131.6*† 95.2† 92.2*† 4.62 4.63 9.44 9.40 6.45 6.09 24.6 24.3 21.7 13.3* 23.1 16.9 87.5 100.2 91.2 16.6*† 222.4 223.9
7.25 7.14 245 266 35.9 31.4 135.6 132.5*† 93.8† 92.6* 4.75 4.79 9.56 9.76 6.57 5.76† 24.9 25.7 17.8 14.0 22.4 17.2 90.4 99.5 95.2 15.6*† 226.3 241.3
7.49 7.57 239 271 35.4 31.3 136.4 135.7* 94.5 94.0* 4.50 4.59 9.64 9.52 6.45 6.18 24.9 26.5 16.2 17.4 19.6 20.6 88.8 83.1 91.4 82.6 221.2 230.5
Abbreviations: BP, blood pressure; PET, peritoneal equlibration test; MTAC, mass transfer area coefficient; WBC, white blood cell count; AST, aspartate transaminase; ALT, alanine aminotransferase. *At least P ⬍ 0.05: P value for significant mean change from baseline, within the group. †At least P ⬍ 0.05: P value for significant differences across treatment group means.
Absorption of Icodextrin and Its Metabolites The plasma levels of icodextrin and its metabolites increased markedly from baseline in the icodextrin group. Total icodextrin (including metabolites) and maltose plasma levels reached a steady state within 1 week of treatment initiation
(6,187 ⫾ 399 mg/L and 1,112 ⫾ 59 mg/L). The levels remained stable throughout the treatment period. After having completed the 2-week follow-up period, during which all patients used the glucose solution, the plasma levels returned to the baseline (Fig 5).
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Fig 5. Total icodextrin and maltose concentration in plasma at each visit of the study in patients treated with glucose or icodextrin for the long dwell. (●) Total icodextrin (icodextrin and metabolites G2-G7 during glucose 2.27%); () maltose (G2, during glucose 2.27%); (E) total icodextrin (icodextrin and metabolites G2-G7 during icodextrin); (‚) maltose (G2, during icodextrin).
The baseline values of total carbohydrate absorbed during the long dwell for the glucose and the icodextrin group were 39.9 ⫾ 3.5 g and 43.4 ⫾ 0.6 g (not significant). During the treatment period, the total long dwell carbohydrate absorption was 51.0 ⫾ 2.4 g in patients receiving icodextrin solution compared with 42.2 ⫾ 1.3 g in patients receiving the 2.27% glucose solution (P ⬍ 0.005). The percentage of carbohydrate absorbed was lower, however, in the patients receiving icodextrin than 2.27% glucose solution (32.6 ⫾ 1.7% versus 88.4 ⫾ 1.8%; P ⬍ 0.001). Icodextrin was significantly more efficient with regard to ultrafiltration per amount of carbohydrate absorbed. Ultrafiltration per mass of carbohydrate absorbed was ⫹5.2 ⫾ 1.2 L/min/g in the icodextrin group and ⫺5.5 ⫾ 2.8 L/min/g in the control group (P ⬍ 0.001) at week 12. Safety Evaluation In total, 56 adverse events (25 in the control group, 31 in the icodextrin group) were reported by 25 patients (12 control [63.2%], 13 icodextrin [65.0%]; not significant) as treatment-emergent; that is, the events occurred after the initiation of study treatment (treatment period ⫹ follow-up). The pattern of occurrence of adverse events was similar in the icodextrin and control groups. Most of the events were judged by the investigators to be unrelated to the control or the test
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solution. Three adverse events (abdominal pain, peripheral edema, and hypertension) occurred in the follow-up period and were reported to be probably or definitely related to the control solution. Three adverse events (anemia, dyspnea, eczema) occurred in the treatment period (icodextrin group) and were reported as potentially related to the use of the icodextrin solution. A thorough analysis of the anemia event did not support any relationship with icodextrin. The dyspnea event was related to a sensation of abdominal distention resulting from an increased ultrafiltration. The reported moderately severe eczema was regarded as an allergic reaction by the investigator which was probably related to icodextrin. Four type 1 diabetic patients (two in the glucose group and two in the icodextrin group) were enrolled in the study, and in only one patient (glucose group) was an increase of 24 hours insulin dose observed during the study period. DISCUSSION
The long daytime dwell in patients on APD considerably contributes to total dialytic clearance. The long dwell may be omitted only in patients with a still relevant residual renal function by using nightly intermittent peritoneal dialysis (NIPD) instead of continuous cycling peritoneal dialysis. To meet current guidelines14 on Kt/V and creatinine clearance for most APD patients, at least one daytime dwell is required. Patients with large body weight or without residual renal function often need an additional daytime exchange to fulfill these criteria. Even in these patients, one long dwell of about 8 to 10 hours usually is applied, and the other daytime exchange often is performed in the late afternoon. Because the osmotic gradient in APD patients, being frequently high or high-average transporters, readily dissipates, the ultrafiltration is often negative with 1.36% or 2.27% glucose. Using a 2.27% glucose solution over a 14 ⫾ 2 hours dwell, we found a mean negative ultrafiltration. The use of icodextrin resulted in nearly all cases in a positive ultrafiltration, giving a net benefit of about 400 mL compared with glucose. This difference may give rise to a moderate decrease in body weight and potentially better body fluid control (dry weight). The gain in ultrafiltration most likely was used to increase
EFFICACY AND SAFETY OF ICODEXTRIN IN APD
fluid intake by most of the patients in the icodextrin group because a statistically significant decrease of body weight was observed only at 6 weeks of icodextrin treatment. Although a high peritoneal transport state usually decreases ultrafiltration (and can diminish solute clearance), the opposite trend to increase ultrafiltration capacity is observed with icodextrin in this setting. This trend probably is due to the recruitment of a higher number of small pores by which the colloid osmotic effect of this solution is mainly driven.15 It has been observed in rats that a macromolecular osmotic/oncotic agent may reduce the peritoneal fluid absorption rate from the peritoneum.16 The reason is not clear but may be attributed to the viscosity of the fluid. This circumstance could contribute additionally to the high long dwell ultrafiltration rate. High transporters, with a type 1 ultrafiltration problem, constitute a patient group for which there is a clear clinical indication for icodextrin prescription. An increase in convective small solute transport explains the significant increase of peritoneal urea and creatinine clearances observed. On the basis of our data, an additional weekly creatinine clearance of 2 to 4 L can be achieved by the use of icodextrin in APD. The results are in accordance with the findings of Posthuma et al17 and Woodrow et al.10 As shown in CAPD,7 icodextrin also may prolong technique survival because of poor ultrafiltration and clearance in APD. The use of icodextrin did not influence creatinine or urea equilibration as related to the standard PET. Dialysate albumin loss was stable before, during, and after 3 months of icodextrin use in this group of patients. In the present study, there was a statistically significant decrease in mean serum sodium at each point in time during the treatment period versus baseline in the icodextrin group (P ⬍ 0.001). Serum sodium levels declined from 138 to 134 mEq/L at week 1 to 132 mEq/L at week 6 and to 133 mEq/L at week 12. Although serum sodium was falling near to the lower limit of normal serum sodium concentrations, this was not associated with any adverse clinical effect and was not considered to be clinically relevant in the setting of a once-daily icodextrin exchange. The MIDAS study was a randomized, controlled, multicenter study of icodextrin in more than 200 CAPD patients comparing iso-
