Glucose Peritoneal Dialysis Solution Research Articles

Sex Modulates Cardiovascular Effects of Icodextrin-Based Peritoneal Dialysis Solutions.

Background/Aims: Some previous observations have noted that after six months of peritoneal dialysis (PD) treatment with icodextrin solutions, blood pressure (BP) and NT-proBNP tend to return to baseline values. This may be due to accumulation of icodextrin products that exert a colloid osmotic effect, which drives water into the bloodstream, causing the rise in blood pressure. Since icodextrin is metabolized by α-Amylase and its gene copies are lower in females than in males, we hypothesized icodextrin metabolites reach higher concentrations in females and that cardiovascular effects of icodextrin are influenced by sex. Methods: Secondary analysis of a RCT comparing factors influencing fluid balance control in diabetic PD patients with high or high average peritoneal transport receiving icodextrin (n = 30) or glucose (n = 29) PD solutions. Serum icodextrin metabolites, osmolality, body composition and Inferior Vena Cava (IVC) diameter were measured at baseline, and at 6 and 12 months of follow-up. Results: After six months of treatment, icodextrin metabolites showed higher levels in females than in males, particularly G5-7 and >G7, serum osmolality was lower in females. In spite of reduction in total and extracellular body water, ultrafiltration (UF) was lower and IVC diameter and BP increased in females, suggesting increment of blood volume. Conclusion: Females undergoing PD present with higher levels of icodextrin metabolites in serum that may exert an increased colloid-osmotic pressure followed by less UF volumes and increment in blood volume and blood pressure. Whether this could be due to the lesser number of α-Amylase gene copies described in diabetic females deserves further investigation.

Calpain activation promotes dialysis-associated peritoneal fibrosis in rats

To explore the role of calpain activation in the progression of peritoneal fibrosis. Twenty-four male Sprague-Dawley rats were randomized equally into control group, MDL28170 (a calpain inhibitor)+normal saline group, peritoneal dialysis (PD) model group and PD + MDL28170 group. In the latter two groups, the rats received daily intraperitoneal injections of 100 mL/kg of 4.25% glucose PD solution, and those in PD+MDL28170 group and MDL28170 saline group received daily infusion of 4 mg/kg MDL28170 every other day. Eight weeks later, the rats were euthanized for pathological examination of the parietal peritoneum, and the visceral peritoneum was used for examining the activation status of calpain and the expressions of fibronectin (FN) and collagen I (COL-I). Calpain activation and expressions of FN, COL-I and α-SMA were also examined using Western blotting and immunofluorescence assay in primary cultures of rat peritoneal mesothelial cells treated with MDL28170, transforming growth factor-β (TGF-β), or both. Compared with the control rats, the rats in PD model group showed significantly increased peritoneal peritoneum thickness, calpain activation in the peritoneal tissue, and expressions of FN and COL-I (P < 0.05). Treatment with MDL28170 significantly alleviated associated peritoneal fibrosis, decreased the thickness of the peritoneum (P < 0.05), and reduced the expressions of FN and COL-I in the rats with daily PD (P < 0.05). In the in vitro experiment, the expressions of FN and COL-I were also significantly lower in rat peritoneal mesothelial cells treated with both MDL28170 and TGF-β than in the cells treated with TGF-β alone (P < 0.05). Peritoneal calpain activity and expressions FN and COL-I all increase significantly in rat models of PD-associated peritoneal fibrosis. Calpain activation can promote peritoneal fibrosis, and inhibition of calpain can alleviate peritoneal fibrosis.

P1210EFFECT OF ICODEXTRIN OR GLUCOSE PERITONEAL DIALYSIS (PD) SOLUTIONS ON TRIGLYCERIDE AND OLEIC ACID LEVELS IN PD PATIENTS (EXIT TRIAL)

Abstract Background and Aims Dyslipidemia is a major cause of cardiovascular disease (CVD) and CVD incidence is definitely increased according to peritoneal dialysis (PD) vintage. The PD solutions contained glucose may affect on dyslipidemia including hypertriglyceridemia. The oleic acid (OA) content in the erythrocyte membrane was increased in patients with acute coronary syndrome and is significantly higher in PD patients than hemodialysis patients. We conducted this trial for comparing effect of icodextrin or glucose PD solutions on triglyceride and oleic acid levels in PD patients. Method This EXIT trial is an open label, randomized, cross-over multi-center trial. Twenty-two patients were enrolled and 15 patients finished this trial. Glucose group was initially exposed to glucose PD solutions for 6 months and then exposed to icodextrin PD solution for 3 months. Extraneal group was initially exposed to icodextrin PD solution for 3 months and then exposed to glucose PD solutions for 6 months. Results The enrolled patients were aged 63.6 ± 9.5 years old and mean PD duration was 10.8 ± 5.9 months. There were no significant differences of baseline clinical and laboratory data between glucose group and extraneal group. There was no significant decrease of triglyceride levels, erythrocyte membrane OA and monounsaturated fatty acid (MUFA) contents after 3 months exposure of icodextrin PD solution compared to baseline. However, there was a tendency of triglyceride levels decrease (p=0.093) after 3 months exposure with icodextrin PD solution and there was a tendency of triglyceride levels increase (p=0.078) after 3 months exposure with glucose PD solutions compared to baseline levels. Continuous 6 months exposure with glucose PD solution significantly increased triglyceride levels (p=0.041), LDL cholesterol levels, erythrocyte membrane OA (p=0.009) and MUFA compared to baseline levels. Conclusion Continuous exposure of glucose PD solutions may negatively affect on triglyceride and erythrocyte membrane OA contents. Combined use of icodextrin and glucose PD solutions may prevent lipid derangement (ClinicalTrial.gov number, NCT NCT02166359).

