Effects of Steady Glucose Concentration Peritoneal Dialysis on Ultrafiltration Volume and Sodium Removal: A Pilot Crossover Trial.

BACKGROUND: Volume overload is common in patients treated with peritoneal dialysis (PD) and is associated with poor clinical outcome. Steady concentration PD is where a continuous glucose infusion maintains the intraperitoneal glucose concentration and as a result provides continuous ultrafiltration throughout the dwell. The primary objective of this study was to investigate the ultrafiltration rate and glucose ultrafiltration efficiency for steady concentration PD in comparison with a standard continuous ambulatory PD (CAPD) dwell, using the novel Carry Life UF device. METHODS: Eight stable patients treated with PD (six fast and two fast average transporters) were investigated four times: a standard 4-hour CAPD dwell with 2 L of 2.5% dextrose solution as control and three 5-hour steady concentration PD treatments (glucose dose 11, 14, 20 g/h, initial fill 1.5 L of 1.5% dextrose solution). All investigations were preceded by an overnight 2 L 7.5% icodextrin dwell. RESULTS: Intraperitoneal glucose concentration increased during the first 1-2 hours of the steady concentration PD treatments and remained stable thereafter. Ultrafiltration rates were significantly higher with steady concentration PD treatments (124±49, 146±63, and 168±78 mL/h with 11, 14, and 20 g/h, respectively, versus 40±60 mL/h with the control dwell). Sodium removal and glucose ultrafiltration efficiency (ultrafiltration volume/gram glucose uptake) were significantly higher with steady concentration PD treatments versus the control dwell, where the 11 g/h glucose dose was most efficient. CONCLUSIONS: Steady concentration PD performed with the Carry Life UF device resulted in higher ultrafiltration rates, more efficient use of glucose (increased ultrafiltration volume/gram glucose absorbed), and greater sodium removal compared with a standard 2.5% dextrose CAPD dwell. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Performance Analysis of the Peritoneal Ultrafiltration (PUF) Achieved With the Carry Life ® UF, NCT03724682 .

Lymphogranuloma venereum rates increased and Chlamydia trachomatis genotypes changed among men who have sex with men in Sweden 2004-2016.

This study aimed to determine the incidence of lymphogranuloma venereum (LGV) in Sweden since 2004 and to study in detail a consecutive number of Chlamydia trachomatis cases in men who have sex with men (MSM) during a 10 month period (September 2014 to July 2015). LGV increased from sporadic import cases in 2004 to comprise a spread within Sweden in 2016. Initially, only the L2b ompA genotype was detected, but in 2015 half of the genotyped LGV cases were L2 genotype. The changing genotype distribution in Sweden is linked to increased LGV spread in Europe. High-resolution multilocus sequence typing of 168 C. trachomatis cases from MSM in 2015 resulted in 29 sequence types, of which 3 accounted for 49 % of cases. The increased rates and different genotypes of LGV indicate that more concern for high-risk taking MSM is needed to avoid further spread of this invasive infection.

Phoxilium(®) reduces hypophosphataemia and magnesium supplementation during continuous renal replacement therapy.

BACKGROUND: Although associated with severe clinical complications, phosphate remains a neglected ion. Additionally, phosphate balance during continuous renal replacement therapy (CRRT) is complex and multifunctional. The present retrospective study investigated the effects of phosphate-containing CRRT fluid on phosphate homeostasis. METHODS: We retrospectively analysed 112 patients treated with CRRT at Skåne University Hospital, Sweden. The control group was treated with Hemosol(®) B0 (no phosphate; n = 36) as dialysis and replacement fluid, while the study group received Phoxilium(®) (phosphate; n = 76) as dialysis fluid and Hemosol(®) B0 as replacement fluid. RESULTS: Hypophosphataemia (<0.7 mM) occurred in 15% of the treatment days in the control group compared with 7% in the study group (P = 0.027). Magnesium substitution was reduced by 40% in the study group (P < 0.001). No differences in acid-base parameters were detected between the groups. CONCLUSIONS: In this larger cohort, we could confirm that Phoxilium(®) reduced the episodes of hypophosphataemia during CRRT. A beneficial effect on magnesium balance could also be observed.

Simplified Citrate Anticoagulation for CRRT Without Calcium Replacement.