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osmolar icodextrin with hyperosmolar glucose solutions in CAPD.8 In patients treated with icodextrin, mean serum sodium also was reported to decrease from 140 ⫾ 0.3 mEq/L at baseline to 137 ⫾ 0.4 mEq/L at week 2 and to 136 ⫾ 0.3 mEq/L at week 4. Posthuma et al17 evaluated 12 patients treated with icodextrin for 2 years while undergoing continuous cycling peritoneal dialysis. In these patients, serum sodium levels decreased from 138 ⫾ 0.7 mEq/L at baseline to an average concentration of 135 ⫾ 0.8 mEq/L at 3 months and 135 and 136 mEq/L at 6 and 9 months. Woodrow et al10 found a significant fall in serum sodium of 4 mEq/L in 17 APD patients. Because ultrafiltration volume is the major determinant of sodium balance in peritoneal dialysis patients, this is a likely explanation for reduced sodium concentration. It has been postulated that in icodextrin-treated patients, ultrafiltration occurs only by way of intercellular pores, resulting in less sodium sieving and higher sodium removal compared with glucose.16 The process of sodium sieving refers to relatively high movement of water relative to sodium into the peritoneal cavity as a result of water transport across ultrasmall transcellular pores (aquaporines) and is a feature of crystalloid osmosis prevalent with glucose. It is not known whether some transcellular water shift could be driven by icodextrin and especially its degradation products in the dialysate. We measured icodextrin and its degradation products to yield a total plasma concentration of approximately 6 g/L during the steady state; this could correspond to an increase of 2 to 4 mm Hg in colloid osmotic pressure. Serum ␣-amylase activity was found to be significantly decreased during icodextrin administration compared with the baseline values and with that found in glucose-treated patients. Serum amylase activity returned to near baseline levels in the follow-up phase, 2 weeks after the final administration of icodextrin. The decrease in serum amylase activity was not reported to be associated with any clinical symptoms or events. Mistry and Gokal18 reported a reduction of serum amylase in five patients treated with icodextrin for 3 months. Bajo et al19 also reported a decrease in serum amylase activity in patients treated with icodextrin while undergoing continuous cycling peritoneal dialysis; to determine
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whether pancreatic and salivary amylase isoenzymes were affected by icodextrin, pancreatic and salivary amylase activities were measured in a subset of patients. The results showed that pancreatic and salivary amylase isoenzyme activity declined during treatment with icodextrin and that the decrease in both isoenzymes is responsible for the decrease in total amylase activity. There is evidence that a competitive interference between icodextrin and the p-nitrophenol marked oligosaccharide, which is used as a substrate in routine laboratory analysis, may disturb the assay.11 In peritoneal dialysis patients treated daily with an icodextrin solution, a decrease of serum amylase activity of 90% must be considered. The decline in serum amylase activity is evident by 1 week from the start of icodextrin treatment. The diagnosis of pancreatitis already is complicated in patients with chronic renal disease,20 and for patients using icodextrin, the use of amylase measurements to diagnose pancreatitis is unreliable. The decline in serum amylase has not been associated with any clinical adverse events in published studies using icodextrin. Lipase measurement, which shows no interference (G. Scho¨nicke, personal communication, September 1999), can be used for diagnostic purposes instead. Secretion of amylase into the digestive tract is not affected because peritoneal dialysis patients treated with icodextrin do not display any malabsorption of starch or other gastrointestinal abnormalities. The safety evaluation of our study did not detect an increased incidence of adverse events in the icodextrin group compared with the glucose controls. A moderate eczema occurring in one patient of the icodextrin group was stated to be probably related to icodextrin.21 The skin reaction appeared after several weeks of treatment and subsided quickly when changing to a glucose solution. The long-term observation of our APD patients showed that the beneficial effect of icodextrin on ultrafiltration and clearance was maintained over 3 months. Despite increased fluid removal and a small intermittent weight loss, the spontaneous decrease in residual diuresis was not higher in the icodextrin group. In APD patients, being high or high-average transporters and requiring increased ultrafiltration and small solute clearance, the use of icodextrin seems to
PLUM ET AL
be favorable. A clear trend to reach a lower dry weight did not become apparent, however. A reduction in blood pressure could not be shown in this study. Improved dry weight and blood pressure have been reported, however, in a group of peritoneal dialysis patients treated with icodextrin.22 The use of icodextrin probably should be combined with a well-controlled fluid intake to achieve long-term cardiovascular benefits. A multicenter study on this topic that we are participating in is near completion (ECBT study). For the long daytime dwells in APD, icodextrin may provide a glucose-sparing effect. Although absolute carbohydrate uptake from the dialysate was higher for 7.5% icodextrin than for 2.27% glucose, the oligosaccharide icodextrin probably is metabolized only partially in the plasma and removed by subsequent glucose dwells. The potential benefit of icodextrin with regard to the long-term preservation of peritoneal function is another important issue. It has been shown that the formation of advanced glycosylation end products, which may lead to peritoneal sclerosis, is reduced with icodextrin in an in vitro setting.23 Other experimental studies have shown as much cell culture cytotoxicity of lactate buffered icodextrin as with conventional glucose lactate solutions, however.24,25 Further longitudinal in vivo studies on biocompatibility issues of icodextrin are necessary. The introduction of neutral, bicarbonate and lactate buffered solutions and the use of icodextrin as an alternative oncotic agent may lead to improvement in patient and technique survival in peritoneal dialysis. This study shows that icodextrin produces enhanced and sustained ultrafiltration in APD without affecting residual renal function; increases peritoneal clearances; and has some specific metabolic side effects, which, however, were not associated with clinical adverse events. REFERENCES 1. Pollock CA, Ibels LS, Caterson RJ, Mahony JF, Waugh DA, Cocksedge B: Continuous ambulatory peritoneal dialysis: Eight years of experience at a single center. Medicine (Baltimore) 68:293-308, 1989 2. Slingeneyer A, Canaud B, Mion C: Permanent loss of ultrafiltration capacity of the peritoneum in long-term peritoneal dialysis: An epidemiological study. Nephron 33:133138, 1983 3. Heimbu¨rger O, Waniewski J, Werynski A, Tranaeus A,
EFFICACY AND SAFETY OF ICODEXTRIN IN APD
