Vascular endothelial growth factor in peritoneal dialysis: a longitudinal follow-up

In a previous study, vascular endothelial growth factor (VEGF) was found to be locally produced in the peritoneal tissue of patients undergoing peritoneal dialysis (PD) who were being treated with glucose-containing PD solutions. Locally produced VEGF (LVEGF) was positively related to the mass transfer area coefficient (MTAC) of creatinine and to glucose absorption, both of which are representative of the peritoneal vascular surface area. It was therefore hypothesized that VEGF is involved in the peritoneal neoangiogenesis found in long-term PD. The aim of the present study was to investigate the time course of peritoneal VEGF levels in PD patients treated with glucose-based PD solutions during longitudinal follow-up. We also studied the effect of the switch to glucose-free PD treatment on VEGF production. Forty standard peritoneal permeability analyses (SPAs) with 3.86% glucose-containing dialysis solution were investigated. The SPAs were performed in 10 PD patients with a median number of three SPAs per patient during a follow-up of 23 months. Duration of PD treatment at the last SPA was 74 months. All patients were initially treated with glucose-containing dialysis solutions. Four patients switched after 114 months of glucose-based PD to glucose-free PD and were followed for 7 months. A PD regimen of icodextrin, glycerol, and amino acid-based dialysis solutions was applied in these patients. Four SPAs were performed per patient in this period. To predict the VEGF dialysate-to-serum ratio (D/S), when diffusion would be the only explanation for the VEGF dialysate concentration, we calculated the power relationship between D/S ratios of serum proteins that are only transported across the peritoneum and the molecular weights of those proteins. The measured VEGF D/S ratio was higher than expected (P <.001) in each observation, pointing to local production of VEGF. LVEGF increased with duration of glucose PD, 11.7 ng/L to 23.45 ng/L (P <.03). LVEGF decreased in all 4 patients undergoing glucose-free PD, from 57.35 ng/L to 23.10 ng/L. A correlation (r = 0.83, P <.001) was found be-tween the differences in MTAC creatinine between the first and last SPA during glucose-based PD and the difference in LVEGF between these observations. A similar correlation was present between the difference in glucose absorption and the difference in LVEGF (r = 0.85, P <.001). This supports a pathogenetic role of high glucose dialysate concentrations in the development of changes in the peritoneum that are found in long-term PD. Treatment with non-glucose-based PD solutions may inhibit further development of these alterations.     

Determinants of peritoneal solute transport rates in newly started nondiabetic peritoneal dialysis patients.

OBJECTIVE: An overrepresentation of a fast peritoneal transport status in new peritoneal dialysis (PD) patients with extensive comorbidity has been reported in some studies. High mass transfer area coefficients (MTACs) of low MW solutes suggest the presence of a large effective peritoneal surface area. The mechanism is unknown. It might include comorbidity, chronic inflammation, or an effect of mesothelial cell mass on peritoneal transport by the production of vasoactive substances. To investigate their relative importance in early PD, peritoneal permeability characteristics in incident PD patients were analyzed for relationships with comorbidity, serum concentrations of inflammatory markers, and products of the mesothelial cells that can be detected in dialysate. DESIGN: A cross-sectional study. SETTING: A university hospital. METHODS: 46 patients who fulfilled the following inclusion criteria were analyzed: a standard peritoneal permeability analysis (SPA) within 6 months after the start of PD, no peritonitis prior to the SPA, older than 18 years, and without diabetes mellitus as a primary renal disease. The patients were divided into tertiles based on the MTAC creatinine: slow, medium, and fast transport groups. The Davies comorbidity score was used to assess comorbidity. Serum and dialysate samples obtained during the SPA were used to determine hyaluronan, interleukin (IL)-6, vascular endothelial growth factor (VEGF), and cancer antigen 125 (CA125). The dialysate concentrations of these substances were expressed as their dialysate appearance rates. RESULTS: No significant differences were present in the three transport groups for comorbidity, serum concentrations of inflammatory markers, or serum VEGF. Interleukin-6 and VEGF concentration attributed to local VEGF production were not different between the tertiles. Levels of VEGF were higher in the medium transport group compared to the slow transport group (p = 0.02); CA125 was higher in the fast transport group compared to the medium transport group (p= 0.01). When analyzed as continuous variables, MTAC creatinine was related to VEGF (r= 0.33, p < 0.05) and CA125 (r= 0.41, p = 0.03). In linear regression analysis, VEGF influenced the association between CA125 and MTAC creatinine; IL-6 weakened this association only marginally. CONCLUSION: A fast peritoneal transport status in incident nondiabetic PD patients was not related to comorbidity. The relationships found between VEGF, CA125, and MTAC creatinine may suggest a role of VEGF in the regulation of the vascular peritoneal surface area, possibly already before structural abnormalities have developed. Our analyses are consistent with the hypothesis that mesothelial cell mass is an important determinant of the peritoneal transport status in incident nondiabetic PD patients without previous peritonitis. Of the many potential mediators produced by mesothelial cells, VEGF was more important than the inflammation marker IL-6.     

Peritoneal accumulation of AGE and peritoneal membrane permeability.