Since 2012, citrate anticoagulation is the recommended anticoagulation strategy for continuous renal replacement therapy (CRRT). The main drawback using citrate as anticoagulant compared with heparin is the need for calcium replacement and the rigorous control of calcium levels. This study investigated the possibility to achieve anticoagulation while eliminating the need for calcium replacement. This was successfully achieved by including citrate and calcium in all CRRT solutions. Thereby the total calcium concentration was kept constant throughout the extracorporeal circuit, whereas the ionized calcium was kept at low levels enough to avoid clotting. Being a completely new concept, only five patients with acute renal failure were included in a short, prospective, intensely supervised nonrandomized pilot study. Systemic electrolyte levels and acid-base parameters were stable and remained within physiologic levels. Ionized calcium levels declined slightly initially but stabilized at 1.1 mmol/L. Plasma citrate concentrations stabilized at approximately 0.6 mmol/L. All postfilter ionized calcium levels were <0.5 mmol/L, that is, an anticoagulation effect was reached. All filter pressures were normal indicating no clotting problems, and no visible clotting was observed. No calcium replacement was needed. This pilot study suggests that it is possible to perform regional citrate anticoagulation without the need for separate calcium infusion during CRRT.

Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions.

Hyperglycaemia and glucose degradation products (GDPs) are closely associated with oxidative stress and inflammation in diabetic patients, a condition that leads to endothelial dysfunction and cardiovascular problems. We evaluated the effect of citrate and gluconate on glucose- and GDP-induced endothelial inflammation by measuring changes in viability, inflammation and function in primary human umbilical vein endothelial cells (HUVECs). The extent of apoptosis/necrosis was measured by flow cytometry and visualised with confocal microscopy by staining with annexin V or propidium iodide, respectively. Protein kinase C-ßII (PKC-ßII) activation was evaluated with Western blotting. Incubation with glucose (30 mM) and GDP (50 µM) significantly increased PKC-ßII expression, endothelial cell death and inflammation. The addition of citrate decreased hyperglycaemia-induced apoptosis (p = 0.021), necrosis (p = 0.04) and reduced PKC-ßII expression (p = 0.021) down to background levels. Citrate improved endothelial function by reducing the inflammatory markers (p = 0.01) and by decreasing neutrophil diapedesis (p = 0.012). These results suggest that citrate may have therapeutic potential by reducing hyperglycaemia-induced endothelial inflammation and abolishing endothelial dysfunction.

Infusion fluids contain harmful glucose degradation products.

PURPOSE: Glucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients' blood. METHODS: The content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated. RESULTS: All investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing. CONCLUSIONS: These findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients.

3,4-dideoxyglucosone-3-ene in peritoneal dialysis fluids infused into the peritoneal cavity cannot be found in plasma.

OBJECTIVE: Glucose degradation products (GDPs) are important for the outcome of peritoneal dialysis (PD) treatment. The most cytotoxic GDP found in conventionally manufactured fluids, 3,4-dideoxyglucosone-3-ene (3,4-DGE), may in addition be recruited from 3-deoxyglucosone (3-DG). What happens with the GDPs in the fluid infused into patients during PD is not known. We investigated whether 3,4-DGE and 3-DG in PD fluid can be found in plasma during treatment. DESIGN: Patients on PD were dialyzed with a conventional PD fluid containing 43 micromol/L 3,4-DGE and 281 micromol/L 3-DG. Parallel experiments were performed in rats and in vitro with human plasma. The rats were dialyzed with a PD fluid containing 100 micromol/L 3,4-DGE and 200 micromol/L 3-DG. RESULTS: The 3,4-DGE concentration in the peritoneum declined at a much higher rate during the dwell than did the 3-DG concentration. However, 3,4-DGE was not detected in the plasma of patients or of rats during dialysis. The 3-DG concentration in plasma peaked shortly after infusion of fluid into the peritoneal cavity. The 3,4-DGE concentration during experimental incubation in plasma declined rapidly; the 3-DG concentration declined only 10% as rapidly (or less). CONCLUSION: During dialysis, 3,4-DGE could not be detected in plasma of either PD patients or rats, presumably because of its high reactivity. On the other hand, 3-DG may pass through the membrane and be detected in the blood.

The effects of low-sodium peritoneal dialysis fluids on blood pressure, thirst and volume status.