Lindholm B: Peritoneal fluid transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney Int 38:495-506, 1990 4. Stegmayr B, Granbom L, Karlsson UM, Lindqvist B: Ultrafiltration failure and dialysate glucose in CAPD. Adv Perit Dial 9:62-64, 1993 5. Churchill DN: Strategies to improve clinical outcomes in peritoneal dialysis patients: Delivered dose and membrane transport. Am J Kidney Dis 32:S58-S62, 1998 (suppl) 6. Davies SJ, Phillips L, Griffiths AM, Russell LH, Naish PF, Russell GI: What really happens to people on long-term peritoneal dialysis? Kidney Int 54:2207-2217, 1998 7. Wilkie ME, Plant MJ, Edwards L, Brown CB: Icodextrin 7.5% dialysate solution (glucose polymer) in patients with ultrafiltration failure: Extension of CAPD technique survival. Perit Dial Int 17:84-87, 1997 8. Mistry CD, Gokal R, Peers E: A randomized multicenter clinical trial comparing isosmolar icodextrin with hyperosmolar glucose solutions in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Peritoneal Dialysis. Kidney Int 46:496-503, 1994 9. Posthuma N, ter Wee PM, Verbrugh HA, Oe PL, Peers E, Sayers J, Donker AJ: Icodextrin instead of glucose during the daytime dwell in CCPD increases ultrafiltration and 24-h dialysate creatinine clearance. Nephrol Dial Transplant 12: 550-553, 1997 10. Woodrow G, Stables G, Oldroyd B, Gibson J, Turney JH, Brownjohn AM: Comparison of icodextrin and glucose solutions for the daytime dwell in automated peritoneal dialysis. Nephrol Dial Transplant 14:1530-1535, 1999 11. Scho¨nicke G, Grabensee B, Plum J: Interference of icodextrin dialysate with serum amylase activity measurement in peritoneal dialysis patients. German Congress of Nephrology 1999. Kidney Blood Press Res 22:189A-190A, 1999 (abstr) 12. Warady BA, Alexander SA, Hossli S, Vonesh E, Geary D, Warkins S, Salusky IB, Kohaut EZ: Peritoneal membrane transport function in children receiving longterm dialysis, J Am Soc Nephrol 7:2385-2391, 1996 13. Burke RA, Hvizd MG, Shockley TR: Direct determination of polyglucose metabolites in plasma using anionexchange chromatography with pulsed amperometric detection. J Chromatogr B Biomed Sci Appl 693:353-357, 1997 14. National Kidney Foundation: NKF-DOQI clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 30:S70-S73, 1997 (suppl)
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15. Ho-dac-Pannekeet MM, Schouten N, Langendijk MJ, Hiralall JK, de Waart DR, Struijk DG, Krediet RT: Peritoneal transport characteristics with glucose polymer based dialysate. Kidney Int 50:979-986, 1996 16. Wang T, Heimburger O, Cheng HH, Bergstrom J, Lindholm B: Peritoneal fluid and solute transport with different polyglucose formulations. Perit Dial Int 18:193203, 1998 17. Posthuma N, ter Wee PM, Donker AJ, Oe PL, van Dorp W, Peers EM, Verbrugh HA: Serum disaccharides and osmolality in CCPD patients using icodextrin or glucose as daytime dwell. Perit Dial Int 17:602-607, 1997 18. Mistry CD, Gokal R: Single daily overnight (12-h dwell) use of 7.5% glucose polymer (Mw 18700; Mn 7300) ⫹0.35% glucose solution: A 3-month study. Nephrol Dial Transplant 8:443-447, 1993 19. Bajo MA, Selgas R, Hevia C, Castro MJ, Aguilera A, Milla´n I, Sa´nchez C, del Peso G: Icodextrin 7.5% dialysate for diurnal exchange in patients treated with CCPD. Perit Dial Int 19:S49A, 1999 (abstr, suppl) 20. Ventrucci M, Campieri C, Di Stefano M, Ubalducci GM, Li Bassi S, Di Grazia A, Giudicissi A, Festi D: Alterations of exocrine pancreas in end-stage renal disease: Do they reflect a clinically relevant uremic pancreopathy? Dig Dis Sci 40:2576-2581, 1995 21. Divino Filho JC: Allergic reactions to icodextrin in patients with renal failure. Lancet 355:1364-1365, 2000 22. Woodrow G, Oldroyd B, Stables G, Gibson J, Turney JH, Brownjohn AM: Effects of icodextrin in automated peritoneal dialysis on blood pressure and bioelectrical impedance analysis. Nephrol Dial Transplant 15:862-866, 2000 23. Ueda Y, Miyata T, Goffin E, Yoshino A, Inagi R, Ishibashi Y, Izuhara Y, Saito A, Kurokawa K, van Ypersele de Strihou C: Effect of dwell time on carbonyl stress using icodextrin and amino acid peritoneal dialysis fluids. Kidney Int 58:2518-2524, 2000 24. Liberek T, Topley N, Mistry CD, Coles GA, Morgan T, Quirk RA, Williams JD: Cell function and viability in glucose polymer peritoneal dialysis fluids. Perit Dial Int 13:104-111, 1993 25. Plum J, Lordnejad MR, Grabensee B: The effect of alternative peritoneal dialysis solutions on cell viability, apoptosis/necrosis and cytokine expression in human monocytes. Kidney Int 54:224-235, 1998
L
OSS OF ULTRAFILTRATION capacity over time is well described in patients undergoing long-term peritoneal dialysis. The reported frequency of loss of ultrafiltration in peritoneal dialysis patients necessitating a transfer to hemodialysis has been reported to vary between 17.7% and 24%.1,2 The cumulative risk of developing From the Department of Nephrology and Rheumatology, Heinrich-Heine-University, Du¨sseldorf, Germany; Unite´ de Dialyse Ce´vitone´ale, Hospital Rene´ Dubos, Pontoise, France; the Department of Nephrology, Klinikum, Hannover, Germany; the Department of Nephrology, Medical University, Wu¨rzburg, Germany; Service de Nephrologie et de Dialyse, Hospital Louis Pasteur, Colmar, France; the Department of Nephrology, A.Z. K.U.L. Gasthuisberg, Leuven, Belgium; Service de Nephrologie et de Dialyse, Hospital Louis Pasteur, Cherbourg, France; the Department of Nephrology, Academic Medical Center, Amsterdam, The Netherlands; and the Renal Division, Baxter S.A., Brussels, Belgium. Received June 4, 2001; accepted in revised form October 19, 2001. Address reprint requests to Joerg Plum, MD, Department of Nephrology and Rheumatology, Heinrich-Heine University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/3904-0025$35.00/0 doi:10.1053/ajkd.2002.32009 862
permanent ultrafiltration loss has been reported to be 3% after 1 year, 10% after 3 years, and 31% after 6 years of continuous ambulatory peritoneal dialysis (CAPD) treatment.3 The most common reason for inadequate ultrafiltration seems to be related to a rapid disappearance of the osmotic gradient, resulting from a high glucose transport rate across the peritoneal membrane.4 Such socalled high transporters generally have relatively good low-molecular-weight solute clearance but decreased ultrafiltration,5 resulting in insufficient fluid and sodium removal, which is likely to affect clinical outcomes.6 Icodextrin is a glucose polymer with an average molecular weight of 17,000 D, which acts as a colloid osmotic agent. Compared with glucose based peritoneal dialysis solutions, icodextrin has many advantages, including the ability to provide a sustained, positive net ultrafiltration for at least 16 hours, making it particularly useful for the long dwell exchange in CAPD and APD patients. It has been shown that in patients with ultrafiltration failure, icodextrin can extend the time on peritoneal dialysis.7 In CAPD patients, the ultrafiltration potential of icodextrin is similar to that achieved by a 3.86% glucose solution for the night dwell.8 In
American Journal of Kidney Diseases, Vol 39, No 4 (April), 2002: pp 862-871
EFFICACY AND SAFETY OF ICODEXTRIN IN APD
APD, a positive effect on ultrafiltration and convective small solute clearance also has been reported.9,10 Some metabolic side effects (eg, hyponatremia, decreased plasma amylase activity) may arise by the accumulation of icodextrin and its degradation products in the plasma.10,11 The use of APD as the initial mode of renal replacement therapy has been increasing continuously. Social reasons, such as patient employment and lifestyle, and medical indications, such as the need for higher clearance rates and the compensation of ultrafiltration loss by shorter dwell times, represent important arguments for this development. Up to now, benefits with regard to ultrafiltration in APD have been shown in two open studies with a limited number of patients.9,10 Metabolic side effects and icodextrin kinetics in APD have not been studied prospectively in a large number of patients so far. In this controlled, randomized, prospective European multicenter study, we investigated solute transport, fluid balance, and metabolic changes in APD patients treated with icodextrin for the long dwell over 3 months. METHODS
Study Design This prospective, randomized, open-label, parallel-group, active-controlled study was performed according to Good Clinical Practice standards. The study started in January 1997 and was completed in February 1998. A total of 39 patients were enrolled to give an evaluable patient group of 32 or more patients. The study included a 2-week baseline period followed by a 12-week treatment period and a subsequent 2-week follow-up period (Fig 1). Patients meeting the
Fig 1.
