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Effect of icodextrin on volume status, blood pressure and echocardiographic parameters: A randomized study

2003; Elsevier BV; Volume: 63; Issue: 4 Linguagem: Inglês

10.1046/j.1523-1755.2003.00887.x

1523-1755

Constantijn Konings, Jeroen P. Kooman, Marc Schonck, Ulrich Gladziwa, J.J.J.M. Wirtz, A W van den Wall Bake, P. G. G. Gerlag, S.J. Hoorntje, Johannes Wolters, Frank M. van der Sande, Karel M.L. Leunissen,

Blood Pressure and Hypertension Studies

Effect of icodextrin on volume status, blood pressure and echocardiographic parameters: A randomized study. Overhydration is a risk factor for hypertension and left ventricular hypertrophy in peritoneal dialysis patients. Recently, a high prevalence of subclinical overhydration was observed in peritoneal dialysis patients. Aim of the present open-label randomized study was to assess the effect of a icodextrin 7.5% solution on fluid status [extracellular water (ECW) bromide dilution], blood pressure regulation (24-hour ambulatory measurements) and echocardiographic parameters during a study period of 4 months, and to relate the effect to peritoneal membrane characteristics (dialysate/plasma creatinine ratio). Forty peritoneal dialysis patients (22 treated with icodextrin, 18 controls) were randomized to either treatment with icodextrin during the long dwell or standard glucose solutions. Thirty-two patients (19 treated with icodextrin, 13 controls] completed the study.The use of icodextrin resulted in a significant increase in daily ultrafiltration volume (744 ± 767 mL vs. 1670 ± 1038 mL; P = 0.012) and a decrease in ECW (17.5 ± 5.2 L vs. 15.8 ± 3.8 L; P = 0.035). Also the change in ECW between controls and patients treated with icodextrin was significant (-1.7 ± 3.3 L vs. +0.9 ± 2.2 L; P = 0.013). The effect of icodextrin on ECW was not related to peritoneal membrane characteristics, but significantly related to the fluid state of the patients (ECW:height) (r = -0.72; P < 0.0001). Left ventricular mass (LVM) decreased significantly in the icodextrin-treated group (241 ± 53 grams vs. 228 ± 42 grams; P = 0.03), but not in the control group.In this randomized open-label study, the use of icodextrin resulted in a significant reduction in ECW and LVM. The effect of icodextrin on ECW was not related to peritoneal membrane characteristics, but was related to the initial fluid state of the patient. Effect of icodextrin on volume status, blood pressure and echocardiographic parameters: A randomized study. Overhydration is a risk factor for hypertension and left ventricular hypertrophy in peritoneal dialysis patients. Recently, a high prevalence of subclinical overhydration was observed in peritoneal dialysis patients. Aim of the present open-label randomized study was to assess the effect of a icodextrin 7.5% solution on fluid status [extracellular water (ECW) bromide dilution], blood pressure regulation (24-hour ambulatory measurements) and echocardiographic parameters during a study period of 4 months, and to relate the effect to peritoneal membrane characteristics (dialysate/plasma creatinine ratio). Forty peritoneal dialysis patients (22 treated with icodextrin, 18 controls) were randomized to either treatment with icodextrin during the long dwell or standard glucose solutions. Thirty-two patients (19 treated with icodextrin, 13 controls] completed the study. The use of icodextrin resulted in a significant increase in daily ultrafiltration volume (744 ± 767 mL vs. 1670 ± 1038 mL; P = 0.012) and a decrease in ECW (17.5 ± 5.2 L vs. 15.8 ± 3.8 L; P = 0.035). Also the change in ECW between controls and patients treated with icodextrin was significant (-1.7 ± 3.3 L vs. +0.9 ± 2.2 L; P = 0.013). The effect of icodextrin on ECW was not related to peritoneal membrane characteristics, but significantly related to the fluid state of the patients (ECW:height) (r = -0.72; P < 0.0001). Left ventricular mass (LVM) decreased significantly in the icodextrin-treated group (241 ± 53 grams vs. 228 ± 42 grams; P = 0.03), but not in the control group. In this randomized open-label study, the use of icodextrin resulted in a significant reduction in ECW and LVM. The effect of icodextrin on ECW was not related to peritoneal membrane characteristics, but was related to the initial fluid state of the patient. Cardiovascular disease is the single most common cause of death in dialysis patients. One of the known risk factors for cardiovascular mortality is left ventricular hypertrophy (LVH)1.Foley R.N. Parfrey P.S. Harnett J.D. et al.Clinical and echocardiographic disease in patients starting end-stage renal disease therapy.Kidney Int. 1995; 47: 186-192Abstract Full Text PDF PubMed Scopus (1072) Google Scholar. Although the pathophysiology of LVH is undoubtedly multifactorially determined, overhydration is known to play a major role, at least in hemodialysis patients2.Dionisio P. Valenti M. Bergia R. et al.Influence of the hydration state on blood pressure values in a group of patients on regular maintenance hemodialysis.Blood Purif. 