BACKGROUND: Poor ultrafiltration is associated with worse outcomes in peritoneal dialysis (PD) patients. This might in part reflect problems associated with salt and water excess. Increasing the diffusive component of peritoneal sodium removal using low-sodium PD fluids might have beneficial effects on blood pressure (BP), thirst and fluid status that could translate into clinical benefits. METHODS: Using a multicentre, prospective, baseline controlled (1 month), non-randomized intervention (2 months) design, two novel solutions designed from predictions using the three-pore model were investigated. In group A ([Na+] = 115 mmol/l), the glucose (G) was increased to 2.0% to compensate for reduced osmolality whereas in group B ([Na+] = 102 mmol/l), it was unchanged (2.5%). Both solutions were substituted for one 3- to 5-h exchange per day and no change was made to the rest of the dialysis regime. RESULTS: Ten patients in group A and 15 in group B completed the study. Both solutions resulted in significant increases (30-50 mmol/dwell) in diffusive sodium removal during the test exchanges, P < 0.001. Ultrafiltration was maintained in group A but reduced in group B. Ambulatory nocturnal mean BP fell in group A [93.1 +/- 10.6 mmHg (+/-SD) versus 85.1 +/- 10.2 mmHg, P < 0.05], but was stable in group B (95.4 +/- 9.4 versus 95.1.1 +/- 10.7 mmHg, NS). Thirst reduced independent of appetite and mood in both groups by 2 months, more markedly in group A. Indices of fluid status, including TBW by bioimpedance and D dilution also improved in group A, P < 0.05, whereas weight increased in group B. CONCLUSIONS: Increasing the diffusive component of sodium removal whilst maintaining ultrafiltration is associated with improvements in BP, thirst and fluid status. The lack of effect seen with uncompensated low-sodium dialysate suggests that these benefits cannot be achieved by manipulation of dialysate sodium removal alone. These observations provide valuable information of the design of future randomized studies to establish the clinical role for low-sodium dialysis fluids.

3,4-DGE in peritoneal dialysis fluids cannot be found in plasma after infusion into the peritoneal cavity.

OBJECTIVE: Glucose degradation products (GDPs) are important in the outcome of peritoneal dialysis (PD) treatment. 3,4-dideoxyglucosone-3-ene (3,4-DGE) is the most cytotoxic GDP found in conventionally manufactured fluids and may, in addition, be recruited from 3-deoxyglucosone (3-DG). It is not known what happens with those GDPs in patients during PD. The aim of this study was to investigate if the 3,4-DGE and 3-DG in PD fluids can be found in plasma during treatment. DESIGN: PD patients were dialyzed with a conventional PD fluid containing 43 micromol/L 3,4-DGE and 281 micromol/L 3-DG. Parallel experiments were performed in rats as well as in vitro with human plasma. The rats were dialyzed with a PD fluid containing 100 micromol/L 3,4-DGE and 200 micromol/L 3-DG. RESULTS: The concentration of 3,4-DGE in the peritoneum decreased at a much higher rate than 3-DG during the dwell. 3,4-DGE was not, however, detected in the plasma of patients or rats during dialysis. The concentration of 3-DG in plasma peaked shortly after infusion of the fluid to the peritoneal cavity. The concentration of 3,4-DGE during experimental incubation in plasma decreased rapidly, while the concentration of 3-DG decreased only 10% as rapidly or less. CONCLUSION: 3,4-DGE could not be detected in plasma from either PD patients or rats during dialysis. This is presumably due to its high reactivity. 3-DG may, on the other hand, pass through the membrane and be detected in the blood.

Effect of peritoneal dialysis on renal morphology and function.

BACKGROUND: Results of clinical studies suggest that peritoneal dialysis (PD) is less harmful to the residual renal function than haemodialysis. However, we have no objective data describing the potential injuring effect of PD to kidney. We studied in rats after unilateral nephrectomy changes in renal structure and function after 12 weeks exposure to standard, glucose-based PD fluid. METHODS: One month after removing one kidney PD catheters were implanted in rats and during the following 12 weeks, twice a day, animals were infused with 20 ml of 3.9% glucose dialysis fluid containing high concentration of glucose degradation products. Rats not infused with the dialysis fluid served as control (CON). At the beginning and after 12 weeks of the study renal creatinine clearance, urinary excretion of albumin, N-acetyl-beta-glucosaminidase (NAG) and cytokines were measured. Concentration of malondialdehyde (MDA), advanced glycation end products (AGEs) and monocyte chemoattractant protein-1 (MCP-1) were measured in serum samples. Morphology of the kidneys was evaluated in the light microscope. RESULTS: After 12 weeks exposure to the dialysis fluid serum MDA, AGEs and MCP levels were increased as compared with CON by 80%, P < 0.002, 29%, P < 0.05 and 71%, P < 0.005, respectively. Renal clearance of creatinine was comparable in both groups, but urinary excretion of albumin was increased by 55% in control group and by 160% in the studied group, P < 0.001; whereas urinary excretion of NAG was not changed in control group but increased by 125% in the studied group, P < 0.01. Increase of the remnant kidney's weight was higher (+77%, P < 0.01) in the CON group, but accumulation of the extramesangial matrix in glomeruli and collagen in the peritubular space was stronger in the studied group by 69%, P < 0.0001 and 274%, P < 0.0001, respectively. CONCLUSION: Chronic exposure of rats to the glucose-based dialysis fluid causes morphological changes in the renal glomeruli similar to diabetic nephropathy. Albuminuria increases what may accelerate progression of the kidney damage.

