TY - JOUR
AU - Kim,, Yong-Lim
AB - Abstract Background. The local peritoneal effects of low-glucose degradation product (GDP)-containing peritoneal dialysis fluid (PDF) have been extensively described. However, the systemic effects of prolonged prescription of these solutions are unknown. This study aimed to evaluate the effects of neutral pH and low-GDP PDF on systemic inflammation and endothelial dysfunction markers in peritoneal dialysis (PD) patients. Methods. This is a multicenter, open labeled, randomized controlled trial including one hundred fifty-two patients initiating continuous ambulatory peritoneal dialysis for end-stage renal disease from seven centers in Korea. Participants were randomly allocated to conventional PDF (Stay safe®; Fresenius Medical Care, Bad Homburg, Germany) or low-GDP PDF (Balance®; Fresenius Medical Care) and were followed for 1 year. Primary outcome variable was the inflammation and endothelial dysfunction index (IEDI), a composite score derived from serum levels of soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cellular adhesion molecule (sVCAM)-1 and high-sensitivity C-reactive protein (hs-CRP). sICAM-1, sVCAM-1, residual renal function (RRF), peritoneal membrane transport characteristics, ultrafiltration volume and nutritional parameters were measured as secondary outcome variables. Results. Of 152 patients randomized, 146 (low-GDP: conventional PDF, 79:67) patients entered the trial (46% male, 53% with diabetes mellitus). At 12-month follow-up, the low-GDP group had significantly lower levels of IEDI, sICAM-1 and sVCAM-1 compared to the conventional group; hs-CRP was not different between groups. Peritoneal transport characteristics, RRF, nutritional parameters, incidence of peritonitis and death-censored technique survival were not different between groups. Conclusion. Neutral pH and low-GDP PDF likely produce fewer changes in markers of endothelial dysfunction compared to conventional PDF in incident PD patients. endothelial dysfunction, glucose degradation products, inflammation, peritoneal dialysis, soluble adhesion molecules Introduction New peritoneal dialysis fluids (PDFs) with neutral pH and low glucose degradation products (GDPs) are used in patients on peritoneal dialysis (PD). Low-GDP fluids are reported to be more biocompatible than conventional PDF. Determination of biocompatibility has mainly focused on local peritoneal effects; recently, there has been interest in evaluating the systemic biocompatibility of these fluids. In recent analyses of two retrospective cohorts of Korean PD patients, significant survival advantage was shown for patients treated with the biocompatible PDF compared to patients treated with the conventional PDF [ 1 , 2 ]. However, due to the limitations of an observational study, the mechanisms of survival advantage with low-GPD PDF in these studies are difficult to assess. Additionally, it is not clear that new PDFs favorably impact risk markers of cardiovascular disease (CVD). Epidemiological studies identified an independent association between inflammation and risk of cardiovascular events and mortality [ 3 ]; this association has been confirmed in patients with advanced chronic kidney diseases (CKD) [ 4 , 5 ]. Other evidence showed that clinically overt vascular events are preceded by endothelial dysfunction and increase in circulating markers of endothelial activation, including vascular cellular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 [ 6 , 7 ]. Moreover, there is an association between inflammation and elevated levels of soluble VCAM-1 and ICAM-1 in patients with or at risk of atherosclerosis [ 8 ]. Elevated levels of soluble adhesion molecules are found in end-stage renal disease (ESRD patients), especially in patients with CVD and malnutrition [ 9 , 10 ]. A single exposure to GDPs induces VCAM-1 expression in cultured human peritoneal mesothelial cells [ 11 ]. However, it is not clear whether GDPs directly activate endothelial cells and increase circulating levels of adhesion molecules or whether the effect is mediated through the activation of receptor for advanced glycation end products (RAGE). Of interest, advanced glycation end products (AGEs) decreased when patients were converted from standard PDF to low-GDP PDF [ 12 , 13 ]. Therefore, we hypothesized that conventional PDF as well as uremia itself lead to local peritoneal changes such as peritoneal neoangiogenesis and fibrosis, effects related to ultrafiltration failure and subsequently volume overload. In addition, direct effect of GDPs and/or increased systemic levels of AGEs activate endothelial cells and increase levels of vascular adhesion molecules and inflammation. Both local and systemic effects of PDF are possibly associated with increased cardiovascular risks and mortality in PD patients. This study aimed to examine the effects of neutral pH and low-GDP-containing PDF on systemic inflammation and endothelial dysfunction markers in incident PD patients in a randomized controlled study. Materials and methods Study design and participants This is a multicenter, open-labeled, randomized controlled trial of incident PD patients. It was registered in ClinicalTrials.gov ( ClinicalTrials.gov Identifier: NCT01315314). The study population included PD patients who initiated dialysis between October 2005 and April 2007 and were being treated by continuous ambulatory peritoneal dialysis (CAPD). Patients were recruited from seven centers in South Korea. Patients were randomly allocated in a 1:1 ratio to conventional PDF (Stay safe®; Fresenius Medical Care, Bad Homburg, Germany) or low-GDP PDF (Balance®; Fresenius Medical Care) groups and were followed for 1 year. Table 1 reports the composition of each study fluid. Male and female patients aged >18 years and <75 years who were capable of adhering to prescription and provided signed informed consent were included. Patients were excluded if deemed to have <80% likelihood of survival for at least 1 year, any malignancy other than treated skin carcinoma, uncontrolled congestive heart failure, recent (within 60 days) myocardial infarction or cerebrovascular accident, active systemic vasculitic disease including systemic lupus erythematosus, polyarteritis nodosa, Anti-neutrophil cytoplasmic antibody-nephritis, active rheumatoid disease or active venous thrombotic-embolic disease, any acute infection at the time of enrollment, active or actively treated tuberculosis or recent (within 30 days) systemic bacterial infection. The Institutional Review Board at Kyungpook National University Hospital approved this study and all patients gave written informed consent. Table 1. Composition of each study fluid a Low-GDP fluid Conventional fluid pH 7 5.5 Sodium (mEq/L) 134 134 Calcium (mEq/L) 3.5 3.5 Magnesium (mEq/L) 1 1 Chloride (mEq/L) 101.5 103.5 Lactate (mg/dL) 315.3 315.3 Bicarbonate (mEq/L) 2 0 Glucose (mg/dL) b 1500–4250 1500–4250 3-deoxyglucosone (μmol/L) b 42–60 172–324 Methylglyoxal (μmol/L) b <1 6–10 Acetaldehyde (μmol/L) b <2 152–182 Formaldehyde (μmol/L) b <3 7–13 Low-GDP fluid Conventional fluid pH 7 5.5 Sodium (mEq/L) 134 134 Calcium (mEq/L) 3.5 3.5 Magnesium (mEq/L) 1 1 Chloride (mEq/L) 101.5 103.5 Lactate (mg/dL) 315.3 315.3 Bicarbonate (mEq/L) 2 0 Glucose (mg/dL) b 1500–4250 1500–4250 3-deoxyglucosone (μmol/L) b 42–60 172–324 Methylglyoxal (μmol/L) b <1 6–10 Acetaldehyde (μmol/L) b <2 152–182 Formaldehyde (μmol/L) b <3 7–13 a Note: values expressed as mean or ranges. Concentrations of GDPs were derived from reference [ 14 ]. b Concentrations in 1.5–4.25% glucose dialysis fluid. Open in new tab Table 1. Composition of each study fluid a Low-GDP fluid Conventional fluid pH 7 5.5 Sodium (mEq/L) 134 134 Calcium (mEq/L) 3.5 3.5 Magnesium (mEq/L) 1 1 Chloride (mEq/L) 101.5 103.5 Lactate (mg/dL) 315.3 315.3 Bicarbonate (mEq/L) 2 0 Glucose (mg/dL) b 1500–4250 1500–4250 3-deoxyglucosone (μmol/L) b 42–60 172–324 Methylglyoxal (μmol/L) b <1 6–10 Acetaldehyde (μmol/L) b <2 152–182 Formaldehyde (μmol/L) b <3 7–13 Low-GDP fluid Conventional fluid pH 7 5.5 Sodium (mEq/L) 134 134 Calcium (mEq/L) 3.5 3.5 Magnesium (mEq/L) 1 1 Chloride (mEq/L) 101.5 103.5 Lactate (mg/dL) 315.3 315.3 Bicarbonate (mEq/L) 2 0 Glucose (mg/dL) b 1500–4250 1500–4250 3-deoxyglucosone (μmol/L) b 42–60 172–324 Methylglyoxal (μmol/L) b <1 6–10 Acetaldehyde (μmol/L) b <2 152–182 Formaldehyde (μmol/L) b <3 7–13 a Note: values expressed as mean or ranges. Concentrations of GDPs were derived from reference [ 14 ]. b Concentrations in 1.5–4.25% glucose dialysis fluid. Open in new tab Intervention Patients were selected when they were scheduled for catheter insertion for PD. Serum was collected prior to first exposure to PDF and evaluated for endothelial dysfunction and inflammation including soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cellular adhesion molecule (sVCAM)-1 and high-sensitivity C-reactive protein (hs-CRP) and biochemistry data. Before break-in, patients were randomly allocated to conventional PDF (Stay safe®) or low-GDP PDF (Balance®) group and began exchanges with each allocated PDF. After a 4-week run-in period during which either allocated PDF was used, baseline peritoneal equilibration test (PET) and biochemical analysis were performed, including the serum markers mentioned above and advance oxidation protein products (AOPP) and serum antioxidant capacity. After baseline, PET and biochemical tests were repeated at 6 and 12 months. Primary outcome variable was the inflammation and endothelial dysfunction index (IEDI), a composite score derived from serum levels of sICAM-1, sVCAM-1 and hs-CRP. This score is the mean of summative categorical variables derived from quartiles of each marker at each time point. Secondary outcome variables were the individual component markers of the IEDI including sICAM-1, sVCAM-1 and hs-CRP, residual renal function (RRF) as average of urea and creatinine clearances, peritoneal clearance as weekly Kt/V urea and creatinine clearance, peritoneal ultrafiltration and peritoneal transport status by PET. In addition, nutritional indices including serum albumin, lean body mass (LBM), normalized protein equivalent of nitrogen appearance (nPNA) and subjective global assessment (SGA) were evaluated. Blood pressure (and use of anti-hypertensive medications), peritonitis rates, technique and patient survival were also assessed. Clinical assessment PET was performed using 3.86% glucose dialysis solution as previously described [ 15 ] and peritoneal membrane transport characteristics were assessed by dialysate-to-plasma creatinine ratio at 4 h of PET. PET was performed after 4 weeks of peritonitis-free interval when patients were diagnosed as peritonitis. Total weekly Kt/V urea (Kt/V urea ) and total weekly creatinine clearance (C Cr ) were estimated by standard methods. As nutritional markers, LBM was estimated from creatinine kinetics using the previously proposed formula [ 16 ] and nPNA was calculated as previously described [ 17 ]. SGA with a four item and seven-point scale was obtained by a trained nurse. RRF was estimated by calculating the average of residual renal clearances of urea and creatinine. Data on duration of survival were not based on actual duration of PD but the duration from baseline visit to the last visit of the study. Biochemical analysis sICAM-1 and sVCAM-1 were measured with enzyme-linked immunosorbent assay (R&D systems, Minneapolis, MN) and hs-CRP with high-sensitivity latex-enhanced immunoturbidimetric assay with MODULAR P analyzer (Roche Diagnostics, Indianapolis, IN). AOPP and total antioxidant activity in serum were measured with AOPP assay kit (Cellbiolabs Inc., San Diego, CA) and antioxidant kit (Cayman, Ann Arbor, MI), respectively. Other biochemical analyses were performed using routine methods at Kyungpook National University Hospital. Statistical analysis Sample size was estimated based on the previous report that showed changes of hs-CRP in PD patients [ 18 ]. Estimated sample size of 69 per arm archives 80% power at a significance level of 0.025 (two-sided) to detect the differences of −2.6 between the conventional and low-GDP groups. Assuming 10% of dropout rate and 3% of screening failures, the study required 79 patients in each group. Statistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL) and Sigma Plot version 11 (Systat software Inc., San Jose, CA). The results are expressed as means and SD. Statistical comparisons between the groups in baseline characteristics were performed using t -test or chi-square test. Changes between the groups were tested by analysis of covariance with baseline values as covariates. Serial data were also analyzed using a linear mixed model. Survival analysis was done by Kaplan–Meier survival analysis with log-rank test. Results Figure 1 diagrams the study flow. Among the 152 patients who signed informed consent, 79 were assigned to low-GDP PDF and 73 to conventional PDF. After allocation, 6 patients from the conventional group were dropped and 146 patients entered baseline PET. Among the 146 patients, 79 in the low-GDP PDF group and 67 in the conventional group met the specific requirements at the baseline visit. In total, 122 patients passed Visit 1 at 6 months and 111 patients passed Visit 2 at 12 months. Reasons for dropout are as follows: in the low-GDP PDF group, one patient transferred to kidney transplantation, five patients transferred to hemodialysis, two withdrew consent, two were withdrawn by an investigator and three died. In the conventional PDF group, three transferred to kidney transplantation, four transferred to hemodialysis, nine transferred to non-trial solution, one was withdrawn by an investigator and two died. Fig. 1. Open in new tabDownload slide Study flow. KT, kidney transplantation; HD, hemodialysis. Fig. 1. Open in new tabDownload slide Study flow. KT, kidney transplantation; HD, hemodialysis. Table 2 reports the baseline characteristics of patients entering the study. There was no difference between groups in terms of sex, age and causes of ESRD. Comorbidity index and body mass index were comparable between the two groups. Blood pressure at baseline was similar in both groups. Among the biochemical parameter, all were similar except serum carbon dioxide (tCO2), which was significantly higher in the low-GDP PDF group. Regarding PET and adequacy data, dialysate-to-plasma ratio of creatinine at 4 h of PET (D4P4cr), at baseline after exposure to the different solutions during the run-in period, was higher in the low-GDP PDF group. Total weekly urea clearance was not different, but peritoneal creatinine clearance was higher