BACKGROUND: In continuous ambulatory peritoneal dialysis (CAPD), the peritoneal membrane is continuously exposed to high-glucose-containing dialysis solutions. Abnormally high glucose concentration in the peritoneal cavity may enhance advanced glycosylation end-product (AGE) formation and accumulation in the peritoneum. Increased AGE accumulation in the peritoneum, decreased ultrafiltration volume, and increased peritoneal permeability in long-term dialysis patients have been reported. AIM: The purpose of the study was to evaluate the relation between peritoneal membrane permeability and peritoneal accumulation of AGE. METHODS: Peritoneal membrane permeability was evaluated by peritoneal equilibration test (PET) using dialysis solutions containing 4.25% glucose. Serum, dialysate, and peritoneal tissue levels of AGE were measured by ELISA method using polyclonal anti-AGE antibody. Peritoneal biopsy was performed during peritoneal catheter insertion [new group (group N), n = 18] and removal [long-term group (group LT), n = 10]. Peritoneal catheters were removed due to exit-site infection not extended into the internal cuff (n = 6) and ultrafiltration failure (n = 4) after 51.6+/-31.5 months (13 - 101 months) of dialysis. PET data obtained within 3 months after the initiation of CAPD or before catheter removal were included in this study. Ten patients in group N and 4 patients in group LT were diabetic. Patients in group LT were significantly younger (46.5+/-11.1 years vs 57.5+/-1.3 years) and experienced more episodes of peritonitis (3.5+/-2.1 vs 0.2+/-0.7) than group N. RESULTS: Peritoneal tissue AGE level in group LT was significantly higher than in group N, in both nondiabetic (0.187+/-0.108 U/mg vs 0.093+/-0.08 U/mg of hydroxyproline, p < 0.03) and diabetic patients (0.384+/-0.035 U/mg vs 0.152+/-0.082 U/mg of hydroxyproline, p < 0.03), while serum and dialysate levels did not differ between the groups in both nondiabetic and diabetic patients. Drain volume (2600+/-237 mL vs 2766+/-222 mL, p = 0.07) and D4/D0 glucose (0.229+/-0.066 vs 0.298+/-0.081, p < 0.009) were lower, and D4/P4 creatinine (0.807+/-0.100 vs 0.653+/-0.144, p< 0.0001) and D1/P1 sodium (0.886+/-0.040 vs 0.822+/-0.032, p < 0.0003) were significantly higher in group LT than in group N. On linear regression analysis, AGE level in the peritoneum was directly correlated with duration of CAPD (r = 0.476, p = 0.012), number of peritonitis episodes (r = 0.433, p = 0.0215), D4/P4 creatinine (r = 0.546, p < 0.027), and D1/P1 sodium (r = 0.422, p = 0.0254), and inversely correlated with drain volume (r = 0.432, p = 0.022) and D4/D0 glucose (r = 0.552, p < 0.0023). AGE level in the peritoneal tissue and dialysate were significantly higher in diabetics than in nondiabetics in group LT, while these differences were not found in group N. Serum AGE level did not differ between nondiabetics and diabetics in either group N or group LT. Drain volume and D4/D0 glucose were lower and D4/P4 creatinine and D1/P1 sodium higher in diabetics than in nondiabetics in both groups. CONCLUSION: Peritoneal accumulation of AGE increased with time on CAPD and number of peritonitis episodes, and was directly related with peritoneal permeability. Peritoneal AGE accumulation and peritoneal permeability in diabetic patients were higher than in nondiabetic patients from the beginning of CAPD.     

Ultrafiltration and small solute transport at initiation of PD: questioning the paradigm of peritoneal function.

BACKGROUND: Human peritoneal function on commencing peritoneal dialysis (PD) is not yet adequately understood. The objective of this study was to determine peritoneal functional patterns on commencing PD. METHODS: 367 end-stage renal disease (ESRD) patients on PD for the first time were studied between their initial second to sixth weeks on PD. Urea and creatinine mass transfer area coefficients (MTAC) and standardized ultrafiltration (UF) capacity were determined. RESULTS: Mean parametric values were MTAC urea 22.9 +/- 7.04 mL/min, MTAC creatinine 10.31 +/- 4.68 mL/min, and UF 896 +/- 344 mL. Gender, patient size, and diabetes or kidney disease did not affect these parameters. The relationship between values of MTAC creatinine and UF reached statistical significance, although with a low value for Pearson's coefficient (r = -0.30, p = 0.001). Age showed a significant inverse linear correlation with UF capacity (r = -0.15, p = 0.003) and MTAC urea (r = -0.11, p < 0.05). Logistic regression analysis demonstrated that UF below 400 mL was independently related to a high MTAC creatinine and older age. Diabetes was least frequent in patients with the lowest UF. However, in the analysis of MTAC creatinine quintiles, UF values did not follow the expected inverse pattern. The lack of differences in UF between the second and third to fourth MTAC creatinine quintiles is remarkable; MTAC creatinine ranged from 6.71 to 13.54. CONCLUSIONS: The functional characteristics of human peritoneum varied markedly and there was a less intense than expected relationship between solute and water transports. This mild inverse relationship is intriguing and suggestive of the necessity of redefining some basic concepts. Age was associated with a lower peritoneal UF capacity, in part independently of small solute transport.     

Effect of glucose degradation products on the peritoneal membrane in a chronic inflammatory infusion model of peritoneal dialysis in the rat.