Study design.
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selection criteria entered the baseline period. During the baseline period, all patients used the 2.27% glucose concentration (Dianeal PD4) for the long dwell day exchange. At the end of the baseline period, 20 patients were randomized into the icodextrin (Extraneal) test group, and 19 patients were assigned to the control group (Dianeal 2.27%). During the follow-up period, all patients used the 2.27% glucose solution for the long dwell day exchange. The physician was free to change the dialysis regimen according to overnight dialysate volume and glucose concentration if clinically necessary. Concomitant medications (eg, antihypertensives, lipid-lowering drugs) were allowed to be adapted according to clinical requirements but did not change significantly in either group. Residual renal function was monitored at baseline and during treatment by averaging creatinine and urea clearance from a 24-hour urine collection period.
Subjects Men and women undergoing APD were recruited from the investigators’ patient populations at eight hospitals. The inclusion criteria were patients who had been treated with APD for at least 90 days before the screening visit and whose standard prescription included a long dwell daytime exchange of 14 ⫾ 2 hours with 2 L of 2.27% glucose PD4 and excluded any dry period. Of the 39 patients randomized, 33 patients completed the study (16 control patients, 17 icodextrin patients). Six patients discontinued the study because of unrelated serious adverse events or because of renal transplantation. There was one death during the study as a result of ventricular fibrillation, which was assessed as unrelated to treatment. Chronic glomerulonephritis was the most common cause of renal failure. None of the demographic variables was significantly different between the groups. The two groups were similar with regard to past medical history. There were four diabetic patients, all type 1 (two in the control group and two in the icodextrin group) enrolled in the study (Table 1). Patients did not differ according to their peritoneal transport properties. The mass transfer area coefficient of
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PLUM ET AL Table 1.
Patients’ Demographics and Anthropometric Data at Baseline
No. enrolled patients Age (y) Male Female White Asian Height (cm) Weight (kg) Blood pressure, sitting (systolic/diastolic, mm Hg) Time on dialysis (mo) Time since PD started (mo) Time since APD started (mo) Residual renal function (average) (creatinine/urea clearance, mL/min) 24-h dialysate volume (L) Long dwell time (h) Infused volume for long dwell (L) Underlying renal disease Diabetic nephropathy Glomerulonephritis Polycystic kidney disease Hypertensive nephropathy Interstitial nephritis Autoimmune disease Obstructive nephropathy Other
Glucose Group
Icodextrin Group
19 45.4 (26-75) 13 6 19 0 170 ⫾ 9 71.1 ⫾ 13.3 131 ⫾ 25/81 ⫾ 16 43.6 (5-235) 25.0 16.0 (2-57)
20 46.1 (27-74) 17 3 19 1 173 ⫾ 10 73.3 ⫾ 7.3 139 ⫾ 19/89 ⫾ 13 26.8 (4-85) 23.4 14.1 (2-30)
2.4 ⫾ 0.6 19.61 ⫾ 3.68 13.5 ⫾ 1.3 1.964 ⫾ 0.047
2.4 ⫾ 0.6 18.10 ⫾ 4.10 13.5 ⫾ 0.9 1.933 ⫾ 0.073
2 7 2 0 1 2 0 5
2 9 1 1 0 1 1 5
NOTE. Values are numbers or mean ⫾ SD. Abbreviations: PD, peritoneal dialysis; APD, automated peritoneal dialysis.
creatinine (MTAC) measured at baseline was 10.8 ⫾ 0.8 mL/min 䡠 1.73 m2 in the icodextrin group and 10.7 ⫾ 0.7 mL/min 䡠 1.73 m2 in the glucose control group (Table 1).
Procedures During the entire study, the dwell time for the daytime exchange was standardized to 14 ⫾ 2 hours. The overall mean long dwell time was 13.4 ⫾ 1.2 hours. The control and the test solutions used were supplied by Baxter S.A. (Brussels, Belgium) and provided in 2-L single bags. The HomeChoice cycler system (Baxter Healthcare, Deerfield, IL) was used for the administration of the night exchanges and the long dwell day exchange in both groups. The overall mean infused volume was 1,914 ⫾ 78 mL. Patients were asked to complete daily records of the solution administered. At the five regular home visits, the nursing staff checked the patient’s compliance. These visits took place in the evening, at the end of the long dwell day exchange. In addition, the patients visited the hospital five times for additional blood sampling and physical examination. A standard peritoneal equilibration test (PET) (using glucose 2.27%) was carried out once in each study phase (baseline and treatment phase, week 12). The PET was performed after the long dwell of at least 8 hours with the long dwell solution currently used. MTAC for creatinine was calculated using the Vonesh formula.12 During the 12-week
treatment phase, the visits were performed at weeks 1, 6, and 12. Complete physical examinations were performed at baseline, at the end of the treatment period, and at the final follow-up visit.