1997; 15: 25-33Crossref PubMed Scopus (41) Google Scholar,3.Gunal A.I. Duman S. Ozkahya M. et al.Strict volume control normalizes hypertension in peritoneal dialysis patients.Am J Kidney Dis. 2001; 37: 588-593Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar. Recently, we and others also showed a huge prevalence of subclinical overhydration in peritoneal dialysis patients, despite the fact that patients were adequately dialyzed according to Dialysis Outcome Quality Initiative (DOQI) guidelines4.Enia G. Mallamaci F. Benedetto F.A. et al.Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients.Nephrol Dial Transplant. 2002; 16: 1459-1464Crossref Scopus (174) Google Scholar,5.Konings C.J.A.M. Kooman J.P. Schonck M. et al.Fluid status, blood pressure, and cardiovascular abnormalities in patients on peritoneal dialysis.Perit Dial Int. 2002; 22: 477-487PubMed Google Scholar. Importantly, volume status was related to both hypertension and eccentric LVH5.Konings C.J.A.M. Kooman J.P. Schonck M. et al.Fluid status, blood pressure, and cardiovascular abnormalities in patients on peritoneal dialysis.Perit Dial Int. 2002; 22: 477-487PubMed Google Scholar. It has been suggested that the use of a glucose polymeric solution, icodextrin 7.5%, is able to improve volume status in peritoneal dialysis patients due to an improved and prolonged ultrafiltration, especially during long dwells6.Posthuma N. ter Wee P.M. Donker A.J. et al.Assessment of the effectiveness, safety, and biocompatibility of icodextrin in automated peritoneal dialysis. The Dextrin in APD in Amsterdam (DIANA) Group.Perit Dial Int. 2000; 20: S106-S113PubMed Google Scholar,7.Johnson D.W. Arndt M. O'Shea A. et al.Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload.BMC Nephrol. 2001; 2: 2Crossref PubMed Google Scholar. Nevertheless, studies toward the effect of icodextrin on volume status in peritoneal dialysis patients are scarce, whereas in the single published study, including patients on automated peritoneal dialysis, which assessed the effect of icodextrin on fluid state in more detail, did not use a randomized design, did not apply reference techniques to assess volume status, and did not assess the effect of icodextrin on cardiac structure (8). Moreover, it is not well known which patients would benefit most of a potential beneficial effect of icodextrin. From a theoretical point of view, especially patients with a peritoneal membrane (so-called high transporters)9.Konings C.J.A.M. et al.Fluid status in CAPD patients is related to peritoneal transport and residual renal function: Evidence from a longitudinal study.Nephrol Dial Transplant. 2003Crossref Scopus (136) Google Scholar would be expected to benefit, although in a recent study of our group the effect of residual renal function on volume status appeared to be more pronounced than the effect of membrane permeability10.Wang T. Heimburger O. Cheng H.H. et al.Does a high peritoneal transport rate reflect a state of chronic inflammation?.Perit Dial Int. 1999; 19: 17-22PubMed Google Scholar. Moreover, the enhanced ultrafiltration imposed by icodextrin might influence diuresis and therefore counteract any potential beneficial effects of icodextrin in those patients with significant residual function. Aims of the present study were (1) to compare the effects of icodextrin on volume status, blood pressure, and cardiac structure in a randomized open-label design using detailed methodology, and (2) to assess the effects of icodextrin in relation to membrane permeability, residual function, and volume status in an unselected group of peritoneal dialysis patients. Forty stable peritoneal dialysis patients were included (29 males; 11 females). Patients with recent complications (e.g., peritonitis, malignancy, or surgery), type I diabetes mellitus, and congestive heart failure or coronary artery disease, defined as New York Heart Association (NYHA III and higher) were excluded. Patient characteristics are displayed in Table 1. Apart from the exclusion criteria, no selection criteria were applied.Table 1Patient demographicsGroupIcodextrin (N = 22)Control (N = 18)NumberMale/female14/815/3CAPD/CCPD16/615/3Mean±SD [range]Age years52.7±10.9 [35–69]56.4±11.6 [36–71]Weight kg77.6±13.6 [46.1–98.1]79.8±14.8 [54.1–109.1]Body surface area m21.9±0.2 [1.34–2.20]2.0±0.2 [1.59–2.34]Time on peritoneal