How to avoid glucose degradation products in peritoneal dialysis fluids.

OBJECTIVE: The formation of glucose degradation products (GDPs) during sterilization of peritoneal dialysis fluids (PDFs) is one of the most important aspects of biocompatibility of glucose-containing PDFs. Producers of PDFs are thus trying to minimize the level of GDPs in their products. 3,4-Dideoxyglucosone-3-ene (3,4-DGE) has been identified as the most bioreactive GDP in PDFs. It exists in a temperature-dependent equilibrium with a pool of 3-deoxyglucosone (3-DG) and is a precursor in the irreversible formation of 5-hydroxymethyl furaldehyde (5-HMF). The aim of the present study was to investigate how to minimize GDPs in PDFs and how different manufacturers have succeeded in doing so. DESIGN: Glucose solutions at different pHs and concentrations were heat sterilized and 3-DG, 3,4-DGE, 5-HMF, formaldehyde, and acetaldehyde were analyzed. Conventional as well as biocompatible fluids from different manufacturers were analyzed in parallel for GDP concentrations. RESULTS: The concentrations of 3-DG and 3,4-DGE produced during heat sterilization decreased when pH was reduced to about 2. Concentration of 5-HMF decreased when pH was reduced to 2.6. After further decrease to a pH of 2.0, concentration of 5-HMF increased slightly, and below a pH of 2.0 it increased considerably, together with formaldehyde; 3-DG continued to drop and 3,4-DGE remained constant. Inhibition of cell growth was paralleled by 3,4-DGE concentration at pH 2.0 - 6.0. A high glucose concentration lowered concentrations of 3,4-DGE and 3-DG at pH 5.5 and of 5-HMF at pH 1. At pH 2.2 and 3.2, glucose concentration had a minor effect on the formation of GDPs. All conventional PDFs contained high levels of 3,4-DGE and 3-DG. Concentrations were considerably lower in the biocompatible fluids. However, the concentration of 5-H M F was slightly higher in all the biocompatible fluids. CONCLUSION: The best way to avoid reactive GDPs is to have a pH between 2.0 and 2.6 during sterilization. If pHs outside this range are used, it becomes more important to have high glucose concentration during the sterilization process. There are large variations in GDPs, both within and between biocompatible and conventionally manufactured PDFs.

Improvement of peritoneal ultrafiltration with peritoneal dialysis solution buffered with bicarbonate/lactate mixture.

BACKGROUND: In computer simulations, according to the three-pore model of peritoneal transport, neutralization of conventional acidic peritoneal dialysis fluids is predicted to produce an improved ultrafiLtration (UF). However, in a previous study, a two-compartment peritoneal dialysis system with a minimum of glucose degradation products (GDP), PD-Bio, having a pH of 6.3 and being conventionalLy lactate buffered, did not produce an increased UF. SETTING: We tested a newly formulated, glucose-based, GDP-reduced solution, denoted "N" for "neutral," containing a mixture of lactate (30 mmol/L) and bicarbonate (10 mmol/L) as buffer system, and having a pH of 7.2. This new formulation was compared with Gambrosol trio (GT) (identical in composition to PD-Bio, but delivered in a three-compartment system; both by Gambro Lundia AB, Lund, Sweden) in an open, prospective controlled study of 13 patients. MATERIAL AND METHODS: Each of the 13 patients used GT for 14 days, followed by 14 days of N. All bags were weighed on a digital scale before instillation and after drainage to assess the UF in each dwell (and during 24 hours). Glucose concentration in each bag was noted. In the morning and night dwells, dialysis fluid glucose concentration was standardized to 2.5%. Body weight was measured every morning (empty abdomen). In the middle of each 14-day period, a 4-hour standardized ("study day") dwell was performed, using 125I-albumin (RISA) as volume marker, during which blood and dialysate samples were taken repeatedly and anaLyzed for RISA, creatinine, urea, phosphate, glucose, standard bicarbonate, lactate, and pH. The permeability surface area product (PS) for small solutes (and A0/deltaX; "area parameter") was calculated. Clearance (Cl) of RISA to plasma (P) (C-->P), "direct lymphatic absorption," and total Cl of RISA out of the peritoneal cavity (Cl(out)) were also determined. RESULTS: The 13 patients using N, compared to GT, displayed an increased daily UF, the difference being 233 mL (p < 0.05). The pH values of N were higher during the first 90 minutes of the 4-hour dwell compared to the pH values of GT. Neither the small solute PS values nor RISA determined UF, nor did body weight differ significantly between the GT and the N periods. CONCLUSIONS: A new bicarbonate/lactate-buffered solution, N, with neutral pH (of 7.2) and low in GDP seems to produce an improved UF compared to a lactate-buffered solution with a pH of 6.3, equally low in GDP, partly in agreement with our earlier predictions. A dialysis solution with a neutral pH combined with a reduced lactate concentration, partially replaced by bicarbonate, evidently increases UF, conceivably by causing less peritoneal vasodilatation than solutions buffered by lactate or high concentrations of bicarbonate alone.