Laboratory Methods Serum biochemistry measurements for urea, creatinine, and sodium were performed by routine methods. Blood glucose levels were determined using a hexokinase-based assay. There was no interference from icodextrin and its metabolites with this method. Serum amylase levels were analyzed by an enzymatic colorimetric test with 4,6ethylidene (G7)-p-nitrophenyl (G1)-a,D-maltoheptaoside (ethylidene-G7PNP) as substrate. Total icodextrin and metabolites in plasma and dialysate were analyzed by highperformance anion-exchange chromatography with pulsed amperometric detection.13
Statistical Analysis The primary efficacy variable was net ultrafiltration for the long dwell, and the smallest clinically meaningful difference between the test and control solutions was predefined as 250 mL. All study results are expressed as mean values ⫾ SE. Changes from baseline were compared within the groups and between the groups. Repeated measures analysis of
EFFICACY AND SAFETY OF ICODEXTRIN IN APD
covariance, analysis of covariance, Pearson’s chi-square test, Fisher’s exact test, and Student paired t-test were used to analyze the data. Statistical significance was defined as P ⱕ 0.05, apart from laboratory safety variables.
RESULTS
Ultrafiltration APD patients using the 7.5% icodextrin solution during the long dwell exchanges showed superior long dwell net ultrafiltration compared with patients using the 2.27% glucose. The mean changes from baseline within the icodextrin group were highly significant during the treatment phase (P ⬍ 0.001), whereas no change in ultrafiltration was registered in the control group at each visit (Fig 2). All patients but one experienced negative ultrafiltration at baseline, and all showed a positive ultrafiltration when using the icodextrin solution. The average long dwell net ultrafiltration registered during the treatment period was 278 ⫾ 43 mL/d in the icodextrin group and ⫺138 ⫾ 81 mL/d in the glucose group. The overall difference in net ultrafiltration between the two patient groups was greater than the postulated difference of 250 mL. In the icodextrin group, mean overnight glucose concentration used was 1.93 ⫾ 0.49%, and total dialysate volume was 18.10 ⫾ 4.10 L at baseline. On treatment with icodextrin, the prescription concerning mean overnight glucose concentration (1.98 ⫾ 0.48%) and total
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dialysate volume did not change (18.6 ⫾ 0.5 L). There also was no significant change in the prescription of the control group. Change in Blood Pressure, Body Weight, and Residual Renal Function Although some patients experienced reduction in body weight, reduction in edema, and improved blood pressure when using icodextrin, no statistically significant differences were observed in blood pressure and the number of prescribed antihypertensive drugs between the groups. At the end of the treatment phase and after switching back to glucose, there was a small increase in systolic blood pressure in the icodextrin group compared with baseline. Body weight decreased slightly, but this trend became significant only after 6 weeks of icodextrin treatment (⫺0.5 kg versus ⫹0.9 kg in the glucose group; P ⬍ 0.05). Residual renal function (average of creatinine and urea clearance) was 2.4 ⫾ 0.6 mL/min 䡠 1.73 m2 in the icodextrin group during baseline period and 2.9 ⫾ 0.8 mL/min 䡠 1.73 m2 after 12 weeks of icodextrin treatment (difference not significant). These values did not differ from the control group, which were 2.4 ⫾ 0.6 mL/min 䡠 1.73 m2 and 1.7 ⫾ 0.6 mL/min 䡠 1.73 m2 (difference not significant). Peritoneal Small Solute Clearance The increased long dwell net ultrafiltration observed with the icodextrin solution was associated with higher peritoneal clearances of creatinine and urea. The average peritoneal creatinine clearance measured during the long dwell period was 2.59 ⫾ 0.09 mL/min for the icodextrin group and 2.16 ⫾ 0.11 mL/min for the glucose group (P ⬍ 0.001) (Fig 3). The average urea clearance measured during the long dwell period was 2.67 ⫾ 0.09 mL/min and 2.28 ⫾ 0.12 mL/min (P ⬍ 0.001). The increase of solute removal by enhanced ultrafiltration accounted for an increase of weekly creatinine clearance of 2 to 4 L in 90% of the patients.
Fig 2. Mean net ultrafiltration during the long dwell period in patients randomized to glucose or icodextrin. *Significant differences from baseline within the icodextrin group (*P < 0.001). #Significant differences between the groups (#P < 0.001). (■) Glucose 2.27% group; (䊐) icodextrin group (receiving icodextrin on week 1 to 12 and glucose at baseline and follow-up).
Peritoneal Equilibration Test Standard PET performed in both study groups at baseline and at the end of the treatment phase did not show any significant changes with regard to the dialysate/plasma (D/P) ratio and MTAC of
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Fig 3. Mean peritoneal creatinine clearance from the long dwell period in patients on either glucose or icodextrin. *Significant differences from baseline within the icodextrin group (*P < 0.001). #Significant differences between the groups (#P < 0.001). (●) Glucose 2.27%; (E) icodextrin.
PLUM ET AL
Serum Biochemistry There was a marked decrease of serum ␣-amylase activity in the patients using icodextrin (P ⬍ 0.001). Values returned to normal in the follow-up period. The decrease was not found to be associated with any clinical adverse event or change in serum glucose concentrations. In patients using icodextrin, there was a transient small decrease in serum aspartate transaminase compared with the glucose group (P ⬍ 0.005). Serum alkaline phosphatase showed a small, but within the normal range, increase during icodextrin treatment. None of these laboratory changes resulted in any reported clinically meaningful side effect (Table 2).
creatinine and urea and the glucose concentration [at time x]/glucose concentration at time 0 in the dialysate (D/D0) ratio of glucose. Ultrafiltration volume during the PET did not differ. The long dwell peritoneal equilibration of urea and creatinine also did not show any differences between the solutions. Albumin D/P ratio at 4 hours measured in the standard PET decreased by 19% from baseline to week 12 in the icodextrin group (P ⬍ 0.02). At week 12, the mean total dialysate albumin loss during the long dwell was 1,692 ⫾ 101 mg for the icodextrin group and 1,878 ⫾ 176 mg for the glucose group, not showing any significant changes from baseline or between the groups. Serum Sodium and Sodium Removal Patients randomized to icodextrin showed a significant decrease in serum sodium and chloride concentrations during the treatment phase compared with baseline, the sodium reduction being about 4 to 7 mEq/L at week 12 (P ⬍ 0.001) (Fig 4A and Table 2). This corresponded to an increase in total dialysate sodium excretion of 43 ⫾ 12 mEq during the long dwell (P ⬍ 0.001) (Fig 4B). The finding of an enhanced dialysate sodium excretion with icodextrin was significant and remained stable throughout the treatment phase. After switching to glucose (follow-up period), serum sodium and sodium dialysate removal in the icodextrin group returned to baseline levels.
Fig 4. Course of serum sodium concentration during the study (A) and total sodium extracted in the dialysate by the long dwell exchange (B) in patients on either glucose or icodextrin. Significant differences from baseline within the icodextrin group (*P < 0.002). Significant differences between the groups (#P < 0.01). (A) (●) Glucose 2.27%; (E) icodextrin. (B) (■) Glucose 2.27%; (䊐) icodextrin.