dialysis months19.1±15.8 [3–47]25.1±18.0 [4–66]Weekly Kt/V urea2.5±0.6 [1.6–4.3]2.4±0.7 [1.7–5.0]Weekly creatinine clearance L/1.73 m285.6±40.0 [67.4–170.5]67.2±33.4 [65.3–134.3]Residal diuresis mL/24 hours1131±1099 [0–4000]1031±849 [0–3490]Residual glomerular filtration rate mL/min5.4±3.6 [0–13.8]4.1±3.2 [0–14.1]D/P creatinine0.64±0.11 [0.45–0.90]0.65±0.09 [0.47–0.79]Serum albumin g/L31.6±3.5 [23.4–37.5]31.8±2.8 [27.4–38.1]Hemoglobin mmol/L7.2±0.8 [5.5–8.7]7.3±0.6 [6.4–8.6]C-reactive protein mg/L11.4±19.5 [2–89]8.3±10.2 [2–37]24-hour systolic blood pressure mm Hg135.6±20.6 [100–177]136.9±18.5 [105–177]24-hour diastolic blood pressure mm Hg81.2±11.9 [56–105]84.2±10.6 [64–107]Antihypertensive agents number2.0±1.1 [0–4]1.9±1.2 [0–4]Patients on antihypertensive treatment %90.989.9Abbreviations are: CAPD, continuous ambulatory peritoneal dialysis; CCPD, continuous cyclic peritoneal dialysis. Data for patients whom were enrolled in the study. Open table in a new tab Abbreviations are: CAPD, continuous ambulatory peritoneal dialysis; CCPD, continuous cyclic peritoneal dialysis. Data for patients whom were enrolled in the study. Patients with severe cardiac failure and/or coronary artery disease were excluded because the underlying disease might severely influence relations between fluid overload, blood pressure, and cardiac structure and, therefore, obscure potentially important effects of icodextrin in a group of peritoneal dialysis patients without cardiac failure. Dry weight was assessed on clinical grounds according to the treating physician, with no signs of overhydration (i.e., an elevated central venous pressure or peripheral or pulmonary edema). The treatment goals for treatment adequacy were set according to the DOQI guidelines. Patients were treated with 1.36% glucose solutions for the long dwell. In this open-label randomized multicenter study, unselected peritoneal dialysis patients were randomized toward treatment with either the continuation of their peritoneal dialysis prescription with standard glucose solutions, or treatment with icodextrin during nighttime [in continuous ambulatory peritoneal dialysis (CAPD) patients] or daytime [in continuing cycling peritoneal dialysis (CCPD) patients]. No other interventions in the dialysate prescription were performed during the study period. At the start of the study and after a follow-up period of 4 months, volume status, blood pressure, and echocardiographic parameters were assessed. Patients were recruited from five dialysis centers in the southeastern part of The Netherlands and one dialysis center in Germany. The study was approved by the Ethics Committee of the University Hospital Maastricht. All patients signed informed consent. Patients were randomized with the use of sealed envelopes. The primary outcome variable was the difference in extracellular water (ECW) between icodextrin-treated patients and the control group. In order to detect a difference of 3 L (α = 0.05, 1β = 0.20) between the icodextrin- and control groups, 33 patients would be needed. However, because we wished to include as many patients as possible (maximum of 50) to maximize power, 50 envelopes were available for randomization. As we learned that additional inclusion of patients in our region was not possible, we terminated the study after the inclusion of 40 patients. Patients were admitted to the research center at the dialysis department of the University Hospital of Maastricht in the early morning after an overnight fast. Peritoneal dialysis fluid was first drained before the measurements were started. After admission, tracer dilution measurements were performed and office blood pressure was measured. During this study period, patients were not allowed to eat or drink. At noon, patients were allowed to eat a light meal, of which the total amount of fluid did not exceed 200 mL. Hereafter, echocardiography was performed, followed by 24-hour ambulatory blood pressure measurements. Peritoneal dialysate and urine collections were performed the day before the study. Patients randomized to icodextrin used this solution during the long dwell (i.e, the nighttime dwell in CAPD patients and the daytime dwell in CCPD patients). Peritoneal ultrafiltration was assessed with the use of the 24-hour dialysate collection, performed before the start and the end of the study. Within a maximum of 2 months before entry of the study the transport status of the peritoneal membrane was characterized using a standard peritoneal equilibrium test after a 4-hour dwell with a 2.27% glucose-containing peritoneal dialysis solution. At entry of study, on the same day, a 24-hour collection of the dialysis fluid and the urine was performed to calculate