BACKGROUND: Long-term use of the peritoneal membrane as a dialyzing membrane is hampered by its eventual deterioration. One of the contributing factors is glucose degradation products (GDPs) in the dialysis solution. In this study, we evaluated the effect of a low GDP solution on peritoneal permeability, the structural stability of the peritoneal membrane, and vascular endothelial growth factor (VEGF) production in a chronic inflammatory infusion model of peritoneal dialysis (PD) in the rat. METHODS: Male Sprague-Dawley rats were divided into 3 groups: a conventional solution group (group C, n = 12), a test solution group (group T, n = 12), and a normal control group (group NC, n = 8). Group T rats were infused with low GDP solution (2.3% glucose solution with two compartments), and group C rats with conventional dialysis solution (2.3% glucose solution), adjusted to pH 7.0 before each exchange. Animals were infused through a permanent catheter with 25 mL of dialysis solution. In both groups, peritoneal inflammation was induced by infusing dialysis solution supplemented with lipopolysaccharide on days 8, 9, and 10 after starting dialysate infusion. Peritoneal membrane function was assessed before and 6 weeks after initiating dialysis using the 1-hour peritoneal equilibration test (PET) employing 4.25% glucose solution. Both VEGF and transforming growth factor beta1 (TGFbeta1) in the dialysate effluent were measured by ELISA. The number of vessels in the omentum was counted after staining with anti-von Willebrand factor, and the thickness of submesothelial matrix of the trichrome-stained parietal peritoneum was measured. Peritoneal tissue was analyzed for VEGF protein using immunohistochemistry. RESULTS: At the end of 6 weeks, the rate of glucose transport (D/D0, where D is glucose concentration in the dialysate and D0 is glucose concentration in the dialysis solution before it is infused into the peritoneal cavity) was higher in group T (p < 0.05) than in group C. Dialysate-to-plasma ratio (D/P) of protein was lower in group T (p < 0.05) than in group C; D/P(urea), D/P(sodium), and drain volumes did not differ significantly between groups C and T. Dialysate VEGF and TGFbeta levels were lower in group T (p < 0.05) than in group C. Immunohistochemical studies also revealed less VEGF in the peritoneal membranes of group T. There were significantly more peritoneal blood vessels in group C (p < 0.05) than in group T, but the thickness of submesothelial matrix of the parietal peritoneum was not different between the two groups. The VEGF levels in the dialysate effluent correlated positively with the number of blood vessels per field (r = 0.622, p < 0.005). CONCLUSION: Using a chronic inflammatory infusion model of PD in the rat, we show that dialysis with GDP-containing PD fluid is associated with increased VEGF production and peritoneal vascularization. Use of low GDP solutions may therefore be beneficial in maintaining the function and structure of the peritoneal membrane during long-term PD.     

A comparison between 1.36% and 3.86% glucose dialysis solution for the assessment of peritoneal membrane function.

OBJECTIVE: To assess peritoneal membrane function with respect to fluid transport, parameters of low molecular weight solute transport, and estimations of the function of peritoneal water channels, comparing the results from a 1.36%/1.5% glucose solution with those from a 3.86%/4.25% solution in standardized peritoneal function tests. DESIGN: The study was performed in 40 stable continuous ambulatory peritoneal dialysis (CAPD) patients [median age 50 years (range: 22-74 years); duration of CAPD 9 months (range: 2-45 months)] who underwent two standard peritoneal permeability analyses (SPAs) within 1 month. One SPA used 1.36% glucose; the other, 3.86% glucose. Mass transfer area coefficients (MTACs) and dialysate-to-plasma (D/P) ratios were compared for the two solutions. Also, two different methods of estimating aquaporin-mediated water transport were compared: the sieving of sodium (3.86% glucose) and the difference in net ultrafiltration (deltaNUF), calculated as NUF 3.86% SPA - NUF 1.36% SPA. RESULTS: Median NUF in the 1.36% glucose SPA was -46 mL (range: -582 mL to 238 mL); in the 3.86% SPA, it was 554 mL (range: -274 mL to 1126 mL). The median difference in NUF for the two SPAs was 597 mL (range: 90-1320 mL). No difference between the two solutions was seen for the MTAC of creatinine (11.4 mL/min for 1.36% vs 12.0 mL/min for 3.86%) and absorption of glucose (64% vs 65%, respectively). Also, D/P creatinine was not different: 0.77 (1.36%) and 0.78 (3.86%). However, the ratio of dialysate glucose at 240 minutes and at 0 minutes (Dt/D0) was 0.34 (1.36%) and 0.24 (3.86%), p < 0.01. Values of D/P creatinine from the two glucose solutions were strongly correlated. The intra-individual differences were small and showed a random distribution. Patient transport category was minimally influenced by the tonicity of the dialysate. The minimum D/P Na+ (3.86%) was 0.884, and it was reached after 60 minutes. After correction for Na+ diffusion, D/P Na+ decreased to 0.849 after 120 minutes. The correlation coefficient between the diffusion-corrected D/P Na+ and the deltaNUF was 0.49, p < 0.01. An inverse relationship was present between MTAC creatinine and D/P Na+ (p < 0.01) This correlation can be explained by the rapid disappearance of the osmotic gradient owing to a large vascular surface area. Such a correlation was not present between MTAC creatinine and deltaNUF. CONCLUSIONS: We conclude that a standardized 4-hour peritoneal permeability test using 3.86%/4.25% glucose is the preferred method to assess peritoneal membrane function, including aquaporin-mediated water transport. The D/P Na+ after correction for Na+ diffusion is probably more useful for the assessment of aquaporin-mediated water transport than is deltaNUF obtained with 3.86%/4.25% and 1.36%/1.5% glucose-based dialysis solutions.     

Peritoneal function and adequacy calculations: current programs versus PD Adequest 2.0.