in the low-GDP PDF group. RRF or urine volume was not different between the two groups. Peritoneal ultrafiltration volume was lower in the low-GDP PDF group at baseline in keeping with higher peritoneal transport characteristics in this group. Nutritional markers including serum albumin, LBM, nPNA and SGA and blood pressure and number of anti-hypertensive medications were not different between the two groups. Table 2. Baseline patient characteristics ( n = 146) a Low-GDP fluid ( n = 79) Conventional fluid ( n = 67) Sex (male, %) 37 (46.8%) 30 (44.8%) Age (years) 52.2 ± 11.4 52.6 ± 11.1 Cause of ESRD ( n , %)     DM 40 (50.6%) 27 (40.3%)     HTN 23 (29.1%) 28 (41.8%)     CGN 10 (12.7%) 4 (6.0%)     Others/unknown 6 (7.6%) 8 (11.9%) Comorbidities     DM ( n , %) 41 (51.9%) 37 (55.2%)     CAD ( n , %) 6 (7.6%) 1 (1.5%) Modified Charlson’s comorbidity index 4.06 ± 1.56 3.99 ± 1.58 Weight (kg) 59.1 ± 9.2 57.9 ± 9.2 BMI (kg/m 2 ) 22.9 ± 3.2 22.6 ± 2.6 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8     DBP 82.2 ± 11.9 81.3 ± 12.1 Use of ACEi or ARB (%) 65.8% 78.1% Biochemistry     Hb (g/dL) 11.1 ± 1.5 10.8 ± 1.7     Serum creatinine (mg/dL) 7.3 ± 2.8 7.2 ± 2.6     Cholesterol (mg/dL) 189.6 ± 47.1 191.4 ± 50.1     Triglyceride (mg/dL) 131.1 ± 73.8 169.3 ± 189.9     Ca (mg/dL) 8.7 ± 0.7 8.8 ± 0.9     P (mg/dL) 4.6 ± 1.3 4.7 ± 1.3     tCO2 (mEq/L) 25.0 ± 3.7 * 23.7 ± 3.4     Urinary protein (mg/day) 1700 ± 2000 2000 ± 2100 PET and adequacy     D4/P4 creatinine 0.74 ± 0.12 * 0.69 ± 0.12     Kt/V urea 2.4 ± 0.6 2.3 ± 0.6     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9     Ccr 38.9 ± 31.3 36.0 ± 26.2     RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 Ultrafiltration volume (mL)     Total fluid removal (mL/day) 1479 ± 762 1636 ± 586     Peritoneal fluid removal (mL/day) 621 ± 520 * 962 ± 527     Urine volume (mL/day) 880 ± 732 717 ± 536     Peritoneal ultrafiltration per  glucose load (mL/g glucose) 5.69 ± 5.04* 9.54 ± 4.73 Nutritional markers     Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5     LBM (kg) 37.5 ± 9.7 35.1 ± 8.6     nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25     SGA 5.9 ± 1.2 5.7 ± 1.1 Low-GDP fluid ( n = 79) Conventional fluid ( n = 67) Sex (male, %) 37 (46.8%) 30 (44.8%) Age (years) 52.2 ± 11.4 52.6 ± 11.1 Cause of ESRD ( n , %)     DM 40 (50.6%) 27 (40.3%)     HTN 23 (29.1%) 28 (41.8%)     CGN 10 (12.7%) 4 (6.0%)     Others/unknown 6 (7.6%) 8 (11.9%) Comorbidities     DM ( n , %) 41 (51.9%) 37 (55.2%)     CAD ( n , %) 6 (7.6%) 1 (1.5%) Modified Charlson’s comorbidity index 4.06 ± 1.56 3.99 ± 1.58 Weight (kg) 59.1 ± 9.2 57.9 ± 9.2 BMI (kg/m 2 ) 22.9 ± 3.2 22.6 ± 2.6 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8     DBP 82.2 ± 11.9 81.3 ± 12.1 Use of ACEi or ARB (%) 65.8% 78.1% Biochemistry     Hb (g/dL) 11.1 ± 1.5 10.8 ± 1.7     Serum creatinine (mg/dL) 7.3 ± 2.8 7.2 ± 2.6     Cholesterol (mg/dL) 189.6 ± 47.1 191.4 ± 50.1     Triglyceride (mg/dL) 131.1 ± 73.8 169.3 ± 189.9     Ca (mg/dL) 8.7 ± 0.7 8.8 ± 0.9     P (mg/dL) 4.6 ± 1.3 4.7 ± 1.3     tCO2 (mEq/L) 25.0 ± 3.7 * 23.7 ± 3.4     Urinary protein (mg/day) 1700 ± 2000 2000 ± 2100 PET and adequacy     D4/P4 creatinine 0.74 ± 0.12 * 0.69 ± 0.12     Kt/V urea 2.4 ± 0.6 2.3 ± 0.6     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9     Ccr 38.9 ± 31.3 36.0 ± 26.2     RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 Ultrafiltration volume (mL)     Total fluid removal (mL/day) 1479 ± 762 1636 ± 586     Peritoneal fluid removal (mL/day) 621 ± 520 * 962 ± 527     Urine volume (mL/day) 880 ± 732 717 ± 536     Peritoneal ultrafiltration per  glucose load (mL/g glucose) 5.69 ± 5.04* 9.54 ± 4.73 Nutritional markers     Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5     LBM (kg) 37.5 ± 9.7 35.1 ± 8.6     nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25     SGA 5.9 ± 1.2 5.7 ± 1.1 a Note: data are shown as mean ± SD. Bold indicates the parameters have significant differences between the two groups and asterisk indicates p < 0.05 versus conventional fluid group. DM, diabetes mellitus; HTN, hypertension; CGN, chronic glomerulonephritis; CAD, coronary artery disease; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; tCO2, total carbon dioxide in serum; PET, peritoneal equilibration test; D4/P4 creatinine, dialyzate-to-plasma creatinine ratio at 4 h of PET; Kt/V urea , total weekly urea clearance; Kpt/V urea , peritoneal urea clearance; Krt/V urea , renal urea clearance; CrCl, total creatinine clearance; Kpcr, peritoneal creatinine clearance; Ccr, renal creatinine clearance; RRF [mean of creatinine clearance (Ccr) and urea clearance (C urea )]. Open in new tab Table 2. Baseline patient characteristics ( n = 146) a Low-GDP fluid ( n = 79) Conventional fluid ( n = 67) Sex (male, %) 37 (46.8%) 30 (44.8%) Age (years) 52.2 ± 11.4 52.6 ± 11.1 Cause of ESRD ( n , %)     DM 40 (50.6%) 27 (40.3%)     HTN 23 (29.1%) 28 (41.8%)     CGN 10 (12.7%) 4 (6.0%)     Others/unknown 6 (7.6%) 8 (11.9%) Comorbidities     DM ( n , %) 41 (51.9%) 37 (55.2%)     CAD ( n , %) 6 (7.6%) 1 (1.5%) Modified Charlson’s comorbidity index 4.06 ± 1.56 3.99 ± 1.58 Weight (kg) 59.1 ± 9.2 57.9 ± 9.2 BMI (kg/m 2 ) 22.9 ± 3.2 22.6 ± 2.6 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8     DBP 82.2 ± 11.9 81.3 ± 12.1 Use of ACEi or ARB (%) 65.8% 78.1% Biochemistry     Hb (g/dL) 11.1 ± 1.5 10.8 ± 1.7     Serum creatinine (mg/dL) 7.3 ± 2.8 7.2 ± 2.6     Cholesterol (mg/dL) 189.6 ± 47.1 191.4 ± 50.1     Triglyceride (mg/dL) 131.1 ± 73.8 169.3 ± 189.9     Ca (mg/dL) 8.7 ± 0.7 8.8 ± 0.9     P (mg/dL) 4.6 ± 1.3 4.7 ± 1.3     tCO2 (mEq/L) 25.0 ± 3.7 * 23.7 ± 3.4     Urinary protein (mg/day) 1700 ± 2000 2000 ± 2100 PET and adequacy     D4/P4 creatinine 0.74 ± 0.12 * 0.69 ± 0.12     Kt/V urea 2.4 ± 0.6 2.3 ± 0.6     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9     Ccr 38.9 ± 31.3 36.0 ± 26.2     RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 Ultrafiltration volume (mL)     Total fluid removal (mL/day) 1479 ± 762 1636 ± 586     Peritoneal fluid removal (mL/day) 621 ± 520 * 962 ± 527     Urine volume (mL/day) 880 ± 732 717 ± 536     Peritoneal ultrafiltration per  glucose load (mL/g glucose) 5.69 ± 5.04* 9.54 ± 4.73 Nutritional markers     Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5     LBM (kg) 37.5 ± 9.7 35.1 ± 8.6     nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25     SGA 5.9 ± 1.2 5.7 ± 1.1 Low-GDP fluid ( n = 79) Conventional fluid ( n = 67) Sex (male, %) 37 (46.8%) 30 (44.8%) Age (years) 52.2 ± 11.4 52.6 ± 11.1 Cause of ESRD ( n , %)     DM 40 (50.6%) 27 (40.3%)     HTN 23 (29.1%) 28 (41.8%)     CGN 10 (12.7%) 4 (6.0%)     Others/unknown 6 (7.6%) 8 (11.9%) Comorbidities     DM ( n , %) 41 (51.9%) 37 (55.2%)     CAD ( n , %) 6 (7.6%) 1 (1.5%) Modified Charlson’s comorbidity index 4.06 ± 1.56 3.99 ± 1.58 Weight (kg) 59.1 ± 9.2 57.9 ± 9.2 BMI (kg/m 2 ) 22.9 ± 3.2 22.6 ± 2.6 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8     DBP 82.2 ± 11.9 81.3 ± 12.1 Use of ACEi or ARB (%) 65.8% 78.1% Biochemistry     Hb (g/dL) 11.1 ± 1.5 10.8 ± 1.7     Serum creatinine (mg/dL) 7.3 ± 2.8 7.2 ± 2.6     Cholesterol (mg/dL) 189.6 ± 47.1 191.4 ± 50.1     Triglyceride (mg/dL) 131.1 ± 73.8 169.3 ± 189.9     Ca (mg/dL) 8.7 ± 0.7 8.8 ± 0.9     P (mg/dL) 4.6 ± 1.3 4.7 ± 1.3     tCO2 (mEq/L) 25.0 ± 3.7 * 