the Kt/Vurea and the weekly creatinine clearance normalized to 1.73 m2 body surface area (BSA) and the residual glomerular filtration rate (rGFR). All calculations were performed using peritoneal dialysis Adequest software (Baxter Healthcare Corp., Deerfield, IL, USA)11.Vonesh E.F. Burkart J. McMurray S.D. Williams P.F. Peritoneal dialysis kinetic modeling: validation in a multicentre clinical study.Perit Dial Int. 1996; 16: 471-481PubMed Google Scholar. In order to obtain maximal accuracy, changes in body weight were assessed by dual-energy x-ray absorptiometry (DEXA)12.Stenver D.I. Gotfredsen A. Hilsted J. Nielsen B. Body composition in hemodialysis patients measured by dual x-ray absorptiometry.Am J Nephrol. 1995; 15: 105-110Crossref PubMed Scopus (51) Google Scholar. DEXA (DPX-L; Lunar Radiation Corp., Madison, WI, USA) was used for measurement of fat mass, lean body mass (comprising muscle, inner organs, and body water), and bone mineral density. Body weight was measured by DEXA because this method allows a very precise measurement of body weight, which is not influenced by clothing, which could disturb the assessment of discrete weight changes. Moreover, it allows a distinction between changes in lean body mass and fat mass (vide supra). It has been shown in dialysis patients that DEXA measurements were linearly related to conventional gravimetric weight procedures and were able to predict small changes in body weight accurately13.Lohman T.G. Dual energy x-ray absorptiometry.in: Roche A.F. Heymsfield S.B. Lohman T.G. Human Body Composition. Human Kinetics, Champaign, IL1996: 63-78Google Scholar. In the present study, the correlation coefficient between body weight measured by DEXA and by conventional gravimetric scales was r = 0.98 (P < 0.0001). DEXA measurements were performed in a standard fashion while the patient was lying in a supine position. From an x-ray source and K-edge filter below the patient, x-ray beams of stable-energy radiation of 38 and 70 KeV were emitted. The composition of the soft tissue was estimated by the ratio of beam attenuation at lower energy relative to the higher energy in soft tissue pixels; this ratio is inversely and linearly related to the percentage fat14.Van Kreel B.K. An improved bromide assay for the estimation of extracellular water volume by capillary gas chromatography.Clin Chim Acta. 1994; 231: 117-128Crossref PubMed Scopus (19) Google Scholar. Body weight was computed by summation of body fat, lean body mass, and bone cell mass. In patients randomized as controls, the coefficient of variation of body weight assessed by DEXA between the beginning and end of the study was 3.2%. Patients received an orally administered dose of 30 mL (150 mmol/L) sodium bromide (NaBr) (Pharmacologic Department, Academical Hospital Maastricht, The Netherlands). Enrichments of NaBr in the body fluid were measured in serum. Immediately before NaBr intake, a (background) blood sample was taken. After the equilibration time of 4 hours, a second blood sample was collected. The concentration of bromide in serum was determined by gas chromatography14.Van Kreel B.K. An improved bromide assay for the estimation of extracellular water volume by capillary gas chromatography.Clin Chim Acta. 1994; 231: 117-128Crossref PubMed Scopus (19) Google Scholar. Bromide dilution spaces were calculated from the enrichment of bromide after 4 hours. The ECW was calculated as the NaBr dilution space corrected for intracellular space penetration of NaBr in erythrocytes, leukocytes, and secretory cells, for unequal NaBr concentrations in the extracellular fluids (Gibbs-Donnan effect), and for the concentration of water in the serum; therefore, NaBr dilution was multiplied by the following correction factor: 0.90 · 0.95 · 0.94 = 0.8015.Miller M.E. Cosgriff J.M. Forbes G.B. Bromide space determination using anion-exchange chromatography for measurement of bromide.Am J Clin Nutr. 1989; 50: 168-171PubMed Google Scholar. In patients randomized as controls, the coefficient of variation of ECW between the beginning and end of the study was 12.6%. Regarding the relation between the effect of icodextrin with regard to the initial fluid state of the patient, extracellular volume was normalized both for BSA and height because the optimal normalization procedure for fluid status is not well known in dialysis patients16.Konings C.J.A.M. Kooman J.P. Schonck M. et al.Assessment of fluid state in peritoneal dialysis patients.Perit Dial Int. 2003Google Scholar. Two-dimensional echocardiography was performed using a HP Sonos 5500 ultrasound system (Hewlett Packard, Palo Alto, CA, USA) with standard imaging transducers with a frequency varying from 1.6 to 3.2 MHz. Parameters included in the analysis were LVM and left ventricular end diastolic diameter (LVEDD) as a parameter of left ventricular eccentric hypertrophy. LVM was calculated according to the formula of Devereux and Reichek17.Devereux R.B. Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method.Circulation. 1977; 55: 613-618Crossref PubMed Scopus (4181) Google Scholar:LVM=1.04[(LVEDD+IVST+PWT)3−(LVEDD)3]−13.6 where IVST is intraventricular septum thickness and PWT is posterior wall thickness. In all patients, 24-hour blood presssure measurements were performed using an oscillometric blood pressure monitor (Space-labs 90207; Redmond, WA, USA). Blood pressure was measured every 15 minutes from 7 a.m till 11 p.m and every 30 minutes from 11 p.m. until 7 a.m. Measurements were only included if more than 85% of the readings were successful. If not, the measurement was repeated. For the separation of day- and nighttime blood pressures, “fixed” hours were 7 a.m. until 11 p.m for daytime and 11 p.m. until 7 a.m. for nighttime blood pressures18.Kooman J.P. Christiaans M.H. Boots J.M. et al.A comparison between office and ambulatory blood pressure measurements in renal transplant patients with chronic transplant nephropathy.Am J Kidney Dis. 2001; 37: 1170-1176Abstract Full Text PDF PubMed Scopus (40) Google Scholar. Data are expressed as mean ± SD. Differences between the icodextrin and control groups were assessed with the unpaired Student t test. Changes within groups were assessed with the paired Student t test. For data which were not normally distributed (ultrafiltration volume, rGFR, residual diuresis, total daily fluid removal, peritoneal glucose presecription, C-reactive protein), nonparametric tests were used (Mann-Whitney and Wilcoxon tests, respectively). Correlations between variables were estimated by the use of Pearson product moment correlations. P values <0.05 were considered significant. Of the 40 patients that were included in the study, 22 patients were randomized to use icodextrin and 18 patients were randomized into the control group. Thirty-two patients (19 patients being treated with icodextrin and 13 controls] completed the study. Three patients dropped out in the icodextrin group (one patient switched to hemodialysis because of technique failure, one patient had a recovery of the renal failure and CAPD was stopped, and one patient developed a hypersensitivity reaction during the use of icodextrin (exfoliative dermatitis) which completely resolved after stopping the icodextrin. In the control group, five patients dropped out (two patients underwent a renal transplantation during follow-up, two patients developed peritonitis, and one patient was switched to hemodialysis because of technique failure). Data for ECW and ambulatory blood pressure are available for all patients and for echocardiography in all but one patient. Urine collections were missing in three patients being treated with icodextrin and two patients in the control group. Data presented in Table 2 comprise those who ended the study.Table 2Data for patients who completed the study (mean ± SE [range])BeginningEndPIcodextrin-treated group (N = 19) ECW L17.5±5.2 [9.0–29.0]15.8±3.8 [8.3–23.9]0.035 UF-volume mL744±767 [-400–2500]1670±1038 [200–4420]0.012 Residual diuresis mL1131±1099 [0–4000]913±962 [0–3800]0.005 Daily fluid removal mL1854±908 [400–3800]2381±1188 [340–4858]0.031 Residual GFR mL/min4.8±3.2 [0–9.0]3.4±3.0 [0–9.3]0.010 Systolic BP mm Hg138±21 [100–177]135±28 [100–194]NS Diastolic BP mm Hg82±12 [56–105]80±11 [54–108]NS LVM g241.2±52.6 [125–346]228.3±41.8 [120–307]0.031 LVEDD mm51.6±6.0 [38–62]50.8±5.7 [37–60]NS Glucose prescribed g/day200±99 [82–524]161±96 [61–490]0.000 Body weight kg76.6±13.8 [42.2–95.7]74.9±14.5 [37.3–93.4]0.002 Lean body mass kg51.8±11.2 [29.5–69.5]50.7±11.3 [27.7–70.0]0.014 Fat mass kg22.1±8.9 [9.9–42.5]21.9±9.1 [8.2–42.8]NS C-reactive protein mg/L12.9±20.6 [2–89]8.2±8.2 [2–30]NS Hemoglobin mmol/L7.2±0.7 [5.5–8.7]7.5±1.0 [6.1–9.8]NS Serum albumin g/L32.1±3.3 [23.4–37.5]31.9±4.6 [19.1–38.0]NSControl group (N = 13) ECW L16.5±3.6 [10.9–22.1]17.4±4.7 [11.1–25.6]NS UF-volume mL907±787 [-820–2355]1063±960 [-1320–2000]NS Residual diuresis mL1061±890 [0–3490]948±858 [0–3100]NS Daily fluid removal mL1968±980 [580–3790]2001±1230 [-370–4080]NS Residual GFR mL/min4.5±3.5 [0–14.1]4.1±4.3 [0–16.4]NS Systolic BP mm Hg138±21 [105–177]133±22 [94–177]NS Diastolic BP mm Hg85±12 [64–107]80±11 [59–95]NS LVM g219±42 [158–310]220±41 [170–320]NS LVEDD mm48.5±4.7 [42–56]49.5±3.9 [43–57]NS Glucose prescribed g/day174±58 [68–259]174±58 [68–259]NS Body weight kg79.6±11.7 [59.6–104.9]80.0±13.1 [58.0–110.5]NS Lean body mass kg51.8±9.8 [34.4–63.8]52.9±9.9 [36.8–71.4]NS Fat