EFFICACY AND SAFETY OF ICODEXTRIN IN APD Table 2.
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Evaluation of Vital Signs, Peritoneal Solute Equilibration, and Serum and Blood Chemistry in the Study Groups Baseline
Vital signs Body weight (109/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) PET MTACcreat (mL/min) D/Do glucose 4 h (%) Laboratory assays WBC (10 ^ 9/L) Platelets (10 ^ 9/L) Hematocrit (%) Sodium (mEq/L) Chloride (mEq/L) Potassium (mEq/L) Calcium (mEq/L) Phosphorus (mEq/L) Bicarbonate (mEq/L) AST (U/L) ALT (U/L) Alkaline phosphate (U/L) Amylase (U/L) Cholesterol (mg/dL)
Group
Week 2
Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin
71.50 72.20 127.4 138.8 84.1 88.6
Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin Glucose Icodextrin
Treatment Period
Week 1
Week 1
72.20 72.40 136.8 138.2 85.0 88.6
Week 6
72.40 71.70* 130.5 138.4 82.1 88.4
10.79 10.74 0.37 0.36 7.58 6.76 246 273 33.9 32.7 136.9 138.7 95.8 96.7 4.47 4.51 9.80 9.64 5.88 5.85 24.9 25.2 22.1 16.2 26.6 18.6 84.9 76.8 102.5 112.9
7.69 7.62 248 260 32.7 30.4 137.1 137.9 95.4 95.6 4.68 4.81 9.56 9.52 6.12 6.39 25.1 25.6 20.5 17.0 25.1 17.0 86.2 80.1 95.2 102.6 230.1 229.7
Follow-up Week 12
71.80 73.30 127.0 146.70* 83.1 92.6
Week 14
71.60 73.90 124.2 145.1* 81.6 91.2
10.88 11.10 0.35 0.36 7.42 7.10 250 271 31.6 30.6 137.3 134.2*† 96.4† 94.0*† 4.51 4.76 9.44 9.28 6.21 6.00 24.5 24.0* 29.9 13.7*† 24.1 15.5* 84.4 92.5 98.9 23.2*†
7.61 6.94 247 268 33.4 30.1 136.4 131.6*† 95.2† 92.2*† 4.62 4.63 9.44 9.40 6.45 6.09 24.6 24.3 21.7 13.3* 23.1 16.9 87.5 100.2 91.2 16.6*† 222.4 223.9
7.25 7.14 245 266 35.9 31.4 135.6 132.5*† 93.8† 92.6* 4.75 4.79 9.56 9.76 6.57 5.76† 24.9 25.7 17.8 14.0 22.4 17.2 90.4 99.5 95.2 15.6*† 226.3 241.3
7.49 7.57 239 271 35.4 31.3 136.4 135.7* 94.5 94.0* 4.50 4.59 9.64 9.52 6.45 6.18 24.9 26.5 16.2 17.4 19.6 20.6 88.8 83.1 91.4 82.6 221.2 230.5
Abbreviations: BP, blood pressure; PET, peritoneal equlibration test; MTAC, mass transfer area coefficient; WBC, white blood cell count; AST, aspartate transaminase; ALT, alanine aminotransferase. *At least P ⬍ 0.05: P value for significant mean change from baseline, within the group. †At least P ⬍ 0.05: P value for significant differences across treatment group means.
Absorption of Icodextrin and Its Metabolites The plasma levels of icodextrin and its metabolites increased markedly from baseline in the icodextrin group. Total icodextrin (including metabolites) and maltose plasma levels reached a steady state within 1 week of treatment initiation
(6,187 ⫾ 399 mg/L and 1,112 ⫾ 59 mg/L). The levels remained stable throughout the treatment period. After having completed the 2-week follow-up period, during which all patients used the glucose solution, the plasma levels returned to the baseline (Fig 5).
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Fig 5. Total icodextrin and maltose concentration in plasma at each visit of the study in patients treated with glucose or icodextrin for the long dwell. (●) Total icodextrin (icodextrin and metabolites G2-G7 during glucose 2.27%); () maltose (G2, during glucose 2.27%); (E) total icodextrin (icodextrin and metabolites G2-G7 during icodextrin); (‚) maltose (G2, during icodextrin).
The baseline values of total carbohydrate absorbed during the long dwell for the glucose and the icodextrin group were 39.9 ⫾ 3.5 g and 43.4 ⫾ 0.6 g (not significant). During the treatment period, the total long dwell carbohydrate absorption was 51.0 ⫾ 2.4 g in patients receiving icodextrin solution compared with 42.2 ⫾ 1.3 g in patients receiving the 2.27% glucose solution (P ⬍ 0.005). The percentage of carbohydrate absorbed was lower, however, in the patients receiving icodextrin than 2.27% glucose solution (32.6 ⫾ 1.7% versus 88.4 ⫾ 1.8%; P ⬍ 0.001). Icodextrin was significantly more efficient with regard to ultrafiltration per amount of carbohydrate absorbed. Ultrafiltration per mass of carbohydrate absorbed was ⫹5.2 ⫾ 1.2 L/min/g in the icodextrin group and ⫺5.5 ⫾ 2.8 L/min/g in the control group (P ⬍ 0.001) at week 12. Safety Evaluation In total, 56 adverse events (25 in the control group, 31 in the icodextrin group) were reported by 25 patients (12 control [63.2%], 13 icodextrin [65.0%]; not significant) as treatment-emergent; that is, the events occurred after the initiation of study treatment (treatment period ⫹ follow-up). The pattern of occurrence of adverse events was similar in the icodextrin and control groups. Most of the events were judged by the investigators to be unrelated to the control or the test
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solution. Three adverse events (abdominal pain, peripheral edema, and hypertension) occurred in the follow-up period and were reported to be probably or definitely related to the control solution. Three adverse events (anemia, dyspnea, eczema) occurred in the treatment period (icodextrin group) and were reported as potentially related to the use of the icodextrin solution. A thorough analysis of the anemia event did not support any relationship with icodextrin. The dyspnea event was related to a sensation of abdominal distention resulting from an increased ultrafiltration. The reported moderately severe eczema was regarded as an allergic reaction by the investigator which was probably related to icodextrin. Four type 1 diabetic patients (two in the glucose group and two in the icodextrin group) were enrolled in the study, and in only one patient (glucose group) was an increase of 24 hours insulin dose observed during the study period. DISCUSSION
The long daytime dwell in patients on APD considerably contributes to total dialytic clearance. The long dwell may be omitted only in patients with a still relevant residual renal function by using nightly intermittent peritoneal dialysis (NIPD) instead of continuous cycling peritoneal dialysis. To meet current guidelines14 on Kt/V and creatinine clearance for most APD patients, at least one daytime dwell is required. Patients with large body weight or without residual renal function often need an additional daytime exchange to fulfill these criteria. Even in these patients, one long dwell of about 8 to 10 hours usually is applied, and the other daytime exchange often is performed in the late afternoon. Because the osmotic gradient in APD patients, being frequently high or high-average transporters, readily dissipates, the ultrafiltration is often negative with 1.36% or 2.27% glucose. Using a 2.27% glucose solution over a 14 ⫾ 2 hours dwell, we found a mean negative ultrafiltration. The use of icodextrin resulted in nearly all cases in a positive ultrafiltration, giving a net benefit of about 400 mL compared with glucose. This difference may give rise to a moderate decrease in body weight and potentially better body fluid control (dry weight). The gain in ultrafiltration most likely was used to increase