Take care in how you store your PD fluids: actual temperature determines the balance between reactive and non-reactive GDPs.

OBJECTIVE: During heat sterilization and during prolonged storage, glucose in peritoneal dialysis fluids (PDF) degrades to carbonyl compounds commonly known as glucose degradation products (GDPs). Of these, 3,4-dideoxyglucosone-3-ene (3,4-DGE) is the most cytotoxic. It is an intermediate in degradation between 3-deoxyglucosone (3-DG) and 5-hydroxymethyl-2-furaldehyde (5-HMF). We have earlier reported that there seems to be equilibrium between these GDPs in PDF. The aim of the present study was to investigate details of this equilibrium. METHODS: Aqueous solutions of pure 3-DG, 3,4-DGE, and 5-HMF were incubated at 40 degrees C for 40 days. Conventional and low-GDP fluids were incubated at various temperatures for up to 3 weeks. Formaldehyde, acetaldehyde, glyoxal, methylglyoxal, 3-DG, 3,4-DGE, and 5-HMF were analyzed using high performance liquid chromatography. RESULTS: Incubation of 100 micromol/L 3,4-DGE resulted in the production of 36 micromol/L 3-DG, 4 micromol/L 5-HMF, and 40 micromol/L unidentified substances. With the same incubation, 200 micromol/L 3-DG was converted to 9 micromol/L 3,4-DGE, 6 micromol/L 5-HMF, and 14 micromol/L unidentified substances. By contrast, 100 micromol/L 5-HMF was uninfLuenced byincubation. In a conventional PDF incubated at 60 degrees C for 1 day, the 3,4-DGE concentration increased from 14 to a maximum of 49 micromol/L. When the fluids were returned to room temperature, the concentration decreased but did not reach original values until after 40 days. In a low GDP fluid, 3,4-DGE increased and decreased in the same manner as in the conventional fluid but reached a maximum of only 0.8 micromol/L. CONCLUSIONS: Considerable amounts of 3,4-DGE may be recruited by increases in temperature in conventional PDFs. Lowering the temperature will again reduce the concentration but much more time will be needed. Precursors for 3,4-DGE recruitment are most probably 3-DG and the enol 3-deoxyaldose-2-ene, but not 5-HMF. Considering the ease at which 3,4-DGE is recruited from its pool of precursors and the difficulty of getting rid of it again, one should be extremely careful with the temperatures conventional PDFs are exposed to.

PD fluids contain high concentrations of cytotoxic GDPs directly after sterilization.

OBJECTIVE: Glucose degradation products (GDPs) in peritoneal dialysis (PD) fluids are cytotoxic and affect the survival of the peritoneal membrane. One of the most reactive GDPs in PD fluids is 3,4-dideoxyglucosone-3-ene (3,4-DGE). 3,4-DGE has been reported as an intermediate between 3-deoxyglucosone (3-DG) and 5-hydroxymethyl furaldehyde (5-HMF) during degradation of glucose. In PD fluids, 3,4-DGE exists in a temperature-dependent equilibrium with a pool of unidentified substances. The aim of this study was to explore this equilibrium and its temperature dependence during the first months of storage after the sterilization procedure. METHODS: GDPs and inhibition of cell growth (ICG) were measured directly after sterilization of the PD fluid and during storage at different temperatures for 60 days. The following GDPs were analyzed: 3-DG, 3,4-DGE, 5-HMF, formaldehyde, acetaldehyde, glyoxal, and methylglyoxal. RESULTS: Immediately after sterilization, the concentration of 3,4-DGE was 125 micromol/L. During the first weeks of storage, it decreased by about 80%. At the same time, the 3-DG concentration increased. None of the other GDPs were significantly affected. Cytotoxicity correlated well with the concentration of 3,4-DGE. When pure 3,4-DGE was substituted for the lost amount of 3,4-DGE after 30 days of storage, the initial ICG was almost completely regained. CONCLUSIONS: Heat sterilization of PD fluids promotes the formation of large quantities of 3,4-DGE, rendering the fluid highly cytotoxic. During storage, the main part of 3,4-DGE is reversibly converted in a temperature-dependent manner to a less cytotoxic pool, consisting mainly of 3-DG. Cytotoxicity seems to be dependent exclusively on 3,4-DGE. In order to avoid higher levels of 3,4-DGE concentrations, PD fluids should not be used too soon after sterilization and should not be stored at temperatures above room temperature.