mass kg24.7±9.8 [8.7–40.5]24.0±8.3 [7.9–35.5]NS C-reactive protein mg/L4.5±3.9 [2–15]4.4±4.4 [2–16]NS Hemoglobin mmol/L7.1±0.6 [6.4–8.6]7.3±0.5 [6.5–8.3]NS Serum albumin g/L32.1±3.3 [23.4–37.5]31.6±3.8 [22.0–37.0]NSAbbreviations are: ECW, extracellular water; UF-volume, peritoneal ultrafiltration volume; BP, blood pressure; GFR, glomerular filtration rate; LVM, left ventricular mass; LVEDD, left ventricular end-diastolic diameter; Glucose prescribed, daily peritoneal glucose prescription; Daily fluid removal, sum of peritoneal fluid removal and diuresis. Open table in a new tab Abbreviations are: ECW, extracellular water; UF-volume, peritoneal ultrafiltration volume; BP, blood pressure; GFR, glomerular filtration rate; LVM, left ventricular mass; LVEDD, left ventricular end-diastolic diameter; Glucose prescribed, daily peritoneal glucose prescription; Daily fluid removal, sum of peritoneal fluid removal and diuresis. Variables for ECW, 24-hour ambulatory blood pressure, LVM and LVEDD are summarized in Table 2. In contrast to the control group, ECW declined significantly in the group treated with icodextrin. In addition, the change in ECW between the icodextrin-treated and control group was significantly different Figure 1 (-1.7 ± 3.3 vs. +0.9 ± 2.2 L; P = 0.013). Body weight and lean body mass also decreased in the icodextrin-treated group, in contrast to control subjects (both P < 0.03). The relation between the change in body weight and lean body mass with changes in ECW did not reach significance. The 24-hour blood pressure readings did not change significantly in the icodextrin-treated and control groups. Nevertheless, LVM decreased in the icodextrin-treated group, in contrast to the control group Figure 2. Still, no direct relation between changes in ECW or body weight with changes in LVM was observed. Although the change in LVEDD in the icodextrin-treated group was not significant, there was a significant relation between the change in LVEDD and LVM (r = 0.69; P = 0.001). In icodextrin-treated patients, there was no relation between peritoneal membrane characteristics and the decline in ECW, but a highly significant relation between the initial fluid state of the patient, expressed as ECW:BSA and the change in ECW was observed (r = -0.75; P < 0.001) This relationship also remained significant when the initial fluid state was expressed as or as ECW:height (r = -0.72; P = 0.001) Figure 3. Residual diuresis declined significantly in the icodextrin-treated group Table 2 but also tended to decline in the control group. GFR decreased slightly, but significantly, in the icodextrin-treated group but not in the control group. The main results of this open-label randomized study are the significant effect of icodextrin on extracellular volume, assessed by tracer dilution techniques, and the significant relation between the initial fluid state of the patient and the effect of icodextrin on extracellular volume. In contrast to the control group, extracellular volume declined significantly in the group treated with icodextrin, with a highly significant difference between the control and icodextrin-treated groups. The decline in extracellular volume is explained by the impressive effect of icodextrin on peritoneal ultrafiltration. The effect of icodextrin on ultrafiltration volume and extracellular volume is in agreement with the study of Woodrow et al.8.Woodrow G. Oldroyd B. Stables G. et al.Effects of icodextrin in automated peritoneal dialysis on blood pressure and bioelectrical impedance analysis.Nephrol Dial Transplant. 2000; 15: 862-866Crossref PubMed Scopus (74) Google Scholar in patients on automated peritoneal dialysis. Nevertheless, this was a nonrandomized study using bioimpedance measurements as a marker of volume state. In the present study, we chose to use tracer dilution techniques in the assessment of volume state, as the reliability of volume measurements by bioimpedance appears to be especially compromised in overhydrated patients19.van den Ham E.C. Kooman J.P. Christiaans M.H. et al.Body composition in renal transplant patients: Bioimpedance analysis compared to isotope dilution, dual energy x-ray absorptiometry, and anthropometry.J Am Soc Nephrol. 1999; 10: 1067-1079PubMed Google Scholar,20.Cox-Reijven P.L. Kooman J.P. Soeters P.B. et al.Role of bioimpedance spectroscopy in assessment of body water compartments in hemodialysis patients.Am J Kidney Dis. 2001; 38: 832-838Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar. In contrast to Woodrow et al8.Woodrow G. Oldroyd B. Stables G. et al.Effects of icodextrin in automated peritoneal dialysis on blood pressure and bioelectrical impedance analysis.Nephrol Dial Transplant. 