23.7 ± 3.4     Urinary protein (mg/day) 1700 ± 2000 2000 ± 2100 PET and adequacy     D4/P4 creatinine 0.74 ± 0.12 * 0.69 ± 0.12     Kt/V urea 2.4 ± 0.6 2.3 ± 0.6     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9     Ccr 38.9 ± 31.3 36.0 ± 26.2     RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 Ultrafiltration volume (mL)     Total fluid removal (mL/day) 1479 ± 762 1636 ± 586     Peritoneal fluid removal (mL/day) 621 ± 520 * 962 ± 527     Urine volume (mL/day) 880 ± 732 717 ± 536     Peritoneal ultrafiltration per  glucose load (mL/g glucose) 5.69 ± 5.04* 9.54 ± 4.73 Nutritional markers     Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5     LBM (kg) 37.5 ± 9.7 35.1 ± 8.6     nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25     SGA 5.9 ± 1.2 5.7 ± 1.1 a Note: data are shown as mean ± SD. Bold indicates the parameters have significant differences between the two groups and asterisk indicates p < 0.05 versus conventional fluid group. DM, diabetes mellitus; HTN, hypertension; CGN, chronic glomerulonephritis; CAD, coronary artery disease; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; tCO2, total carbon dioxide in serum; PET, peritoneal equilibration test; D4/P4 creatinine, dialyzate-to-plasma creatinine ratio at 4 h of PET; Kt/V urea , total weekly urea clearance; Kpt/V urea , peritoneal urea clearance; Krt/V urea , renal urea clearance; CrCl, total creatinine clearance; Kpcr, peritoneal creatinine clearance; Ccr, renal creatinine clearance; RRF [mean of creatinine clearance (Ccr) and urea clearance (C urea )]. Open in new tab Inflammation and endothelial dysfunction markers After 12 months of PD, IEDI was significantly lower in the low-GDP PDF group after adjusting for baseline IEDI ( Figure 2 ). However, we are unable to find any significant time and group effect with linear mixed model analysis. As an individual endothelial dysfunction marker, sICAM-1 at 12 months was also significantly lower in the low-GDP PDF group. By linear mixed analysis, it was also significantly different between the two groups, although we could not find any significant time effect ( Figure 3A ). sVCAM-1 was also significantly lower at 6 and 12 months in the low-GDP PDF group. The difference was also significant by linear mixed analysis, but we could not find any significant time effect ( Figure 3B ). In contrast to the endothelial dysfunction markers, level of log-transformed hs-CRP was not different between the two groups at 12 months. Log-transformed hs-CRP level at 6 months was slightly higher in the low GDP PDF group ( Figure 3C ). AOPP and total antioxidant capacity were not significantly different between the two groups (data not shown). In a separate analysis, level of IEDI and individual component, such as sICAM-1, sVCAM-1 and log-transformed hs-CRP, were slightly higher in diabetic patients, but we could not find statistical significance in the levels of these variables (data not shown). Fig. 2. Open in new tabDownload slide Changes of IEDI. Gray bar denotes low-GDP group and white bar conventional group. In box plots, horizontal lines at the top, middle and bottom of the boxes show the 75th, 50th and 25th percentiles, respectively, and vertical lines above and below the boxes show the 90th and 10th percentiles, respectively. The lower and upper circles show the 95th and 5th percentiles, respectively. *P < 0.05 versus conventional group by analysis of covariance. In linear mixed model analysis, P = 0.156 for time effect and P = 0.147 for group effect. Fig. 2. Open in new tabDownload slide Changes of IEDI. Gray bar denotes low-GDP group and white bar conventional group. In box plots, horizontal lines at the top, middle and bottom of the boxes show the 75th, 50th and 25th percentiles, respectively, and vertical lines above and below the boxes show the 90th and 10th percentiles, respectively. The lower and upper circles show the 95th and 5th percentiles, respectively. *P < 0.05 versus conventional group by analysis of covariance. In linear mixed model analysis, P = 0.156 for time effect and P = 0.147 for group effect. Fig. 3. Open in new tabDownload slide Changes of sICAM-1 ( A ), sVCAM-1 ( B ) and log-transformed hs-CRP ( C ). Gray bar denotes low-GDP group and white bar conventional group. *P < 0.05 versus conventional group by analysis of covariance. In linear mixed model analysis, P = 0.928 (time), P = 0.003 (group) for sICAM-1 (A), P = 0.117 (time), P = 0.006 (group) for sVCAM-1 (B) and P = 0.504 (time), P = 0.007 (group) for log-transformed hs-CRP (C). Fig. 3. Open in new tabDownload slide Changes of sICAM-1 ( A ), sVCAM-1 ( B ) and log-transformed hs-CRP ( C ). Gray bar denotes low-GDP group and white bar conventional group. *P < 0.05 versus conventional group by analysis of covariance. In linear mixed model analysis, P = 0.928 (time), P = 0.003 (group) for sICAM-1 (A), P = 0.117 (time), P = 0.006 (group) for sVCAM-1 (B) and P = 0.504 (time), P = 0.007 (group) for log-transformed hs-CRP (C). To evaluate whether conventional PD solution would be more harmful in patients with active inflammation, we analyzed the interaction between inflammation and solution group on sICAM-1 and sVCAM-1 at 12 months. In two-way analysis of variance, there was no interaction effect between solution group and hs-CRP. Main effect of solution group controlling for the effect of hs-CRP was significant for sICAM-1 (P = 0.012) and sVCAM-1 (P = 0.024), respectively. Therefore, reduced sICAM-1 and sVCAM-l levels in the low-GDP PDF group were independent of baseline hs-CRP ( Figure 4A and B ). Fig. 4. Open in new tabDownload slide Effect of inflammation and solution group on sICAM-1 ( A ) and sVCAM-1 ( B ) at 12 months of PD. hs-CRP group was divided by median value of hs-CRP level before PD start. Main effect of solution group controlling for the effect of hs-CRP was significant. P = 0.012 (sICAM-1, A) and P = 0.024 (sVCAM-1, B), respectively. Fig. 4. Open in new tabDownload slide Effect of inflammation and solution group on sICAM-1 ( A ) and sVCAM-1 ( B ) at 12 months of PD. hs-CRP group was divided by median value of hs-CRP level before PD start. Main effect of solution group controlling for the effect of hs-CRP was significant. P = 0.012 (sICAM-1, A) and P = 0.024 (sVCAM-1, B), respectively. Dialysis adequacy, peritoneal membrane transport characteristics, RRF and nutritional status Table 3 reports the changes in secondary variables. Adequacy data including total Kt/V urea and creatinine clearance were not different except peritoneal creatinine clearance at baseline. Peritoneal creatinine clearance was significantly higher in the low-GDP PDF group only at baseline, but changes of adequacy were not different between the two groups. The change of D4P4cr and peritoneal ultrafiltration volume per glucose loading was significantly different between the two groups by linear mixed model analysis ( Figure 5A and B ). However, the change of RRF ( Figure 5C ) or urine volume was not different between the two groups. The change of nutritional markers including serum albumin, LBM, nPNA and SGA was not different between the two groups. In addition, changes in blood pressure and number of anti-hypertensive medications were not different between the two groups. Table 3. Changes in secondary outcome variables a Period Baseline 6 