OBJECTIVE: Our current programs (CPs) were compared to PD Adequest 2.0 (PD-A) for calculations of peritoneal membrane transport and dialysis adequacy. DESIGN: Thirty peritoneal equilibration tests (PETs) and 24-hour balances (24hBs) were conducted and calculated using our CPs and PD-A. PATIENTS AND METHODS: Thirty hospital-controlled peritoneal dialysis (PD) patients were studied. The inclusion of correction factors (for glucose or plasmatic water) and of residual volume, and the use of 3 or 6 peritoneal samples were analyzed to discover the differences between programs. The main outcome measures were peritoneal permeability and adequacy parameters, evaluated by Student t-test (mean and paired comparisons) and linear regression for correlation. RESULTS: No significant differences were found in D/P values for small solutes. At the first step, mass transfer area coefficient (MTAC) urea and MTAC creatinine were significantly higher in DP-A than in CP, but MTAC glucose did not differ. The causes of differences were: (1) inclusion of a correction factor for aqueous plasmatic concentration of small solutes in CP; (2) lack of Inclusion of residual volume in peritoneal volumes in CP; and (3) use of 6 peritoneal samples in CP versus 3 in PD-A. At the second step, when the input data were made equivalent for both programs, the differences disappeared for MTAC urea, creatinine, and glucose (mean comparison), but creatinine and glucose remained different by paired comparison. Similar results were obtained when a correction for plasmatic aqueous concentration was applied to the data in both programs [MTAC urea: 22.60 +/- 4.27 ml/min (CP) vs 22.43 +/- 4.61 mL/min (PD-A), nonsignificant, r= 0.97; MTAC creatinine: 9.76 +/- 3.83 mL/min (CP) vs 10.61 +/- 3.07 mL/min (PD-A), nonsignificant, r = 0.98; MTAC glucose: 13.30 +/- 3.12 mL/min (CP) vs 11.87 +/- 3.41 m/min (PD-A), nonsignificant, r= 0.92]. Creatinine and glucose were different by paired t-test. No significant differences were found in Kt/V and urea generation rate. Weekly creatinine clearance [WCCr: 70.71 +/- 16.71 L (CP) versus 79.33 +/- 18.73 L (PD-A), p < 0.001] and creatinine generation rate [CrGR: 0.56 +/- 0.18 mg/min (CP) versus 0.61 +/- 0.19 mg/min (PD-A), p < 0.001) were significantly higher in PD-A than In CP owing to the lack of creatinine correction according to glucose concentration In the PD-A adequacy program. Finally, normalized protein nitrogen appearance according to Bergstr?m [1.09 +/- 0.20 g/kg/d (CP) versus 1.03 +/- 0.21 g/kg/d (PD-A), p = 0.01] was different owing to the different algorithms and normalization method: standardized body weight in CP and actual body weight in PD-A. CONCLUSIONS: Provided that equivalent data are used, PD-A and CP yield similar results. The PD-A program needs external correction of data input: (1) for plasmatic water concentration in MTAC calculations, and (2) for peritoneal glucose interference with creatinine analysis (Jaffé method) In WCCr and CrGR calculations; otherwise, It may give falsely optimistic results.     

Peritoneal function and assessment of reference values using a 3.86% glucose solution.

BACKGROUND: The most widely used peritoneal function test, the peritoneal equilibration test (PET), is performed with a 2.27% glucose solution. Recently, the International Society for Peritoneal Dialysis committee on ultrafiltration failure (UFF) advised performing the test with 3.86% glucose solution because it is more sensitive for detecting clinically significant UFF. Because no reference values for this test were available, we analyzed the results of standard peritoneal permeability analyses (SPAs) using 3.86% glucose. METHODS: The tests were performed in our center on 154 clinically stable peritoneal dialysis (PD) patients that were free of peritonitis for at least 4 weeks. For the assessment of reference values, we used two approaches. In approach A, patients with UFF, defined as net ultrafiltration (UF) < 400 mL/4 hours, were excluded. In approach B, only patients within their first 2 years of PD treatment were included, regardless of net UF. Means and 95% confidence intervals (95% CI) were calculated for the transport parameters of the PET and SPA. RESULTS: Means of normal distribution with 95% CI in approach A were as follows: for 2.0-L exchanges, mass transfer area coefficient (MTAC) for creatinine 8.8 mL/minute (4.7 - 12.7 mL/min), dialysate/plasma ratio (D/P) creatinine 0.70 (0.52 - 0.88), glucose absorption 58% (44% - 72%), dialysate240/initial dialysate ratio of glucose (Dt/D0) 0.28 (0.18- 0.38), net UF 675 mL (375 - 975 mL), and maximal dip in D/P sodium after correction for diffusion from the circulation 0.110 (0.050 - 0.164); for 1.5-L exchanges, MTAC creatinine 7.4 mL/min (3.8 - 11.0 mL/min), D/P creatinine 0.69 (0.52 - 0.86), glucose absorption 62% (52% - 72%), Dt/D0 glucose 0.25 (0.17- 0.32), net UF 551 mL (430 - 670 mL), and maximal dip D/P sodium 0.120 (0.048 - 0.166). In approach B, most of the transport values were similar; however, values for lymphatic absorption were significantly higher [1.52 mL/min (2-L) and 1.40 mL/min (1.5-L), p < 0.01] and values for the maximum dip in D/P sodium were lower [0.101 (2-L) and 0.112 (1.5-L), p > 0.05]. This was probably the result of including patients with UFF in approach B, since these parameters can be causative factors of UFF. CONCLUSIONS: A peritoneal transport function test using 3.86% glucose provides data on various aspects of transport. This study gives normal reference values that can be used for analysis of causes of UFF.     