2000; 15: 862-866Crossref PubMed Scopus (74) Google Scholar, we did not observed a significant effect on 24-hour ambulatory blood pressure measurements. It is possible that absence of a significant effect of icodextrin on blood pressure regulation might be explained (1) by the fact that, in line with a recent survey of patients on peritoneal dialysis21.Cocchi R. Esposti E.D. Fabbri A. et al.Prevalence of hypertension in patients on peritoneal dialysis: Results of an Italian multicentre study.Nephrol Dial Transplant. 1999; 14: 1536-1540Crossref PubMed Scopus (103) Google Scholar, most of our patients used antihypertensive medication, which may have blunted the effect of changes in volume status, and (2) that other factors than fluid state, such as arterial wall properties, have an important on blood pressure in peritoneal dialysis patients5.Konings C.J.A.M. Kooman J.P. Schonck M. et al.Fluid status, blood pressure, and cardiovascular abnormalities in patients on peritoneal dialysis.Perit Dial Int. 2002; 22: 477-487PubMed Google Scholar. In contrast, in the icodextrin group, LVM decreased significantly, in contrast to controls. In addition to the decline in ECW and the reduction in LVM, also body weight and lean body mass declined significantly in the icodextrin-treated patients, whereas body weight remained stable in the control group. It is likely that the decline in body weight and lean body mass also reflects an improvement in fluid state. The fact that the relation between the change in body weight and ECW did not reach significance might be due to variation in ECW measurements. Another explanation for this phenomenon might reside in the fact that, even during a relatively short time period, changes in body composition, unrelated to fluid state, may occur in peritoneal dialysis patients22.Jager K.J. Merkus M.P. Huisman R.M. et al.Nutritional status over time in hemodialysis and peritoneal dialysis. NECOSAD Study Group.J Am Soc Nephrol. 2001; 12: 1272-1279PubMed Google Scholar. In a recent analysis, we observed significant changes in body cell mass and fat mass in individual patients during a 4-month follow-up period (submitted data). Moreover, the fact that in the icodextrin-treated group, ECW, body weight, lean body mass, and LVM all changed significantly in the same direction appears to be a strong argument for a beneficial effect of icodextrin on fluid state in unselected peritoneal dialysis patients. Body fat mass did not decrease in the icodextrin-treated group, despite the reduction in peritoneal glucose prescription. This might be explained by the fact that the follow-up time was relatively short or by the fact that the reduction in glucose prescription (± 40 grams/day) was too small to achieve a significant reduction in body fat. The effect of icodextrin on ECW was not related to peritoneal membrane characteristics but highly significantly related to volume status (i.e., much more pronounced in patients with an expanded ECW compartment). The mechanisms behind this phenomenon cannot be elucidated from the present study. One could speculate that the effect of icodextrin on peritoneal ultrafiltration is most pronounced in overhydrated patients (e.g., due to a higher peritoneal capillary pressure). Another hypothetical explanation could reside in the possibility that the increased peritoneal ultrafiltration by icodextrin would result in increased thirst and water intake in normovolemic patients, counteracting the effect on volume status. The fact that icodextrin was most effective in patients with an expanded ECW leads to the problem of the diagnosis of overhydration in peritoneal dialysis patients. Although this problem is beyond the scope of the present study, it should be mentioned that clinical examination appears to be insufficiently sensitive for this purpose, as a high prevalence of subclinical overhydration, assessed by tracer dilution methods, was observed in an unselected group of peritoneal dialysis patients with adequate treatment according to DOQI guidelines with dry weight prescription according to the clinical judgment of the physician4.Enia G. Mallamaci F. Benedetto F.A. et al.Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients.Nephrol Dial Transplant. 2002; 16: 1459-1464Crossref Scopus (174) Google Scholar,5.Konings C.J.A.M. Kooman J.P. Schonck M. et al.Fluid status, blood pressure, and cardiovascular abnormalities in patients on peritoneal dialysis.Perit Dial Int. 2002; 22: 477-487PubMed Google Scholar. Nevertheless, we admit that the use of tracer dilution techniques is not suitable for daily clinical practice. As already mentioned, multifrequency-bioimpedance analysis (MF-BIA), which is a simple and noninvasive tool, carries the disadvantage of a lack of agreement with tracer dilution techniques, especially in overhydrated patients17.Devereux R.B. Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method.Circulation. 1977; 55: 613-618Crossref PubMed Scopus (4181) Google Scholar,20.Cox-Reijven P.L. Kooman J.P. Soeters P.B. et al.Role of bioimpedance spectroscopy in assessment of body water compartments in hemodialysis patients.Am J Kidney Dis. 2001; 38: 832-838Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar. In a recent study by our group in peritoneal dialysis patients, it was not possible to find a cut-off point for MF-BIA that could predict left ventricular dilatation with adequate sensitivity and specificity17.Devereux R.B. Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method.Circulation. 1977; 55: 613-618Crossref PubMed Scopus (4181) Google Scholar. Additional studies, including an adequate sample of control subjects, should be carried out in order to find whether it is possible to elucidate a cut-off point for MF-BIA measurements which also carries a predictive value for hemodynamic abnormalities in peritoneal dialysis patients. A potential point of concern is the fact that residual diuresis declined in the icodextrin group, although this phenomenon was also observed, although to a lesser degree, in patients treated with a standard treatment regimen, the latter possibly due to the progressive decline in renal function normally observed in dialysis patients23.Lysaght M.J. Vonesh E.F. Gotch F. et al.The influence of dialysis treatment modality on the decline of remaining renal function.ASAIO Trans. 1991; 37: 598-604PubMed Google Scholar. Possibly, part of this phenomenon might be explained by reduction in so-called pressure diuresis, stimulated by overhydration24.Granger J.P. Alexander B.T. Llinas M. Mechanisms of pressure natriuresis.Curr Hypertens Rep. 2002; 4: 152-159Crossref PubMed Scopus (81) Google Scholar. Nevertheless, the small but significant decline in rGFR observed in the patients treated with icodextrin cannot be neglected. Whether the observed decline in rGFR outweighs the beneficial effect of icodextrin on fluid state cannot be answered from the present study. Drawbacks of the present study are the relatively short follow-up period, which was chosen because longer follow-up periods in dialysis patients may result in significant drop-out due to factors such as transplantation and morbidity. We should also point to the fact that in the present study, both patients on CAPD and CCPD were included, although the potential disturbing effects of this factor are counteracted by the randomized treatment design. Moreover, patients with severe cardiac failure and other underlying pathology, who might especially benefit from the effects of icodextrin, were not included in the present study because of the potential overwhelming effect of the underlying disease on ECW. Another potential drawback of the study is the fact that icodextrin dwells were compared with 1.36% glucose solutions. Use of 1.36% glucose solutions for long dwells is standard procedure in our region, due to the potential negative effects of high glucose absorption on the metabolic profile of the patient and because of the potentially negative effects of high glucose concentrations on the structure of the peritoneal membrane25.Davies S.J. Phillips L. Naish P.F. Russell G.I. Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis.J Am Soc Nephrol. 2001; 12: 1046-1051PubMed Google Scholar. Despite this fact, one should keep in mind that also side effects have been described with the use of icodextrin, such as skin eruptions, which also occurred in one of our patients, and sterile peritonitis26.Williams P.F. Foggensteiner L. Sterile/allergic peritonitis with icodextrin in CAPD patients.Perit Dial Int. 2002; 22: 89-90PubMed Google Scholar,27.Ai-Hoquil I.A. Crawford R. Acute generalized exanthematous pustulosis induced by icodextrin.Br J Dermatol. 2001; 21: 414-415Google Scholar. Nevertheless, according to the small number of available literature data and the widespread use of icodextrin solutions, the incidence of these complications is probably small28.Divino Fiho J.C. Allergic reactions to icodextrin in patients with renal failure.Lancet. 2000; 355: 1364-1365PubMed Google Scholar. In this randomized study, the use of icodextrin during the long dwell resulted in a significant increase in peritoneal ultrafiltration and an improvement in fluid status and LVM during a 4-month period compared to a control group using standard glucose solutions. The effect of icodextrin was not found to be related to peritoneal membrane characteristics, but was related to the initial fluid state of the patient.