months 12 months Group Low-GDP Conventional Low-GDP Conventional Low-GDP Conventional Kt/V urea 2.4 ± 0.6 2.3 ± 0.6 2.2 ± 0.5 2.3 ± 0.7 2.2 ± 0.6 2.1 ± 0.7     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5 1.5 ± 0.4 1.6 ± 0.4 1.6 ± 0.5 1.8 ± 1.1     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5 0.7 ± 0.5 0.6 ± 0.6 0.5 ± 0.5 0.5 ± 0.6     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9 74.8 ± 25.6 74.4 ± 28.1 67.9 ± 24.4 68.6 ± 28.7     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9 38.0 ± 7.3 40.4 ± 8.0 38.8 ± 9.3 39.9 ± 8.6     Ccr 38.9 ± 31.3 36.0 ± 26.2 33.1 ± 25.7 29.0 ± 28.0 25.9 ± 23.4 24.3 ± 30.3 RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 3.4 ± 2.5 3.1 ± 2.8 2.9 ± 2.3 2.9 ± 3.1 Total fluid removal (mL/day) 1479 ± 762 1636 ± 586 1440 ± 512 1659 ± 665 1469 ± 721 1459 ± 646 Peritoneal fluid removal (mL/day) 621 ± 520* 962 ± 527 673 ± 522 * 1045 ± 600 845 ± 633 939 ± 683 Urine volume (mL/day) 880 ± 732 717 ± 536 803 ± 513 677 ± 568 714 ± 537 644 ± 575 Peritoneal UF per glucose load (mL/g glucose) 5.69 ± 5.04 * 9.54 ± 4.73 6.29 ± 5.60 * 9.69 ± 5.47 7.92 ± 5.86 8.72 ± 6.68 Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5 3.7 ± 0.6 3.7 ± 0.5 3.7 ± 0.6 3.7 ± 0.4 LBM (kg) 37.5 ± 9.7 35.1 ± 8.6 38.7 ± 10.0 37.5 ± 8.4 39.7 ± 11.1 37.8 ± 9.2 nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25 0.88 ± 0.18 0.91 ± 0.18 0.88 ± 0.19 0.89 ± 0.21 SGA 5.9 ± 1.2 5.7 ± 1.1 6.0 ± 1.3 5.8 ± 1.1 6.0 ± 1.4 5.9 ± 1.3 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8 132.0 ± 16.8 132.5 ± 21.7 134.5 ± 20.8 129.6 ± 19.3     DBP 82.2 ± 11.9 81.3 ± 12.1 82.2 ± 9.9 80.9 ± 12.6 82.5 ± 11.3 81.2 ± 11.3 Anti-hypertensive agents (numbers) 2.2 ± 0.8 2.2 ± 0.8 2.1 ± 0.7 2.2 ± 0.9 2.3 ± 0.9 2.4 ± 1.0 Period Baseline 6 months 12 months Group Low-GDP Conventional Low-GDP Conventional Low-GDP Conventional Kt/V urea 2.4 ± 0.6 2.3 ± 0.6 2.2 ± 0.5 2.3 ± 0.7 2.2 ± 0.6 2.1 ± 0.7     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5 1.5 ± 0.4 1.6 ± 0.4 1.6 ± 0.5 1.8 ± 1.1     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5 0.7 ± 0.5 0.6 ± 0.6 0.5 ± 0.5 0.5 ± 0.6     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9 74.8 ± 25.6 74.4 ± 28.1 67.9 ± 24.4 68.6 ± 28.7     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9 38.0 ± 7.3 40.4 ± 8.0 38.8 ± 9.3 39.9 ± 8.6     Ccr 38.9 ± 31.3 36.0 ± 26.2 33.1 ± 25.7 29.0 ± 28.0 25.9 ± 23.4 24.3 ± 30.3 RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 3.4 ± 2.5 3.1 ± 2.8 2.9 ± 2.3 2.9 ± 3.1 Total fluid removal (mL/day) 1479 ± 762 1636 ± 586 1440 ± 512 1659 ± 665 1469 ± 721 1459 ± 646 Peritoneal fluid removal (mL/day) 621 ± 520* 962 ± 527 673 ± 522 * 1045 ± 600 845 ± 633 939 ± 683 Urine volume (mL/day) 880 ± 732 717 ± 536 803 ± 513 677 ± 568 714 ± 537 644 ± 575 Peritoneal UF per glucose load (mL/g glucose) 5.69 ± 5.04 * 9.54 ± 4.73 6.29 ± 5.60 * 9.69 ± 5.47 7.92 ± 5.86 8.72 ± 6.68 Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5 3.7 ± 0.6 3.7 ± 0.5 3.7 ± 0.6 3.7 ± 0.4 LBM (kg) 37.5 ± 9.7 35.1 ± 8.6 38.7 ± 10.0 37.5 ± 8.4 39.7 ± 11.1 37.8 ± 9.2 nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25 0.88 ± 0.18 0.91 ± 0.18 0.88 ± 0.19 0.89 ± 0.21 SGA 5.9 ± 1.2 5.7 ± 1.1 6.0 ± 1.3 5.8 ± 1.1 6.0 ± 1.4 5.9 ± 1.3 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8 132.0 ± 16.8 132.5 ± 21.7 134.5 ± 20.8 129.6 ± 19.3     DBP 82.2 ± 11.9 81.3 ± 12.1 82.2 ± 9.9 80.9 ± 12.6 82.5 ± 11.3 81.2 ± 11.3 Anti-hypertensive agents (numbers) 2.2 ± 0.8 2.2 ± 0.8 2.1 ± 0.7 2.2 ± 0.9 2.3 ± 0.9 2.4 ± 1.0 a Note: data are shown as mean ± SD. Bold indicates the parameters have significant differences between the two groups and asterisk indicates p < 0.05 versus conventional fluid group. Kt/V urea , total weekly urea clearance; Kpt/V urea , peritoneal urea clearance; Krt/V urea , renal urea clearance; CrCl, total creatinine clearance; Kpcr, peritoneal creatinine clearance; Ccr, renal creatinine clearance; RRF [mean of creatinine clearance (Ccr) and urea clearance (C urea )]; SBP, systolic blood pressure; DBP, diastolic blood pressure. Open in new tab Table 3. Changes in secondary outcome variables a Period Baseline 6 months 12 months Group Low-GDP Conventional Low-GDP Conventional Low-GDP Conventional Kt/V urea 2.4 ± 0.6 2.3 ± 0.6 2.2 ± 0.5 2.3 ± 0.7 2.2 ± 0.6 2.1 ± 0.7     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5 1.5 ± 0.4 1.6 ± 0.4 1.6 ± 0.5 1.8 ± 1.1     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5 0.7 ± 0.5 0.6 ± 0.6 0.5 ± 0.5 0.5 ± 0.6     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9 74.8 ± 25.6 74.4 ± 28.1 67.9 ± 24.4 68.6 ± 28.7     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9 38.0 ± 7.3 40.4 ± 8.0 38.8 ± 9.3 39.9 ± 8.6     Ccr 38.9 ± 31.3 36.0 ± 26.2 33.1 ± 25.7 29.0 ± 28.0 25.9 ± 23.4 24.3 ± 30.3 RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 3.4 ± 2.5 3.1 ± 2.8 2.9 ± 2.3 2.9 ± 3.1 Total fluid removal (mL/day) 1479 ± 762 1636 ± 586 1440 ± 512 1659 ± 665 1469 ± 721 1459 ± 646 Peritoneal fluid removal (mL/day) 621 ± 520* 962 ± 527 673 ± 522 * 1045 ± 600 845 ± 633 939 ± 683 Urine volume (mL/day) 880 ± 732 717 ± 536 803 ± 513 677 ± 568 714 ± 537 644 ± 575 Peritoneal UF per glucose load (mL/g glucose) 5.69 ± 5.04 * 9.54 ± 4.73 6.29 ± 5.60 * 9.69 ± 5.47 7.92 ± 5.86 8.72 ± 6.68 Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5 3.7 ± 0.6 3.7 ± 0.5 3.7 ± 0.6 3.7 ± 0.4 LBM (kg) 37.5 ± 9.7 35.1 ± 8.6 38.7 ± 10.0 37.5 ± 8.4 39.7 ± 11.1 37.8 ± 9.2 nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25 0.88 ± 0.18 0.91 ± 0.18 0.88 ± 0.19 0.89 ± 0.21 SGA 5.9 ± 1.2 5.7 ± 1.1 6.0 ± 1.3 5.8 ± 1.1 6.0 ± 1.4 5.9 ± 1.3 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8 132.0 ± 16.8 132.5 ± 21.7 134.5 ± 20.8 129.6 ± 19.3     DBP 82.2 ± 11.9 81.3 ± 12.1 82.2 ± 9.9 80.9 ± 12.6 82.5 ± 11.3 81.2 ± 11.3 Anti-hypertensive agents (numbers) 2.2 ± 0.8 2.2 ± 0.8 2.1 ± 0.7 2.2 ± 0.9 2.3 ± 0.9 2.4 ± 1.0 Period Baseline 6 months 12 months Group Low-GDP Conventional Low-GDP Conventional Low-GDP Conventional Kt/V urea 2.4 ± 0.6 2.3 ± 0.6 2.2 ± 0.5 2.3 ± 0.7 2.2 ± 0.6 2.1 ± 0.7     Kpt/V urea 1.7 ± 0.4 1.7 ± 0.5 1.5 ± 0.4 1.6 ± 0.4 1.6 ± 0.5 1.8 ± 1.1     Krt/V urea 0.8 ± 0.5 0.7 ± 0.5 0.7 ± 0.5 0.6 ± 0.6 0.5 ± 0.5 0.5 ± 0.6     CrCl (L/week/1.73m 2 ) 84.1 ± 30.9 77.5 ± 27.9 74.8 ± 25.6 74.4 ± 28.1 67.9 ± 24.4 68.6 ± 28.7     Kpcr 41.4 ± 7.3 * 37.9 ± 6.9 38.0 ± 7.3 40.4 ± 8.0 38.8 ± 9.3 39.9 ± 8.6     Ccr 38.9 ± 31.3 36.0 ± 26.2 33.1 ± 25.7 29.0 ± 28.0 25.9 ± 23.4 24.3 ± 30.3 RRF (mL/min) 3.9 ± 3.1 3.7 ± 2.6 3.4 ± 2.5 3.1 ± 2.8 2.9 ± 2.3 2.9 ± 3.1 Total fluid removal (mL/day) 1479 ± 762 1636 ± 586 1440 ± 512 1659 ± 665 1469 ± 721 1459 ± 646 Peritoneal fluid removal (mL/day) 621 ± 520* 962 ± 527 673 ± 522 * 1045 ± 600 845 ± 633 939 ± 683 Urine volume (mL/day) 880 ± 732 717 ± 536 803 ± 513 677 ± 568 714 ± 537 644 ± 575 Peritoneal UF per glucose load (mL/g glucose) 5.69 ± 5.04 * 9.54 ± 4.73 6.29 ± 5.60 * 9.69 ± 5.47 7.92 ± 5.86 8.72 ± 6.68 Serum albumin (g/dL) 3.6 ± 0.6 3.6 ± 0.5 3.7 ± 0.6 3.7 ± 0.5 3.7 ± 0.6 3.7 ± 0.4 LBM (kg) 37.5 ± 9.7 35.1 ± 8.6 38.7 ± 10.0 37.5 ± 8.4 39.7 ± 11.1 37.8 ± 9.2 nPNA (g/kg/day) 0.91 ± 0.18 0.90 ± 0.25 0.88 ± 0.18 0.91 ± 0.18 0.88 ± 0.19 0.89 ± 0.21 SGA 5.9 ± 1.2 5.7 ± 1.1 6.0 ± 1.3 5.8 ± 1.1 6.0 ± 1.4 5.9 ± 1.3 Blood pressure (mmHg)     SBP 131.6 ± 19.3 131.4 ± 20.8 132.0 ± 16.8 132.5 ± 21.7 