P1186PRELIMINARY RESULTS OF THE FIRST PHASE II CLINICAL TRIAL ON THE USE OF AN INNOVATIVE GLUCOSE-SPARING PD SOLUTION (FIRST)

Abstract Background and Aims High amounts of glucose as the main osmotic agent for peritoneal dialysis (PD) could be harmful, as it may significantly increase cardiovascular morbidity and mortality. Glucose has long-term detrimental effects on the peritoneum, which ultimately may result in ultrafiltration failure, worsening fluid overload and cardiovascular disease. The absorption of glucose from the dialysate accentuates the disturbances of the carbohydrate metabolism, which is already impaired in the uremic state, leading to insulin resistance. XyloCore (Iperboreal Pharma, Pescara, Italy), is a low glucose containing PD solution (PDS) proposed as an alternative to glucose PDS only regimen. It has been formulated replacing most of the glucose with two crystalloid agents, D-xylitol and L-carnitine. PDS containing osmolar agents like xylitol and L-Carnitine added to glucose, used for the nocturnal exchange, may lead to a significant reduction of glucose level in PDS during the night dwell, while preserving or even improving the depurative efficacy of the standard PDS containing 2.5% glucose. The reduction of glucose level could be further enhanced if the PDS with xylitol and carnitine will be used for the diurnal exchanges and a PDS with icodextrin will substitute the standard PDS containing glucose 2.5% for the nocturnal dwell. The aims of the study are to evaluate the effects of (I) the XyloCore PDS IPX15 [containing glucose (0.5%), xylitol (1.5%) and L-carnitine (0.02%) as osmotic agents, as compared to the standard 2.5% glucose PDS] for the nocturnal exchange, and (II) the XyloCore PDS IPX07 [containing glucose (0.5%), xylitol (0.7%) and L-carnitine (0.02%), as compared to the standard 1.5% glucose PDS] for the diurnal (short dwell) exchanges. Method Prospective, randomized, controlled clinical trial in stable ESRD patients treated by CAPD (study protocol registered as NCT 04001036). Key inclusion criteria are: ESRD treated for at least three months with CAPD, stable clinical condition within the four weeks before the screening, hemoglobin ≥ 9g/dL, absence of acute peritonitis and/or peritoneal catheter infection in the three months before. Key exclusion criteria are: androgen therapy, active infections, congestive heart failure stage III and IV NYHA; major cardiovascular events in the last 3 months, clinically relevant cardiac arrhythmia; clinically relevant abnormal hepatic tests; treatment with L-carnitine in the previous three months, pregnancy, life expectancy of less than one year, allergy to L-carnitine or xylitol. The sample size is 40 patients. Treatment duration is 4 weeks plus a 4 weeks safety follow up with no treatment. Primary end-point is the daily peritoneal ultrafiltration volume. Secondary end-points are the peritoneal equilibration test (D/P creatinine, D/P glucose), weekly total Kt/V urea, weekly total creatinine clearance, Adverse Events. Results Two centers participate in the study. One center has so far recruited 10 patients, 6 in the IPX15 group and 4 in the IXP07 group. The six patients in the IXP15 group were 4 males and 2 males, aged 69.5 ±5.1 years. The four patients in the IXP07 were all male, mean age 56 ± 12 years. One patient already completed the study period. Results for Kt/V, creatinine clearance, D/P creatinine, D/P glucose, ultrafiltration volume, at time (T) 0 are 1.17, 85.6, 0.75, 0.18, 400 ml, respectively; at T28 (days) are 3.1, 80, 0.82, 0.23, 400 ml respectively, and at T56 are 3.5, 80, 0.77, 023, 450 ml, respectively. D/P glucose results indicate that this patient is a high transporter and D/P creatinine that the patient was an average/ high transporter. There were no adverse events reported and tolerability has been excellent so far. Conclusion In the first 10 ESRD patients included in the study, XyloCore PDS used for 4 weeks has been well tolerated without significant adverse events. The study is in progress.