Continuous flow peritoneal dialysis: assessment of fluid and solute removal in a high-flow model of "fresh dialysate single pass".

BACKGROUND: Growing concern over the limited capacity of the peritoneal dialysis (PD) system has revived interest in continuous flow peritoneal dialysis (CFPD), a modality in which continuous circulation of PD fluid is maintained at a high flow rate using two separate catheters or one dual-lumen catheter.The CFPD regimen contrasts the "inflow/outflow" regimen, which requires specific times devoted to filling and draining the peritoneum via a single-lumen catheter. Historical data established CFPD capabilities in providing higher solute clearance and ultrafiltration rate (UFR) using either an open loop system with a single pass of fresh PD fluid, or various external purifications of the spent dialysate. OBJECTIVE: To compare, in patients with various peritoneal transport patterns, fluid and solute removal achieved during a standardized program of CFPD versus two control schedules: nightly intermittent peritoneal dialysis (NIPD) and nightly tidal peritoneal dialysis (NTPD). This study focused on small solute clearances and UFR using only isotonic PD solution (Dianeal PD1 1.36%; Baxter Healthcare, Castlebar, Ireland). The model of fresh dialysate, single pass, was used to optimize solute gradients and to characterize the impact of a continuous flow regimen on peritoneal transport characteristics. METHODS: In a crossover trial, 4-hour CFPD sessions were performed at a fixed dialysate flow rate (100 mL/ minute) in 5 patients being treated with automated PD. A hemofiltration monitor (BM25; Baxter Healthcare, Brussels, Belgium) was adapted to the CFPD technique. The peritoneal cavity was filled through a temporary second catheter and simultaneously drained using the permanent peritoneal access. Fluid and solute removal were compared to data obtained from a control period based on 8-hour sessions of NIPD or NTPD using 13 L of isotonic dialysate. RESULTS: High-flow CFPD enhanced the diffusive transport coefficient compared with the alternative flow regimen in patients ranging from low to high transporters. Weekly creatinine clearance increased from 36.9 L (22.3 - 49.6 L) and 37.3 L (27.5 - 45.0 L) with NIPD and NTPD respectively, to 74.9 L (42.3 - 107.5 L) with CFPD. Mean UFR was 2.44 mL/min with CFPD versus 0.92 and 0.89 mL/min with NIPD and NTPD respectively. The mass transfer area coefficient (MTAC) of creatinine with CFPD was 2.5-fold that obtained from the peritoneal equilibration test data. CONCLUSION: Our results confirm that CFPD is highly effective in increasing fluid and solute removal. Furthermore, consistent with historical data, our findings indicate that the enhanced solute transfer is not due only to steeper solute gradients, but also depends on increased MTAC in a wide range of peritoneum transport characteristics.     

Analysis of the prevalence and causes of ultrafiltration failure during long-term peritoneal dialysis: a cross-sectional study.

BACKGROUND: Ultrafiltration failure (UFF) is a major complication of peritoneal dialysis (PD). It can occur at any stage of PD, but develops in time and is, therefore, especially important in long-term treatment. To investigate its prevalence and to identify possible causes, we performed a multicenter study in The Netherlands, where patients treated with PD for more than 4 years were studied using a peritoneal function test (standard peritoneal permeability analysis) with 3.86% glucose. UFF was defined as net UF < 400 mL after a 4-hour dwell. RESULTS: 55 patients unselected for the presence or absence of UFF were analyzed. Mean age was 48 years (range 18 - 74 years); duration of PD ranged from 48 to 144 months (median 61 months); UFF was present in 20 patients (36%). Patients with and without UFF did not differ in age or duration of PD. Median values for patients with normal UF compared to patients with UFF were, for net UF 659 mL versus 120 mL (p < 0.01), transcapillary UF rate 3.8 versus 2.1 mL/ minute (p < 0.01), effective lymphatic absorption 1.0 versus 1.6 mL/min (p < 0.05), mass transfer area coefficient (MTAC) for creatinine 9.0 versus 12.9 mL/min (p< 0.01), dialysate-to-plasma ratio (D/P) for creatinine 0.71 versus 0.86 (p < 0.01), glucose absorption 60% versus 73% (p < 0.01), maximum dip in D/P sodium (as a measure of free water transport) 0.109 versus 0.032 (p < 0.01), and osmotic conductance to glucose 3.0 versus 2.1 microL/min/mmHg (p < 0.05). As causes for UFF, high MTAC creatinine, defined as > 12.5 mL/min, or a glucose absorption > 72%, both reflecting a large vascular surface, a lymphatic absorption rate (LAR) of > 2.14 mL/min, and a decreased dip in D/P sodium of < 0.046 were identified. Most patients had a combination of causes (12 patients), whereas there was only a decreased dip in D/P sodium in 3 patients, only high MTAC creatinine in 1 patient, and only high LAR in 2 patients. We could not identify a cause in 2 patients. Both groups had similar clearances of serum proteins and peritoneal restriction coefficients. However, dialysate cancer antigen 125 concentrations, reflecting mesothelial cell mass, were lower in the UFF patients (2.79 vs 5.38 U/L). CONCLUSION: The prevalence of UFF is high in long-term PD. It is caused mainly by a large vascular surface area and by impaired channel-mediated water transport. In addition, these patients also had signs of a reduced mesothelial cell mass, indicating damage of the peritoneum on both vascular and mesothelial sites.     

High peritoneal permeability predisposes to hepatic steatosis in diabetic continuous ambulatory peritoneal dialysis patients receiving intraperitoneal insulin.