134.5 ± 20.8 129.6 ± 19.3     DBP 82.2 ± 11.9 81.3 ± 12.1 82.2 ± 9.9 80.9 ± 12.6 82.5 ± 11.3 81.2 ± 11.3 Anti-hypertensive agents (numbers) 2.2 ± 0.8 2.2 ± 0.8 2.1 ± 0.7 2.2 ± 0.9 2.3 ± 0.9 2.4 ± 1.0 a Note: data are shown as mean ± SD. Bold indicates the parameters have significant differences between the two groups and asterisk indicates p < 0.05 versus conventional fluid group. Kt/V urea , total weekly urea clearance; Kpt/V urea , peritoneal urea clearance; Krt/V urea , renal urea clearance; CrCl, total creatinine clearance; Kpcr, peritoneal creatinine clearance; Ccr, renal creatinine clearance; RRF [mean of creatinine clearance (Ccr) and urea clearance (C urea )]; SBP, systolic blood pressure; DBP, diastolic blood pressure. Open in new tab Fig. 5. Open in new tabDownload slide Changes of dialysate-to-plasma ratio of creatinine (D4/P4cr) ( A ), peritoneal ultrafiltration (UF) volume per glucose load (mL/g glucose) ( B ) and RRF (mL/min) ( C ). Closed circle denotes low-GDP group and open circles conventional group. *P < 0.05 versus, conventional group by analysis of covariance. P = 0.194 (time), P = 0.002 (group) for D4/P4cr (A), P = 0.518 (time), P = 0.003 (group) for UF/glucose (B) and P = 0.309 (time), P = 0.589 (group) for RRF (C). Fig. 5. Open in new tabDownload slide Changes of dialysate-to-plasma ratio of creatinine (D4/P4cr) ( A ), peritoneal ultrafiltration (UF) volume per glucose load (mL/g glucose) ( B ) and RRF (mL/min) ( C ). Closed circle denotes low-GDP group and open circles conventional group. *P < 0.05 versus, conventional group by analysis of covariance. P = 0.194 (time), P = 0.002 (group) for D4/P4cr (A), P = 0.518 (time), P = 0.003 (group) for UF/glucose (B) and P = 0.309 (time), P = 0.589 (group) for RRF (C). Peritonitis and survival Total peritonitis incidence was 46 episodes of peritonitis per 1550 patient-months. Mean follow-up period of PD was 11.0 versus 10.1 months for the low-GDP PDF and conventional PDF groups, respectively. Frequency of peritonitis was not different between the two groups (one episode per 34.8 versus 32.3 patient-months for low-GDP PDF and conventional PDF groups, respectively). During follow-up of 12 months, five deaths were reported. In survival analysis, patient survival and death-censored technique survival were not different between the two groups ( Figure 6A and B ). Fig. 6. Open in new tabDownload slide Survival analyses for patients ( A ) and technique survival ( B ). Solid line denotes low-GDP group and dashed line conventional group. In log-rank test, P = 0.849 and 0.928, respectively. Fig. 6. Open in new tabDownload slide Survival analyses for patients ( A ) and technique survival ( B ). Solid line denotes low-GDP group and dashed line conventional group. In log-rank test, P = 0.849 and 0.928, respectively. Discussion This is the first prospective, randomized controlled study investigating inflammation and endothelial dysfunction markers as primary outcomes in incident PD patients exposed to different levels of GDP-containing PDF. Our study demonstrates that endothelial dysfunction markers were significantly lowered in PD patients exposed to low-GDP PDF compared to standard PDF after 12 months of PD. The local peritoneal effects of low-GDP PDF are well known from previous studies, showing improvement of peritoneal effluent markers of peritoneal integrity, such as CA125 or hyaluronic acid [ 12 , 19 ]. Consistently, animal models of PD demonstrate fewer structural alterations in the local peritoneum, such as peritoneal inflammation, neoangiogenesis and fibrosis, with low GPD PDF compared to standard PDF [ 20 ]. In addition to its local effects, the systemic effects of low-GDP PDF were partly reported in previous studies, showing lower concentration of systemic AGEs and/or C-reactive protein levels in low-GDP PDF-treated patients [ 12 , 13 , 18 , 19 ]. AGEs are commonly seen in patients with CKD; their production is promoted by oxidative and carbonyl stress. The levels of systemic AGEs were more markedly elevated after exposure to conventional PDF compared to low-GDP PDF [ 21 ]. Interestingly, the levels of selected AGEs decrease when patients are converted from standard PDF to low-GDP PDF [ 12 , 13 , 22 ]. AGEs activate inflammatory cells and directly stimulate endothelial cells to express adhesion molecules [ 23 ]. Certain subtypes of AGEs activate monocytes, which have important pathogenic roles in the progression of atherosclerosis, and subsequently increase production of adhesion molecules and cytokines [ 24 ]. Vascular adhesion molecules, such as sVCAM-1 or sICAM-1, are known biochemical markers of endothelial dysfunction [ 25 ]. Endothelial dysfunction was partly mediated by AGEs-induced inhibition of nitric oxide synthase through receptor for AGE (RAGE) [ 26 ]. In addition, elevated levels of soluble adhesion molecules are found in CKD patients, especially in malnourished, inflamed patients and patients with CVD [ 9 , 10 ]. Clinically overt vascular events are reportedly preceded by endothelial dysfunction [ 27 ]. Endothelial dysfunction and inflammation are suggested to be novel risk markers, in addition to other uremia-related factors, and they act synergistically with the highly prevalent traditional risk factors for CVD in the CKD population. In this study, we observed less elevation of vascular adhesion molecules in patients receiving low-GDP PDF. This might be associated with a reduction in elevation of systemic AGEs in patients treated with low-GDP PDF. In addition, indirect evidence, such as induced VCAM-1 expression in cultured human peritoneal mesothelial cells following a single exposure to GDPs [ 11 ], suggests a direct effect of GDP on vascular endothelial cells. However, there is currently a paucity of scientific evidence supporting a direct effect of GDPs on vascular endothelial cell activation. Besides soluble adhesion molecules, however, we were unable to demonstrate significant differences in inflammation and oxidative stress markers between the two treatment groups. In this study, hs-CRP was not significantly different between the two groups after 12 months of PD. This is in contrast to previous reports, which found lower hs-CRP in the low-GDP groups in prevalent and incident PD patients [ 18 , 19 ]. We could not explain exactly how this difference in the changes of hs-CRP occurs in our study. However, we assume that a higher level of hs-CRP at baseline, even though it is not statistically significant, may affect the change of hs-CRP, at least, at 6 months. Moreover, from an other point of view, if the low-GDP solution harmfully affects hs-CRP levels beyond 6 months, the difference would be more prominent at 12 months. However, we could not find a significant difference of hs-CRP at 12 months. In a retrospective analysis of Korean PD patients, use of bicarbonate/lactate, low-GDP PDF is associated with improvement in overall patient survival [ 2 ]. However, it is not clear whether the favorable effect of low-GDP PDF is directly linked to the improvement of cardiovascular outcomes in PD patients. Based on our results, changes in vascular adhesion molecules as a marker of endothelial dysfunction, in addition to surrogate markers for cardiovascular outcomes in PD patients, may provide evidence of cardiovascular effects. Considering