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fluid intake by most of the patients in the icodextrin group because a statistically significant decrease of body weight was observed only at 6 weeks of icodextrin treatment. Although a high peritoneal transport state usually decreases ultrafiltration (and can diminish solute clearance), the opposite trend to increase ultrafiltration capacity is observed with icodextrin in this setting. This trend probably is due to the recruitment of a higher number of small pores by which the colloid osmotic effect of this solution is mainly driven.15 It has been observed in rats that a macromolecular osmotic/oncotic agent may reduce the peritoneal fluid absorption rate from the peritoneum.16 The reason is not clear but may be attributed to the viscosity of the fluid. This circumstance could contribute additionally to the high long dwell ultrafiltration rate. High transporters, with a type 1 ultrafiltration problem, constitute a patient group for which there is a clear clinical indication for icodextrin prescription. An increase in convective small solute transport explains the significant increase of peritoneal urea and creatinine clearances observed. On the basis of our data, an additional weekly creatinine clearance of 2 to 4 L can be achieved by the use of icodextrin in APD. The results are in accordance with the findings of Posthuma et al17 and Woodrow et al.10 As shown in CAPD,7 icodextrin also may prolong technique survival because of poor ultrafiltration and clearance in APD. The use of icodextrin did not influence creatinine or urea equilibration as related to the standard PET. Dialysate albumin loss was stable before, during, and after 3 months of icodextrin use in this group of patients. In the present study, there was a statistically significant decrease in mean serum sodium at each point in time during the treatment period versus baseline in the icodextrin group (P ⬍ 0.001). Serum sodium levels declined from 138 to 134 mEq/L at week 1 to 132 mEq/L at week 6 and to 133 mEq/L at week 12. Although serum sodium was falling near to the lower limit of normal serum sodium concentrations, this was not associated with any adverse clinical effect and was not considered to be clinically relevant in the setting of a once-daily icodextrin exchange. The MIDAS study was a randomized, controlled, multicenter study of icodextrin in more than 200 CAPD patients comparing iso-
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osmolar icodextrin with hyperosmolar glucose solutions in CAPD.8 In patients treated with icodextrin, mean serum sodium also was reported to decrease from 140 ⫾ 0.3 mEq/L at baseline to 137 ⫾ 0.4 mEq/L at week 2 and to 136 ⫾ 0.3 mEq/L at week 4. Posthuma et al17 evaluated 12 patients treated with icodextrin for 2 years while undergoing continuous cycling peritoneal dialysis. In these patients, serum sodium levels decreased from 138 ⫾ 0.7 mEq/L at baseline to an average concentration of 135 ⫾ 0.8 mEq/L at 3 months and 135 and 136 mEq/L at 6 and 9 months. Woodrow et al10 found a significant fall in serum sodium of 4 mEq/L in 17 APD patients. Because ultrafiltration volume is the major determinant of sodium balance in peritoneal dialysis patients, this is a likely explanation for reduced sodium concentration. It has been postulated that in icodextrin-treated patients, ultrafiltration occurs only by way of intercellular pores, resulting in less sodium sieving and higher sodium removal compared with glucose.16 The process of sodium sieving refers to relatively high movement of water relative to sodium into the peritoneal cavity as a result of water transport across ultrasmall transcellular pores (aquaporines) and is a feature of crystalloid osmosis prevalent with glucose. It is not known whether some transcellular water shift could be driven by icodextrin and especially its degradation products in the dialysate. We measured icodextrin and its degradation products to yield a total plasma concentration of approximately 6 g/L during the steady state; this could correspond to an increase of 2 to 4 mm Hg in colloid osmotic pressure. Serum ␣-amylase activity was found to be significantly decreased during icodextrin administration compared with the baseline values and with that found in glucose-treated patients. Serum amylase activity returned to near baseline levels in the follow-up phase, 2 weeks after the final administration of icodextrin. The decrease in serum amylase activity was not reported to be associated with any clinical symptoms or events. Mistry and Gokal18 reported a reduction of serum amylase in five patients treated with icodextrin for 3 months. Bajo et al19 also reported a decrease in serum amylase activity in patients treated with icodextrin while undergoing continuous cycling peritoneal dialysis; to determine
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whether pancreatic and salivary amylase isoenzymes were affected by icodextrin, pancreatic and salivary amylase activities were measured in a subset of patients. The results showed that pancreatic and salivary amylase isoenzyme activity declined during treatment with icodextrin and that the decrease in both isoenzymes is responsible for the decrease in total amylase activity. There is evidence that a competitive interference between icodextrin and the p-nitrophenol marked oligosaccharide, which is used as a substrate in routine laboratory analysis, may disturb the assay.11 In peritoneal dialysis patients treated daily with an icodextrin solution, a decrease of serum amylase activity of 90% must be considered. The decline in serum amylase activity is evident by 1 week from the start of icodextrin treatment. The diagnosis of pancreatitis already is complicated in patients with chronic renal disease,20 and for patients using icodextrin, the use of amylase measurements to diagnose pancreatitis is unreliable. The decline in serum amylase has not been associated with any clinical adverse events in published studies using icodextrin. Lipase measurement, which shows no interference (G. Scho¨nicke, personal communication, September 1999), can be used for diagnostic purposes instead. Secretion of amylase into the digestive tract is not affected because peritoneal dialysis patients treated with icodextrin do not display any malabsorption of starch or other gastrointestinal abnormalities. The safety evaluation of our study did not detect an increased incidence of adverse events in the icodextrin group compared with the glucose controls. A moderate eczema occurring in one patient of the icodextrin group was stated to be probably related to icodextrin.21 The skin reaction appeared after several weeks of treatment and subsided quickly when changing to a glucose solution. The long-term observation of our APD patients showed that the beneficial effect of icodextrin on ultrafiltration and clearance was maintained over 3 months. Despite increased fluid removal and a small intermittent weight loss, the spontaneous decrease in residual diuresis was not higher in the icodextrin group. In APD patients, being high or high-average transporters and requiring increased ultrafiltration and small solute clearance, the use of icodextrin seems to