OBJECTIVE: To evaluate hepatic fat accumulation in diabetic patients taking intraperitoneal or subcutaneous insulin treatment during continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Cross-sectional study. SETTING: Tertiary-care university hospital. PATIENTS: We studied 16 patients with diabetic end-stage renal disease currently treated with CAPD. Median age was 42 years (range: 34-70 years), duration of diabetes was 27.5 years (range: 17-39 years), and duration of CAPD was 16.5 months (range: 2-59 months). OUTCOME MEASURES: Ultrasound measures of liver steatotic area and thickness, peritoneal equilibration test (PET), weekly Kt/V urea, protein catabolic rate (PCR), hemoglobin A1c (HbA1c), lipoproteins, alanine aminotransferase, alkaline phosphatase, insulin dose, and dialysate glucose load. RESULTS: Focal hepatic fat accumulation was found. The location of steatosis was subcapsular; a negligible amount was periportal. Hepatic subcapsular steatosis was present in 7 of 8 patients taking insulin intraperitoneally and in 0 of 8 patients taking insulin subcutaneously. The maximal thickness of subcapsular steatosis correlated directly with peritoneal transport rate (2-hour dialysate-to-plasma creatinine ratio in PET, r = 0.80, p < 0.05) and inversely with PCR (r = -0.82, p < 0.05). The area of the lesions correlated directly with body weight (r = 0.80, p < 0.05) and inversely with weekly Kt/V urea (r = -0.90, p < 0.01). CONCLUSIONS: Intraperitoneal insulin, together with glucose-based peritoneal dialysate, induces hepatic subcapsular steatosis. The amount of hepatic subcapsular steatosis increases when peritoneal transfer rate and body weight are high.     

Pharmacokinetics of aztreonam administered i.p. in continuous ambulatory peritoneal dialysis (CAPD) patients

The pharmacokinetics of Aztreonam (AZT) administered i.p. in six stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD) for end-stage renal disease (ESRD) were studied. One gram of AZT was added into a 2 L bag of dialysate (Medital-Bieffe) just prior to infusion into the peritoneal cavity. The dwell time was 8 h. The serum maximum concentration of AZT was 42.5 +/- 12.4 mg/L (mean +/- SD), achieved in 4.6 +/- 1.0 h. The elimination half-life was 2.4 +/- 0.8 h, almost equal to that found in normal subjects (1.7-2 h). The pharmacokinetic parameters of elimination, as elimination rate constant and clearance of AZT from peritoneal cavity were found 0.305 +/- 0.101 h-1 and 10.05 +/- 3.7 mL/min, respectively, while the bioavailability via the peritoneal membrane was 90.8 +/- 3.05% of administered dose. It is concluded that AZT is eliminated from dialysate at a high rate after i.p. administration and its dialysate and serum levels exceed the MIC for the majority of sensitive organisms including Pseudomonas species. Aztreonam appears to be a potentially useful antibiotic for CAPD peritonitis.     

Small and middle molecular weight solute clearance in nocturnal intermittent peritoneal dialysis.

OBJECTIVES: To determine the dialysate-to-plasma (D/P) concentration ratios and peritoneal dialytic clearance (CI(D)) of substances with a wide range of molecular weights in subjects receiving a simulated nocturnal intermittent peritoneal dialysis (NIPD) session. DESIGN: Open-label single-dose study. SUBJECTS: Six end-stage renal disease patients undergoing peritoneal dialysis (PD). SETTING: Clinical research center of a university-affiliated hospital. INTERVENTIONS: Subjects received intravenous gentamicin and vancomycin on the first day of the study. Subjects received no PD until their return on the following day, when subjects underwent a simulated NIPD session utilizing four 2- to 2.5-L peritoneal dialysate dwells of 2 hours. Blood and dialysate samples were collected immediately before the session and after each dialysate dwell for determination of urea, creatinine, gentamicin, vancomycin, and beta2-microglobulin (beta2M) concentrations. Each solute's D/P concentration ratio and peritoneal CI(D) were calculated. MEASUREMENTS AND MAIN RESULTS: The (mean +/- SD) 2-hour D/P concentration ratios were 0.78 +/- 0.05 (urea), 0.49 +/- 0.11 (creatinine), 0.38 +/- 0.08 (gentamicin), 0.11 +/- 0.06 (vancomycin), and 0.07 +/- 0.03 (beta2M). Peritoneal CI(D) values (mL/min of dialysis) were 19.0 +/- 2.8 (urea), 12.1 +/- 3.5 (creatinine), 8.4 +/- 2.8 (gentamicin), 2.7 +/- 1.5 (vancomycin), and 1.7 +/- 0.8 (beta2M).The D/P concentration ratios and peritoneal CI(D) values for urea, creatinine, and gentamicin were significantly different from vancomycin and beta2M (repeated measures ANOVA, p < 0.05). Beta2-microglobulin peritoneal CI(D) was strongly related to gentamicin peritoneal CI(D) (r = 0.96, p < 0.05). CONCLUSION: Small molecular weight solutes have significantly greater D/P and peritoneal CI(D) than middle molecular weight solutes in NIPD. In NIPD, daily peritoneal CI(D) of beta2M is lower than that reported in continuous ambulatory PD. NIPD also results in lower drug CI(D) than that reported in continuous ambulatory PD studies.     

Intraperitoneal hyaluronan production in stable continuous ambulatory peritoneal dialysis patients.