Biocompatibility of peritoneal dialysis fluids: long-term exposure of nonuremic rats.

OBJECTIVES: Long-term peritoneal dialysis (PD) leads to structural and functional changes in the peritoneum. The aim of the present study was to investigate the long-term effects of PD fluid components, glucose and glucose degradation products (GDP), and lactate-buffered solution on morphology and transport characteristics in a nonuremic rat model. METHODS: Rats were subjected to two daily intraperitoneal injections (20 mL/day) during 12 weeks of one of the following: commercial PD fluid (Gambrosol, 4%; Gambro AB, Lund, Sweden), commercial PD fluid with low GDP levels (Gambrosol trio, 4%; Gambro AB), sterile-filtered PD fluid (4%) without GDP, or a glucose-free lactate-buffered PD fluid. Punctured and untreated controls were used. Following exposure, the rats underwent a single 4-hour PD dwell (30 mL, 4% glucose) to determine peritoneal function. Additionally, submesothelial tissue thickness, percentage of high mesothelial cells (perpendicular diameter > 2 microm), vascular density, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF) beta1 mRNA expression were determined. Submesothelial collagen concentration was estimated by van Gieson staining. RESULTS: Submesothelial tissue thickness and vascular density, mediated by VEGF and TGFbeta production, in the diaphragmatic peritoneum increased significantly in rats exposed to any PD fluid. Gambrosol induced a marked increased fibrosis of the hepatic peritoneum. A significant increase in high mesothelial cells was observed in the Gambrosol group only. Net ultrafiltration was reduced in the Gambrosol and in the glucose-free groups compared to untreated controls. Small solute transport was unchanged, but all groups exposed to fluids showed significantly increased lymph flow. CONCLUSIONS: Our results show that long-term exposure to different components of PD fluids leads to mesothelial cell damage, submesothelial fibrosis, and neoangiogenesis. Mesothelial cell damage could be connected to the presence of GDP; the other changes were similar for all fluids. Peritoneal transport characteristics did not change in any consistent way and the neoangiogenesis observed was not paralleled by increased solute transport.

Transvascular passage of macromolecules into the peritoneal cavity of normo- and hypothermic rats in vivo: active or passive transport?

During the last decades there has been a debate regarding whether transvascular protein transport is an active (transcytosis) or a passive (porous) process. To separate cooling-sensitive transcytosis from passive transport processes between blood and peritoneal fluid, we induced hypothermia in rats in vivo, reducing their body temperature to 19 degrees C. Control rats were kept at 37 degrees C. Either human albumin, or IgG, or IgM, or LDL, radiolabeled with (125)I, was given intra-arterially together with (51)Cr-EDTA. During tracer administration, a 2-hour peritoneal dialysis dwell was performed. Clearance of the tracers to dialysate, and the permeability-surface area coefficient (PS) for (51)Cr-EDTA and glucose were assessed. During cooling, mean arterial blood pressure (MAP) was reduced to 40% of control and plasma viscosity increased by 48.5%, while peritoneal blood flow was reduced to 10%. At 19 degrees C, clearance of albumin to dialysate fell from 9.30 +/- 1.62 (SEM) to 3.13 +/- 0.28 microl/min (p < 0.05), clearance of IgG from 6.33 +/- 0.42 to 2.54 +/- 0.12 microl/min (p < 0.05), clearance of IgM from 3.65 +/- 0.33 to 1.10 +/- 0.12 microl/min (p < 0.05), and clearance of LDL from 3.54 +/- 0.20 to 0.73 +/- 0.06 microl/min (p < 0.05). The fall in PS for (51)Cr-EDTA was from 0.320 +/- 0.01 to 0.075 +/- 0.003 ml/min (p < 0.05), and that for glucose from 0.438 +/- 0.02 to 0.105 +/- 0.01 ml/min (p < 0.05). Tissue cooling reduced large solute transport largely in proportion to the cooling-induced reductions of MAP (to 40%), and the concomitant increase in viscosity (to 67%), i.e. to approximately 20-30% (0.40 x 0.67) of control, though LDL clearance was reduced further. The fall in small solute PS, in excess of the viscosity effect, mirrored the fall in peritoneal blood flow occurring during hypothermia. In conclusion, the good correlation of predicted to calculated changes suggests that the overall transendothelial macromolecular passage in vivo occurs passively, and not due to active processes.