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be favorable. A clear trend to reach a lower dry weight did not become apparent, however. A reduction in blood pressure could not be shown in this study. Improved dry weight and blood pressure have been reported, however, in a group of peritoneal dialysis patients treated with icodextrin.22 The use of icodextrin probably should be combined with a well-controlled fluid intake to achieve long-term cardiovascular benefits. A multicenter study on this topic that we are participating in is near completion (ECBT study). For the long daytime dwells in APD, icodextrin may provide a glucose-sparing effect. Although absolute carbohydrate uptake from the dialysate was higher for 7.5% icodextrin than for 2.27% glucose, the oligosaccharide icodextrin probably is metabolized only partially in the plasma and removed by subsequent glucose dwells. The potential benefit of icodextrin with regard to the long-term preservation of peritoneal function is another important issue. It has been shown that the formation of advanced glycosylation end products, which may lead to peritoneal sclerosis, is reduced with icodextrin in an in vitro setting.23 Other experimental studies have shown as much cell culture cytotoxicity of lactate buffered icodextrin as with conventional glucose lactate solutions, however.24,25 Further longitudinal in vivo studies on biocompatibility issues of icodextrin are necessary. The introduction of neutral, bicarbonate and lactate buffered solutions and the use of icodextrin as an alternative oncotic agent may lead to improvement in patient and technique survival in peritoneal dialysis. This study shows that icodextrin produces enhanced and sustained ultrafiltration in APD without affecting residual renal function; increases peritoneal clearances; and has some specific metabolic side effects, which, however, were not associated with clinical adverse events. REFERENCES 1. Pollock CA, Ibels LS, Caterson RJ, Mahony JF, Waugh DA, Cocksedge B: Continuous ambulatory peritoneal dialysis: Eight years of experience at a single center. Medicine (Baltimore) 68:293-308, 1989 2. Slingeneyer A, Canaud B, Mion C: Permanent loss of ultrafiltration capacity of the peritoneum in long-term peritoneal dialysis: An epidemiological study. Nephron 33:133138, 1983 3. Heimbu¨rger O, Waniewski J, Werynski A, Tranaeus A,
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Lindholm B: Peritoneal fluid transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney Int 38:495-506, 1990 4. Stegmayr B, Granbom L, Karlsson UM, Lindqvist B: Ultrafiltration failure and dialysate glucose in CAPD. Adv Perit Dial 9:62-64, 1993 5. Churchill DN: Strategies to improve clinical outcomes in peritoneal dialysis patients: Delivered dose and membrane transport. Am J Kidney Dis 32:S58-S62, 1998 (suppl) 6. Davies SJ, Phillips L, Griffiths AM, Russell LH, Naish PF, Russell GI: What really happens to people on long-term peritoneal dialysis? Kidney Int 54:2207-2217, 1998 7. Wilkie ME, Plant MJ, Edwards L, Brown CB: Icodextrin 7.5% dialysate solution (glucose polymer) in patients with ultrafiltration failure: Extension of CAPD technique survival. Perit Dial Int 17:84-87, 1997 8. Mistry CD, Gokal R, Peers E: A randomized multicenter clinical trial comparing isosmolar icodextrin with hyperosmolar glucose solutions in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Peritoneal Dialysis. Kidney Int 46:496-503, 1994 9. Posthuma N, ter Wee PM, Verbrugh HA, Oe PL, Peers E, Sayers J, Donker AJ: Icodextrin instead of glucose during the daytime dwell in CCPD increases ultrafiltration and 24-h dialysate creatinine clearance. Nephrol Dial Transplant 12: 550-553, 1997 10. Woodrow G, Stables G, Oldroyd B, Gibson J, Turney JH, Brownjohn AM: Comparison of icodextrin and glucose solutions for the daytime dwell in automated peritoneal dialysis. Nephrol Dial Transplant 14:1530-1535, 1999 11. Scho¨nicke G, Grabensee B, Plum J: Interference of icodextrin dialysate with serum amylase activity measurement in peritoneal dialysis patients. German Congress of Nephrology 1999. Kidney Blood Press Res 22:189A-190A, 1999 (abstr) 12. Warady BA, Alexander SA, Hossli S, Vonesh E, Geary D, Warkins S, Salusky IB, Kohaut EZ: Peritoneal membrane transport function in children receiving longterm dialysis, J Am Soc Nephrol 7:2385-2391, 1996 13. Burke RA, Hvizd MG, Shockley TR: Direct determination of polyglucose metabolites in plasma using anionexchange chromatography with pulsed amperometric detection. J Chromatogr B Biomed Sci Appl 693:353-357, 1997 14. National Kidney Foundation: NKF-DOQI clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 30:S70-S73, 1997 (suppl)
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15. Ho-dac-Pannekeet MM, Schouten N, Langendijk MJ, Hiralall JK, de Waart DR, Struijk DG, Krediet RT: Peritoneal transport characteristics with glucose polymer based dialysate. Kidney Int 50:979-986, 1996 16. Wang T, Heimburger O, Cheng HH, Bergstrom J, Lindholm B: Peritoneal fluid and solute transport with different polyglucose formulations. Perit Dial Int 18:193203, 1998 17. Posthuma N, ter Wee PM, Donker AJ, Oe PL, van Dorp W, Peers EM, Verbrugh HA: Serum disaccharides and osmolality in CCPD patients using icodextrin or glucose as daytime dwell. Perit Dial Int 17:602-607, 1997 18. Mistry CD, Gokal R: Single daily overnight (12-h dwell) use of 7.5% glucose polymer (Mw 18700; Mn 7300) ⫹0.35% glucose solution: A 3-month study. Nephrol Dial Transplant 8:443-447, 1993 19. Bajo MA, Selgas R, Hevia C, Castro MJ, Aguilera A, Milla´n I, Sa´nchez C, del Peso G: Icodextrin 7.5% dialysate for diurnal exchange in patients treated with CCPD. Perit Dial Int 19:S49A, 1999 (abstr, suppl) 20. Ventrucci M, Campieri C, Di Stefano M, Ubalducci GM, Li Bassi S, Di Grazia A, Giudicissi A, Festi D: Alterations of exocrine pancreas in end-stage renal disease: Do they reflect a clinically relevant uremic pancreopathy? Dig Dis Sci 40:2576-2581, 1995 21. Divino Filho JC: Allergic reactions to icodextrin in patients with renal failure. Lancet 355:1364-1365, 2000 22. Woodrow G, Oldroyd B, Stables G, Gibson J, Turney JH, Brownjohn AM: Effects of icodextrin in automated peritoneal dialysis on blood pressure and bioelectrical impedance analysis. Nephrol Dial Transplant 15:862-866, 2000 23. Ueda Y, Miyata T, Goffin E, Yoshino A, Inagi R, Ishibashi Y, Izuhara Y, Saito A, Kurokawa K, van Ypersele de Strihou C: Effect of dwell time on carbonyl stress using icodextrin and amino acid peritoneal dialysis fluids. Kidney Int 58:2518-2524, 2000 24. Liberek T, Topley N, Mistry CD, Coles GA, Morgan T, Quirk RA, Williams JD: Cell function and viability in glucose polymer peritoneal dialysis fluids. Perit Dial Int 13:104-111, 1993 25. Plum J, Lordnejad MR, Grabensee B: The effect of alternative peritoneal dialysis solutions on cell viability, apoptosis/necrosis and cytokine expression in human monocytes. Kidney Int 54:224-235, 1998