Valsartan ameliorates high glucose-induced peritoneal fibrosis by blocking mTORC1 signaling.

Our study provided new insight into the mechanism underlying the preservation of the peritoneum by valsartan. The results demonstrated that the mice receiving chronic high glucose (HG) peritoneal dialysis solution infusion showed a typical feature of peritoneal fibrosis (PF), as well as higher expression of α-smooth muscle actin (α-SMA) and collagen I. In vitro, HG increased the protein expression of α-SMA and collagen I in a dose-dependent manner, while valsartan significantly ameliorated these pathological changes. Interestingly, there was a parallel decrease in the activity of mammalian target of rapamycin complex 1 (mTORC1) and the protein expression levels of α-SMA and collagen I upon treatment with valsartan in vivo and in vitro. Moreover, the mTOR agonist MHY1485 reversed the downregulation of α-SMA and collagen I in vitro, even in the presence of valsartan. Altogether, our findings reported for the first time that valsartan exerts a protective effect against HG-induced PF by inhibiting the activity of the mTORC1 pathway.

Pyridine levels in ceftazidime - peritoneal dialysis admixtures stored at body temperature.

For the treatment of peritoneal dialysis-associated peritonitis (PDAP), ceftazidime is routinely admixed with peritoneal dialysis (PD) solutions before its intraperitoneal administration. One of the major degradation products of ceftazidime is pyridine, a potentially toxic compound. Depending on the type of PD solution, ceftazidime is exposed to an environment with acidic or basic pH, and depending on the type of dosing and individual unit practices related to preparation and storage, ceftazidime can be at body temperature for 4-10 h, resulting in potentially varying rates of degradation to pyridine by-product. No study has investigated whether the amount of generated pyridine exceeds the maximum daily exposure limit of 2 mg when ceftazidime-PD admixtures are kept at body temperature. Therefore, the current study aimed to determine the levels of pyridine generated in PD-ceftazidime admixtures kept at 37°C for various time points. Ceftazidime was admixed with 2 L Dianeal (1.5%, 2.5% and 4.25% dextrose) and 2 L Physioneal (1.36%, 2.27% and 3.86% glucose) PD solutions to obtain a concentration of 125 mg/L (continuous dosing model) or 500 mg/L (intermittent dosing model). A total of 36 PD admixtures (3 bags for each type of PD solution and 3 bags for each type of dosing) were prepared and stored at 37°C for 10 h. An aliquot was withdrawn at time 0 (baseline) and after 2, 6, 8 and 10 h of storage. The withdrawn samples were then analysed to determine the concentrations of ceftazidime and pyridine using high-performance liquid chromatography. With the intermittent dosing model (500 mg/L), ceftazidime was found to be stable for only 2 and 6 h when admixed with 3.86% and 2.27% glucose Physioneal PD solutions, respectively. While ceftazidime (500 mg/L) retained more than 90% of its initial concentration in the three types of Dianeal and 1.36% dextrose Physioneal solutions for 10 and 8 h, respectively, the generated amount of pyridine ranged between approximately 290% and 371% more than the daily recommended limit. With the continuous dosing model (125 mg/L), ceftazidime was found to be stable for 6 h in all three types of Physioneal PD solutions, but the total amount of generated pyridine with four daily exchanges (6 h each) was estimated to be 170-360% over the daily recommended limit. Ceftazidime (125 mg/L) was chemically stable when admixed with three types of Dianeal PD solutions and stored at 37°C for 10 h, and the levels of pyridine were estimated to be less than the maximum recommended daily limit. Until the outcomes of this in vitro study are confirmed by appropriate in vivo studies, continuous dosing of ceftzadime-Dianeal admixtures for the treatment of PDAP may be preferred over continuous dosing of ceftazidime-Physioneal admixtures, and intermittent dosing of ceftazidime-Physioneal and ceftazidime-Dianeal admixtures, as ceftazidime remains stable and the generated levels of pyridine are below the maximum recommended daily exposure.