OBJECTIVE: Several cytokines and proteins are excreted intraperitoneally during the course of peritonitis and stable states in continuous ambulatory peritoneal dialysis (CAPD) patients. Dialysate hyaluronan (HYA) is also regarded as a marker of peritoneal healing during bacterial peritonitis. We examined here, intraperitoneal HYA production in stable CAPD patients and compared the results to those of the peritoneal equilibration test (PET), the length of time on dialysis, and other marker proteins. DESIGN: We determined the concentration of HYA and other marker proteins in the 4-hour-dwell dialysate at 1-year intervals. SETTING: CAPD unit in Hitachi General Hospital. PATIENTS: The subjects were 46 stable CAPD patients who underwent 104 PETs. RESULTS: A correlation was found between the length of time on dialysis and the amount of HYA excretion in the 4-hr-dwell dialysate (r = 0.403, p < 0.001). A positive but weak correlation was found between the dialysate-to-plasma ratio of the creatinine concentration and dialysate HYA excretion (r = 0.229, p < 0.05). Seven patients were over the 90th percentile in both the concentration of HYA (>349.2 ng/mL) and the amount of HYA (>743.6 microg/4-hr dwell). Five patients exceeded 1000 microg of HYA excretion in the 4-hr-dwell dialysate, 4 of whom showed an abrupt increase of HYA excretion to more than 1000 microg/4-hr dwell, and discontinued CAPD within 6 months due to ultrafiltration failure. Two of these 4 patients were diagnosed with sclerosing encapsulating peritonitis at autopsy. CONCLUSION: Intraperitoneal HYA production increased with both higher permeable membrane and the length of time on CAPD. Monitoring of HYA in the peritoneal dialysate may be useful as a marker to assess functional and morphological changes in the peritoneum in long-term CAPD patients.     

Does a high peritoneal transport rate reflect a state of chronic inflammation?

OBJECTIVE: It has recently been reported that a high peritoneal transport rate was associated with increased mortality in continuous ambulatory peritoneal dialysis (CAPD) patients. One possible explanation is that a high peritoneal transport rate might be caused by a state of chronic inflammation, which also per se might result in increased mortality. Therefore, in this study we investigated whether high peritoneal transport rate patients are in a state of chronic inflammation. METHODS: The study included 39 clinically stable peritoneal dialysis patients (free of peritonitis) who had been on PD for more than 3 months (16.8+/-11.8 months). Seven patients were treated with continuous cycling peritoneal dialysis (CCPD) and the others were on CAPD. A 4-hour standard peritoneal equilibration test (PET) using 2.27% glucose solution was performed in each patient. Dialysate samples at 4 hours and blood samples at 2 hours were measured for interleukin-1beta (IL-1beta), tumor necrosis factor(alpha)(TNFalpha), C-reactive protein (CRP), and hyaluronan as markers of inflammation. RESULTS: There was no significant correlation between dialysate/plasma (DIP) creatinine (0.82+/-0.15, range 0.51 - 1.15) and blood concentrations of IL-1beta (11.2 ng/L, range <5 - 65.9 ng/L),TNFalpha (12.1 ng/L, range <5 - 85.4 ng/L), CRP (<10 mg/L, range <10 - 76 mg/L), nor with the blood hyaluronan concentration (165 microg/L, range 55 - 955 microg/L).The dialysate concentrations of IL-1beta and TNFalpha were below the detectable level in most of the samples. Although dialysate hyaluronan concentration (334 microg/L, range 89 - 1100 microg/L) was correlated with D/P creatinine (r= 0.36, p< 0.05), there was no correlation between the total amount of hyaluronan in the effluent and D/P creatinine. However, a significant correlation was found between serum hyaluronan concentration and glomerular filtration rate (GFR) (r = -0.49, p< 0.005); GFR also tended to be correlated with serum TNFalpha (r = -0.31, p = 0.058) but not with serum IL-1beta and serum CRP. CONCLUSION: Our results suggest that a high peritoneal transport rate is not necessarily related to a state of chronic inflammation in CAPD patients.The high mortality rate observed in high transporters may relate to other issues, such as fluid balance or abnormal nutrition and metabolism, rather than to chronic inflammation.     

Continuous ambulatory peritoneal dialysis is responsible for an increase in plasma norepinephrine.

OBJECTIVE: To investigate the reason for increasing norepinephrine (NE) levels reported in continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: Norepinephrine was measured in the plasma and peritoneal dialysate of CAPD patients (n = 22) and in the plasma and the urine of healthy subjects (n = 20). It was also measured in the plasma of patients with chronic renal failure (CRF) (n = 15) and patients on hemodialysis (HD) (n = 15). RESULTS: It was found that NE was increased in CAPD patients compared with healthy individuals (687+/-221 pg/mL vs 199+/-25 pg/mL, p < 0.01).The daily removal of NE from the peritoneum of CAPD patients was lower compared with the amount of NE excreted in the urine of healthy subjects. Plasma NE increased after infusion of peritoneal dialysate. In 15 new patients on CAPD, it was found that NE plasma levels increased from 329+/-67 pg/mL before initiation of dialysis, to 584+/-173 pg/mL after 12 months of treatment (p < 0.01). Finally, plasma NE in CAPD patients (687+/-221 pg/mL) was significantly higher compared with the already increased levels in patients on HD or with CRF (406+/-143 pg/mL and 378+/-142 pg/mL, respectively). CONCLUSIONS: It is concluded that CAPD in patients with end-stage renal disease is responsible for a progressive increase of plasma norepinephrine.     

Procalcitonin levels in peritoneal dialysis patients.