Mass transfer of calcium across the peritoneum at three different peritoneal dialysis fluid Ca2+ and glucose concentrations.

BACKGROUND: In peritoneal dialysis, the rate of ultrafiltration has been predicted to be a major determinant of peritoneal calcium (Ca2+) removal. Hence, dialysis fluid glucose concentration should be an important factor governing the transperitoneal Ca2+ balance. The aim of this study was to test the effect of various dialysate glucose levels and selected dialysate Ca2+ levels on Ca2+ removal in peritoneal dialysis patients. METHODS: Patients (N = 8) received, during a 7-week period, 2 L of lactate (30 mmol/L)/bicarbonate (10 mmol/L)-buffered peritoneal dialysis solutions containing either 1.5% glucose and 1.0 mmol/L Ca2+ or 2.5% glucose and 1.6 mmol/L Ca2+, or 4% glucose and 2.5 mmol/L Ca2+, respectively, provided in a three-compartment bag (trio system). Patients underwent standardized (4-hour) dwells, one for each of the three dialysates to assess permeability-surface area product (PS) or mass transfer area coefficients (MTAC) for ionized and "freely diffusible" Ca2+, lactate, glucose, bicarbonate, phosphate, creatinine, and urea. RESULTS: There was a clear-cut dependence of peritoneal Ca2+ removal on the rate of ultrafiltration. For large peritoneal to dialysate Ca2+ gradients (2.5 mmol/L Ca2+ in 4% glucose) a close fit of measured to simulated data was predicted by the three-pore model using nonelectrolyte equations. For low transperitoneal Ca2+ concentration gradients, however, directly measured Ca2+ data agreed with the simulated ones only when the peritoneal Ca2+ PS was set lower than predicted from pore theory (6 mL/min). CONCLUSION: There was a marked ultrafiltration dependence of transperitoneal Ca2+ transport. Nonelectrolyte equations could be used to simulate peritoneal ion (Ca2+) transport provided that the transperitoneal ion concentration gradients were large. Based on our data 1.38 mmol/L Ca2+ in the dialysis fluid would have created zero net Ca2+ gain during a 4-hour dwell for 1.5% glucose, whereas 1.7 and 2.2 mmol/L Ca2+ would have been needed to produce zero Ca2+ gain for 2.5% glucose and 3.9% glucose, respectively.

Low-dose prostacyclin improves cortical perfusion following experimental brain injury in the rat.

It was recently shown that prostacyclin at a low dose reduces cortical cell death following brain trauma in the rat. Conceivably, prostacyclin with its vasodilatory, anti-aggregatory, anti-adhesive and permeability-reducing properties improved a compromised perfusion caused by post-traumatic vasoconstriction, microthrombosis and increased microvascular permeability. The objective of the present study was therefore to investigate the hemodynamic effects of low-dose prostacyclin in the traumatized rat cortex. Following a fluid percussion brain injury or a sham procedure, animals were treated with a continuous intravenous infusion of prostacyclin of 1 or 2 ng x kg(-1) x min(-1), or vehicle. Blood flow ([(14)C]-iodoantipyrine), the permeability-surface area product (PS) for [(51)Cr]-EDTA, and brain water content were measured after 3 or 48 h of treatment. Blood flow values in the injured cortex were transiently reduced to 0.42 +/- 0.2 mL x min(-1) in the vehicle group 3 h following trauma from a corresponding value of about 1.6 mL x min(-1) in the sham group, with recovery of blood flow after 48 h. Prostacyclin treatment caused a dose-dependent increase in blood flow which reached statistical significance 48 h following trauma. Brain water content and PS increased in the injured cortex post trauma and the higher dose of prostacyclin increased these parameters further at 48 h compared to the vehicle group (p < 0.05). The latter effects of prostacyclin cannot be attributed to an increase in permeability, as prostacyclin did not influence PS or brain water content following sham trauma. In fact prostacyclin has been shown to have permeability-decreasing properties. We conclude that prostacyclin improves cortical perfusion following brain trauma. The simultaneous aggravation of brain edema can be explained by an increased surface area, perhaps in combination with increased capillary hydrostatic pressure.