secondary outcome variables, we found higher peritoneal membrane transport characteristics in the low-GDP group at baseline. During the run-in period before baseline PET, patients were already exposed to different dialysis solutions for at least 4 weeks; thus, peritoneal membrane transport characteristics might be affected by a different PDF. Similarly, the Eurobalance trial [ 12 ] reported higher peritoneal membrane transport in the low-GDP group after 12 weeks of PDF exposure. In addition, in this study, peritoneal ultrafiltration volume was significantly lowered until 6 months of PD without difference in RRF. Change of urine volume was not significantly different between the two treatment groups. Therefore, differences in peritoneal ultrafiltration volume may be associated with peritoneal membrane transport characteristics rather than RRF in our study. The effects of low-GDP fluid on RRF were not consistent in several studies, with some reporting protective effects [ 12 , 28 ] and others finding no influence [ 19 ]. Similar to our study, changes of RRF and urine volume were not statistically different between the incident PD patients (including automated PD) treated with biocompatible PDF and standard PDF in a randomized controlled trial of 1-year [ 29 ]. However, in an another 1-year of randomized study in incident CAPD patients, low-GDP PDF was beneficial for maintaining RRF, especially in patients with a GFR of ≥2 mL/min/1.73m 2 [ 30 ]. This may be related to variations in compounding factors affecting RRF as well as population of patients. Peritonitis incidence, expressed as episodes per patient-months, was not different between the two groups. This is consistent with previous studies with low-GDP PDF. Moreover, the data for survival analysis were also consistent with a previously reported randomized study [ 19 ]. Some limitations of this study should be noted. We measured endothelial dysfunction only by biomedical markers not by functional endothelial dysfunction due to the limitation of standard instruments and procedures in different multiple centers. Previous reports show that flow-mediated vasodilatation, a commonly used method for endothelial dysfunction, correlates with levels of vascular adhesion molecules [ 31 , 32 ]. This indicates that vascular adhesion molecules could be a useful biomarker for functional endothelial dysfunction. Secondly, in this multicenter study, center effect was not fully adjusted. We assumed minimal center effect because all centers have similar characteristics regarding the PD program. In addition, allocation of patients was performed randomly at each center. All seven centers participating in this randomized study have experienced PD-oriented doctors with >100 PD patients for five centers and 40 patients for two centers. Lastly, the number of patients in both groups was not completely balanced when entering baseline study period because of higher drop rate during the run-in period for the conventional PDF group. This may lead to a selection bias. In conclusion, neutral pH and low-GDP PDF likely have a beneficial effect on endothelial dysfunction markers compared to standard PDF in incident PD patients, although the association of these surrogate outcome markers and long-term clinical outcomes of low GDP PDF needs to be evaluated in further studies. We thank the investigators of this MCS for PD in Korea. The list of MCS for PD in Korea—Park J.W. in Yeungnam University Hospital; Kim Y.W., Gang S.W. in Inje University Pusan Paik Hospital; Park S.B., Han S.Y., Hwang E.A. in Keimyung University Dongsan Hospital; Kim S.Y., Lee S.J. in Daejeon St Mary’s Hospital; Hong S.Y., Lee E.Y., Gil H.W. in Soonchunhyang University Cheonan Hospital; Lee J.S., Park J.H., Lim J.H. in Ulsan University Hospital; Han G.G. in Pusan Veterans Hospital; Kim D.J. in Samsung Medical Center; Kim S.R., Cho S. in Samsung Changwon Hospital; Hwang S.D., Kim J.K., Choi S.J. in Soonchunhyang University Bucheon Hospital; Ahn C., Kim Y.S., Joo K.W., Oh K.H. in Seoul National University Hospital; Yang D.H., Kim H.J. in Bundang Cha Hospital; Yoon S.C., Cho J.T., Lee E.K. in Dankook University Hospital; Seo B.J. in Wallace Memorial Baptist Hospital; Bang J.H. in Andong Hospital; Kim Y.S., Yang C.W., Choi B.S. in Seoul St Mary’s Hospital; Choi E.J., Song H.C. in Bucheon St Mary’s Hospital; Kim H.J., Kim S.G. in Hallym University Sacred Heart Hospital; Shin S.J., Chung H.W. in Incheon St Mary’s Hospital; Kim G.H., Kang C.M., Lee C.H. in Hanyang University Hospital; Han S.Y., Han K.H. in Inje University Ilsan Paik Hospital; Song G.I. in Gangneung Asan Hospital; Rim H., Jung Y.S. in Kosin University Gospel Hospital; Jeon G.U., Oh H.J. in Dong Rae Bong Seng Hospital; Kwak I.S., Lee S.B., Lee D.W., Song S.H. in Pusan National University Hospital; Kim S.H. in Daegu Fatima Hospital; Kim B.S., Shin M.J. in St Paul’s Hospital; Chung W.K., Lee H.H. in Gachon University Gil Hospital; Kim H.J., Kim M.O., Lee Y.S. in Daejeon Eulji University Hospital; Lee S.Y., Sung S.A., Hwang Y.H. in Eulji General Hospital; Oh J.E., Kim S.J. in Kangdong Sacred Heart Hospital; Jo Y.I. in Konkuk University Hospital; Go J.H. in Mokpo Jungang Hospital; Kwon S.K., Yoon S.I. in Chungbuk National University Hospital; Kwon Y.J. in Korea University Guro Hospital; Kim B. in Veterans Hospital; Gang W.H., Jang E.H. in Jeju National University Hospital; Hwang D.Y. in Cheong-Ju St Mary’s Hospital; Ahn K.S. in Daegu Catholic University Hospital; Park W.D., Kim S.H. in Inje University Sanggye Paik Hospital; Hur D. in Daedong Hospital; Lee D.R., Kong J.M. in Maryknoll Medical Center. The study was supported in part by Fresenius Medical Care, Korea, and also in part by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A084001). Part of this study was presented at the 2010 annual meeting of American Society of Nephrology; 16 November 2010 through 21 November 2010; Denver, CO. USA. Conflict of interest statement . The study was supported in part by Fresenius Medical Care, Korea. All authors declare that they have no relevant financial interest. References 1. Lee HY , Park HC , Seo BJ , et al. Superior patient survival for continuous ambulatory peritoneal dialysis patients treated with a peritoneal dialysis fluid with neutral pH and low glucose degradation product concentration (Balance) , Perit Dial Int , 2005 , vol. 25 (pg. 248 - 255 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat 2. Han SH , Ahn SV , Yun JY , et al. Mortality and technique failure in peritoneal dialysis patients using advanced peritoneal dialysis solutions , Am J Kidney Dis , 2009 , vol. 54 (pg. 711 - 720 ) Google Scholar Crossref Search ADS PubMed WorldCat 3. Danesh J , Collins R , Appleby P , et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies , JAMA , 1998 , vol. 279 (pg. 1477 - 1482 ) Google Scholar Crossref Search ADS PubMed WorldCat 4. Stenvinkel P , Heimburger O , Paultre F , et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure , Kidney Int , 1999 , vol. 55 (pg. 1899 - 1911 ) Google Scholar Crossref Search ADS PubMed WorldCat 5. Zimmermann J , Herrlinger S , Pruy A , et al. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients , Kidney Int , 1999 , vol. 55 (pg. 648 - 658 ) Google Scholar Crossref Search ADS PubMed WorldCat 6. Hwang SJ , Ballantyne CM , Sharrett AR , et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study , Circulation , 1997 , vol. 96 (pg. 4219 - 4225 ) Google Scholar Crossref Search ADS PubMed WorldCat 7. Ridker PM , Hennekens CH , Roitman-Johnson B , et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men , Lancet , 1998 , vol. 351 (pg. 88 - 92 ) Google Scholar Crossref Search ADS PubMed WorldCat 8. Papayianni A , Alexopoulos E , Giamalis P , et al. Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events , Nephrol Dial Transplant , 2002 , vol. 17 (pg. 435 - 441 ) Google Scholar Crossref Search ADS PubMed WorldCat 9. Stenvinkel P , Lindholm B , Heimburger M , et al. Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease , Nephrol Dial Transplant , 2000 , vol. 15 (pg. 1624 - 1630 ) Google Scholar Crossref Search ADS PubMed WorldCat 10. Choi HY , Lee JE , Han SH , et al. Association of inflammation and protein-energy wasting with endothelial dysfunction in peritoneal dialysis patients , Nephrol Dial Transplant , 2010 , vol. 25 (pg. 1266 - 1271 ) Google Scholar Crossref Search ADS PubMed WorldCat 11. Welten AG , Schalkwijk CG , ter Wee PM , et al. Single exposure of mesothelial cells to glucose degradation products (GDPs) yields early advanced glycation end-products (AGEs) and a proinflammatory response , Perit Dial Int , 2003 , vol. 23 (pg. 213 - 221 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat 12. Williams JD , Topley N , Craig KJ , et al. The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane , Kidney Int , 2004 , vol. 66 (pg. 408 - 418 ) Google Scholar Crossref Search ADS PubMed WorldCat 13. Schmitt CP , von Heyl D , Rieger S , et al. Reduced systemic advanced glycation end products in children receiving peritoneal dialysis with low glucose degradation product content , Nephrol Dial Transplant , 2007 , vol. 22 (pg. 2038 - 2044 ) Google Scholar Crossref Search ADS PubMed WorldCat 14. Lage C , Pischetsrieder M , Aufricht C , et al. First in vitro and in vivo experiences with Stay-Safe Balance, a pH-neutral solution in a dual-chambered bag , Perit Dial Int , 2000 , vol. 20 Suppl 5 (pg. S28 - S32 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat 15. La Milia V , Pozzoni P , Virga G , et al. Peritoneal transport assessment by peritoneal equilibration test with 3.86% glucose: a long-term prospective evaluation , Kidney Int , 2006 , vol. 69 (pg. 927 - 933 ) Google Scholar Crossref Search ADS PubMed WorldCat 16. Keshaviah PR , Nolph KD , Moore HL , et al. Lean body mass estimation by creatinine kinetics , J Am Soc Nephrol , 1994 , vol. 4 (pg. 1475 - 1485 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat 17. Randerson DH , Chapman GV , Farrell PC . Atkins RC , Farrell PC , Thomson N . Amino acid and dietary status in long-term CAPD patients , Peritoneal Dialysis , 1981 Edinburgh, UK Churchill Livingstone (pg. 171 - 191 ) Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 18. Choi HY , Kim DK , Lee TH , et al. The clinical usefulness of peritoneal dialysis fluids with neutral pH and low glucose degradation product concentration: an open randomized prospective trial , Perit Dial Int , 2008 , vol. 28 (pg. 174 - 182 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat 19. Szeto CC , Chow KM , Lam CW , et al. Clinical biocompatibility of a neutral peritoneal dialysis solution with minimal glucose-degradation products—a 1-year randomized control trial , Nephrol Dial Transplant , 2007 , vol. 22 (pg. 552 - 559 ) Google Scholar Crossref Search ADS PubMed WorldCat 20. Park SH , Lee EG , Kim IS , et al. Effect of glucose degradation products on the peritoneal membrane in a chronic inflammatory infusion model of peritoneal dialysis in the rat , Perit Dial Int , 2004 , vol. 24 (pg. 115 - 122 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat 21. Fusshoeller A , Plail M , Grabensee B , et al. Biocompatibility pattern of a bicarbonate/lactate-buffered peritoneal dialysis fluid in APD: a prospective, randomized study , Nephrol Dial Transplant , 2004 , vol. 19 (pg. 2101 - 2106 ) Google Scholar Crossref Search ADS PubMed WorldCat 22. Zeier M , Schwenger V , Deppisch R , et al. Glucose degradation products in PD fluids: do they disappear from the peritoneal cavity and enter the systemic circulation? , Kidney Int , 2003 , vol. 63 (pg. 298 - 305 ) Google Scholar Crossref Search ADS PubMed WorldCat 23. Schmidt AM , Hori O , Chen JX , et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes , J Clin Invest , 1995 , vol. 96 (pg. 1395 - 1403 ) Google Scholar Crossref Search ADS PubMed WorldCat 24. Takahashi HK , Mori S , Wake H , et al. Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells , J Pharmacol Exp Ther , 2009 , vol. 330 (pg. 89 - 98 ) Google Scholar Crossref Search ADS PubMed WorldCat 25. Jacobson SH , Egberg N , Hylander B , et al. Correlation between soluble markers of endothelial dysfunction in patients with renal failure , Am J Nephrol , 2002 , vol. 22 (pg. 42 - 47 ) Google Scholar Crossref Search ADS PubMed WorldCat 26. Linden E , Cai W , He JC , et al. Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation , Clin J Am Soc Nephrol , 2008 , vol. 3 (pg. 691 - 698 ) Google Scholar Crossref Search ADS PubMed WorldCat 27. Reddy KG , Nair RN , Sheehan HM , et al. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis , J Am Coll Cardiol , 1994 , vol. 23 (pg. 833 - 843 ) Google Scholar Crossref Search ADS PubMed WorldCat 28. Haag-Weber M , Kramer R , Haake R , et al. Low-GDP fluid (Gambrosol trio) attenuates decline of residual renal function in PD patients: a prospective randomized study , Nephrol Dial Transplant , 2010 , vol. 25 (pg. 2288 - 2296 ) Google Scholar Crossref Search ADS PubMed WorldCat 29. Fan SL , Pile T , Punzalan S , et al. Randomized controlled study of biocompatible peritoneal dialysis solutions: effect on residual renal function , Kidney Int , 2008 , vol. 73 (pg. 200 - 206 ) Google Scholar Crossref Search ADS PubMed WorldCat 30. Kim S , Oh J , Chung W , et al. Benefits of biocompatible PD fluid for preservation of residual renal function in incident CAPD patients: a 1-year study , Nephrol Dial Transplant , 2009 , vol. 24 (pg. 2899 - 2908 ) Google Scholar Crossref Search ADS PubMed WorldCat 31. Lupattelli G , Lombardini R , Schillaci G , et al. Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles , Am Heart J , 2000 , vol. 140 (pg. 521 - 526 ) Google Scholar Crossref Search ADS PubMed WorldCat 32. Vallbracht KB , Schwimmbeck PL , Seeberg B , et al. Endothelial dysfunction of peripheral arteries in patients with immunohistologically confirmed myocardial inflammation correlates with endothelial expression of human leukocyte antigens and adhesion molecules in myocardial biopsies , J Am Coll Cardiol , 2002 , vol. 40 (pg. 515 - 520 ) Google Scholar Crossref Search ADS PubMed WorldCat © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
TI - Effects of neutral pH and low-glucose degradation product-containing peritoneal dialysis fluid on systemic markers of inflammation and endothelial dysfunction: a randomized controlled 1-year follow-up study
JF - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gfr451
DA - 2012-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/effects-of-neutral-ph-and-low-glucose-degradation-product-containing-j7kTYY7iaw
SP - 1191
EP - 1199
VL - 27
IS - 3
DP - DeepDyve
ER -