OBJECTIVE: To examine whether the levels of procalcitonin (PCT), a new marker of infection and/or inflammation, differ between peritoneal dialysis (PD) patients and healthy volunteers, and whether PCT is detectable in uninfected drained dialysate. DESIGN: Observational cross-sectional study. SETTING: PD unit, department of medicine, in a university hospital. PATIENTS: A total of 28 PD patients, free of systemic infection, and 28 age- and sex-matched healthy volunteers. METHODS: PCT was determined by immunoluminometry; detection range 0.01 - 500 ng/mL, reference range < 0.5 ng/mL. RESULTS: Plasma levels of PCT were significantly higher (Wilcoxon's paired test, p < 0.001) in PD patients (median 0.33 ng/mL) compared with healthy volunteers (0.18 ng/mL). Spearman's test demonstrated a significant positive correlation between PCT and serum C-reactive protein (CRP) (r = 0.59, p < 0.01); correlations between PCT and transferrin, total weekly creatinine clearance (ClCr), and the renal components of ClCr and Kt/V urea were negative. PCT levels in dialysate (PCTd) were 0.07 ng/mL and correlated positively with plasma PCT, serum CRP, and dialysate fibrinogen levels. The dialysate-to-plasma ratio (D/P) of PCT was 0.2. Neither PCTd nor D/P PCT correlated with D/P creatinine at 4-hours of dwell. CONCLUSION: Compared with healthy volunteers, PD patients without overt signs of infection showed increased plasma PCT levels. Given the study design, it is impossible to determine to what extent the increase in plasma PCT is due to reduced elimination and to what extent it reflects the microinflammation of uremia. Based on the D/P PCT gradient, we assume that PCT transport is more likely to occur from the systemic circulation to the peritoneal cavity than vice versa.     

Does the biocompatibility of the peritoneal dialysis solution matter in assessment of peritoneal function?

BACKGROUND: Peritoneal function tests are performed in peritoneal dialysis (PD) patients to characterize peritoneal membrane status. A low pH/high glucose degradation product (GDP) dialysis solution is used as the test solution. The objective of the present study was to compare a 3.86% glucose, low pH/high GDP dialysis solution (pH 5.5) with a 3.86% glucose, normal pH/low GDP dialysis solution (pH 7.4) in assessments of peritoneal membrane function. METHODS: Two standard peritoneal permeability analyses (SPA) were performed in 10 stable PD patients within 2 weeks. One SPA was done with the 3.86% low pH/high GDP solution, and the other with the 3.86% normal pH/low GDP solution. The sequence of the two tests was randomized. RESULTS: Fluid transport parameters and glucose absorption were not different between the two groups. No differences were found for the mass transfer area coefficients (MTACs) of low molecular weight solutes calculated over the whole dwell. However, MTAC urea in the first hour of the dwell was higher in the test done with low pH/high GDP dialysate, suggesting more peritoneal vasodilation. No difference was found in protein clearances. Sodium sieving at multiple time points during the dwell was similar with the two solutions. CONCLUSION: The results obtained with the glucose-containing normal pH/low GDP dialysis solution were similar to those obtained with the glucose-containing low pH/high GDP dialysate in assessments of peritoneal membrane function.     

Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes

OBJECTIVE: Transforming growth factor (TGF)-beta1 is an important mediator in the pathogenesis of diabetic nephropathy. Urinary TGF-beta1 reflects TGF-beta1 production in the kidney, and alpha1-microglobulin tubular dysfunction. These 2 markers were studied in the early phases of type 1 diabetes. RESEARCH DESIGN AND METHODS: There were 113 type 1 diabetic children and adolescents (mean +/- SD: age 14.1 +/- 2.9 years, and diabetes duration 7.4 +/- 2.9 years, HbA1c 9.3 +/- 1.5%) and 39 healthy subjects (age 13.8 +/- 2.8 years) who participated in the study. Of the diabetic patients, 105 were normoalbuminuric (2-3 consecutive overnight urinary albumin excretion rates [AERs] <20 microg/min) and 8 had microalbuminuria (at least 2 AERs 20-200 microg/min). Overnight urinary TGF-beta1 and alpha1-microglobulin levels were measured and the results expressed as the ratio to urinary creatinine concentration. RESULTS: Data are medians (range). Diabetic patients had higher urinary TGF-beta1 levels than those of control subjects: 0.9 ng/mg (0.05-122.3) vs. 0.3 ng/mg (0.05-2.2) creatinine, respectively (P = 0.003). Urinary TGF-beta1 levels correlated with urinary glucose (r = 0.2, P = 0.03) and alpha1-microglobulin (r = 0.2, P = 0.02) levels, but not with HbA1c, AER, age, or duration of diabetes. In 43 patients with urinary TGF-beta1 above the control levels, urinary TGF-beta1 levels correlated with urinary glucose (r = 0.6, P < 0.001) and alpha1-microglobulin (r = 0.6, P < 0.001) levels. Diabetic patients had higher urinary alpha1-microglobulin levels than those of control subjects: 4.8 microg/mg (0.6-48.8) vs. 2.7 microg/mg (0.8-11.6) creatinine, respectively (P < 0.001). Alpha1-microglobulin levels correlated with AER (r = 0.2, P = 0.02), HbA1c (r = 0.3, P = 0.001), urinary glucose (r = 0.5, P < 0.001), and urinary TGF-beta1 levels. CONCLUSIONS: An early rise in urinary TGF-beta1 levels was observed in young type 1 diabetic patients. Urinary TGF-beta1 is associated with 2 interrelated tubular markers, alpha1-microglobulin and urinary glucose.