Personal dialysis capacity (PDC(TM)) test: a multicentre clinical study.

BACKGROUND: The assessment of the peritoneal membrane capacity and physiology of the individual patient is becoming increasingly important. It allows the prescription of an individualized peritoneal dialysis (PD)-regimen, and the monitoring of peritoneal membrane function over time. The PDC(TM) program offers the possibility to evaluate the peritoneal membrane characteristics and to predict solute and water removal by simulation of different treatment regimens. METHODS: This study evaluates the relevance of the PDC(TM) program when routinely used. The PDC(TM) data of 336 patients from nine different centres in Europe were evaluated. RESULTS: The area parameter was 20 985+/-7578 cm/1.73 m(2) (mean+/-SD). The reabsorption of fluid after dissipation of glucose, Jv(AR), was 1.97+/-1.00 ml/min/1.73 m(2). The large pore fluid flux, Jv(L), was 0.11+/-0.07 ml/min/1.73 m(2). A multivariate model for prediction of serum albumin included dialysate protein loss, Jv(L), Jv(AR), nPCR, A(0)/deltaX, BMI and gender (R(2)=0.81, P<0.001). Total clearance fell with increasing PD duration (P<0.001). A negative relation between A(0)/deltaX and ultrafiltration (rho=-0.26, P<0.05), a positive relation between A(0)/deltaX and peritoneal creatinine clearance (rho=0.52, P<0.05) and urea clearance (rho=0.36, P<0.05), and a positive relation between measured peritoneal creatinine and urea clearance (rho=0.64, P<0.01) was observed. CONCLUSIONS: In summary, the present study shows that the PDC(TM) program is a robust, accurate method to describe the peritoneal membrane transport characteristics. Analysis of PDC(TM) data of large groups of patients, especially if followed up over time, can give interesting information on the physiology of the peritoneal membrane and the impact of different parameters on it.

Comparison of the radioiodinated serum albumin (RISA) dilution technique with direct volumetric measurements in animal models of peritoneal dialysis.

BACKGROUND: Rat models of peritoneal dialysis (PD) are useful for studying the physiology of peritoneal transport and evaluating new osmotic agents. Intraperitoneal (IP) solute concentrations and their evolution over time are easy to measure, but IP volume (IPV) is not. Direct volumetric measurements are the "gold standard:" but they are expensive and do not allow for repetitive measurements in the same animal. The Indicator dilution technique is therefore used as an alternative. However, that technique is based on assumptions that are not always valid. The present study compares direct volume measurement with the Indicator dilution technique [radioiodinated serum albumin (RISA)] to determine the IPV over time curves In a rat model of PD. METHODS: In series 1, 17 Sprague-Dawley rats were instilled IP with 25 mL 1.36% glucose dialysate through a Teflon catheter. In 9 animals, 0.35 mL dialysate was sampled and discarded at time points 0, 3,15, 30, 60, 180, and 240 minutes. In the other 8 animals, no sampling was performed. At 240 minutes, all 12 animals were humanely killed, and direct volumetric measurements of IPV were performed. In series 2, rats were instilled IP with 25 mL 1.36% glucose dialysate containing 18.5 kBq 1311 RISA. In 9 animals, dialysate was sampled at 0, 3, 15, 30, 60, 90, 120,180, and 240 minutes for the construction of the RISA concentration-over-time curve, and to calculate the elimination constant Ke. At 30, 60, 180, and 240 minutes, dialysate was sampled in 6 different animals (total n = 24) to calculate IPV using the RISA dilution technique. Immediately afterward, the animals were humanely killed, and direct volumetric measurements of IPV were performed. RESULTS: In series 1, after 240 minutes' dwell time, the IPV was lower in the sampled animals as compared with the non sampled animals (27.11 +/- 1.85 mL vs 30.75 +/- 0.59 mL, p = 0.001). In series 2, the evolution of RISA activity in the dialysate over time was described by piecewise linear regression, yielding 3,288--8.2T counts (cts) for T < 52.72 minutes and 2,973--1.99T counts for T > 52.72 minutes. The IPV was better predicted with a Ke that took into account the disappearance of RISA by sampling than with a Ke that took into account disappearance of RISA only by absorption. CONCLUSIONS: If indicator dilution techniques are used to measure IPV, attention must be paid to the disappearance of the osmotic agent and the marker by multiple sampling. The best way to meet that goal is to use micropipettes to avoid large sample volumes.