The role of icodextrin in peritoneal dialysis: protocol for a systematic review and meta-analysis

BackgroundPrevious meta-analyses have found several advantages of icodextrin compared with glucose in the application of peritoneal dialysis (PD), such as an improvement of peritoneal ultrafiltration during the long dwell and a reduction in episodes of uncontrolled fluid overload. However, the effect of icodextrin on patient-relevant outcomes remains unclear. This review aims to evaluate the benefits and harms of icodextrin in comparison with conventional glucose PD solution in patients with end-stage kidney disease receiving PD.MethodsRandomized controlled trials of icodextrin comparing with conventional glucose solution in patients with end-stage kidney disease who received PD will be deemed eligible. We will conduct systematic searches in MEDLINE, EMBASE, CENTRAL, Ichushi-Web, Chinese and Japanese databases, and in clinical trials registries (ClinicalTrials.gov, International Clinical Trials Registry Platform Search Portal (ICTRP), EU Clinical Trials Register, Japan Registries Network (JPRN), China’s Clinical Trial Registry (ChiCTR)). Furthermore, we will check conference proceedings and search references from relevant studies manually. Relevant pharmaceutical companies, authors, and experts will be contacted in an effort to identify further studies. We will not apply any limitations regarding language, publication status, and publication date when searching for eligible studies. The selection of studies, data extraction, and risk of bias assessment will be carried out by two independent reviewers. Data synthesis will be performed using RevMan 5 software with either a fixed effects model or random-effects model, depending on the presence of heterogeneity. For the assessment of statistical heterogeneity, I2 will be calculated. Sources of clinical heterogeneity will be evaluated through subgroup analyses. If there are ten or more studies included in the meta-analysis, we will investigate the publication bias using funnel plots and Egger’s test. The quality of the body of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.DiscussionWe assume that our systematic review will be more comprehensive compared to those published previously due to contacting the relevant pharmaceutical companies and a systematic search of published and unpublished non-English studies from China, Taiwan, and Japan.Systematic review registrationPROSPERO CRD42018096951

Regimen-related Mortality Risk in Patients Undergoing Peritoneal Dialysis Using Hypertonic Glucose Solution: A Retrospective Cohort Study.

ObjectivesThe main purpose of this study was to quantify the risk of mortality linked to various regimens of hypertonic peritoneal dialysis (PD) solution.MethodsA retrospective cohort study of patients using home-based PD was carried out. The prescribed regimen of glucose-based PD solution for all patients, determined on the basis of their individual conditions, was extracted from their medical chart records. The primary outcome was death. The treatment regimens were categorized into 3 groups according to the type of PD solution used: original PD (1.5% glucose), shuffle PD (1.5 and 2.5% glucose), and serialized PD (2.5 and 4.5% glucose). Multivariate analysis (using the Weibull model) was applied to comprehensively examine survival probabilities related to the explanatory variable, while adjusting for other potential confounders.ResultsOf 300 consecutive patients, 38% died over a median follow-up time of 30 months (interquartile range: 15-46 months). Multivariate analysis showed that a treatment regimen with continued higher-strength PD solution (serialized PD) resulted in a lower survival rate than when the conventional strength solution was used (adjusted hazard ratio, 2.6; 95% confidence interval, 1.6 to 4.6, p<0.01). Five interrelated risk factors (age, length of time on PD, hemoglobin levels, albumin levels, and oliguria) were significant predictors contributing to the outcome.ConclusionsFrequent exposure to high levels of glucose PD solution significantly contributed to a 2-fold higher rate of death, especially when hypertonic glucose was prescribed continuously.

Blood Pressure Control in Peritoneal Dialysis Patients.

In the general population, hypertension (HT) is defined as systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg. In dialysis patients, the definition is thought to be the same as in the general population. But there is no clear description about the definition of HT for dialysis patients, especially in peritoneal dialysis (PD) patients. The prevalence of HT in PD patients is much higher compared to the general population. The association of BP and cardiovascular (CV) mortality in PD patients who are not exposed to huge hemodynamic changes during hemodialysis (HD) has been inconsistently reported. The International Society of Peritoneal Dialysis (ISPD) guideline recommends that BP be evaluated by home BP measurement at least once a week and at each visit to the clinic and that active screening and periodic monitoring of BP be performed in this population. When collecting BP data via our telemedicine system, HD patients' weekly BP variability was unclear if data were analyzed by the day of the week, but was clear if data were analyzed by the day of dialysis. There is weekly BP variability probably due to volume status, not due to the day of the week. The range of variability of morning SBP in a week was almost 16 mm Hg in HD patients. But continuous ambulatory PD patients' home morning SBP variability in a week was only 3 mm Hg. Comparing data of PD patients and HD patients, weekly BP variability is much wider in HD, which might increase CV event risk. PD patients should undertake physical activity and salt restriction compatible with CV health and tolerance, which might reduce BP as some reports suggested. Keeping good volume status is crucial for the treatment of BP. Using the bioelectrical impedance device is a good method to measure dry weight. Conventionally, we should check dry weight confirming no edema on body, normal BP and normal heart rate, cardiothoracic ratio, plasma concentration of human atrial natriuretic peptide, diameter of inferior vena cava, etc. Before starting or increasing antihypertensive medications, PD patients with HT should have volume status optimized. Although the utility of hypertonic glucose PD solutions for volume removal in PD is not disputed, the minimization of PD glucose exposure by salt restriction, diuretic use among those with residual renal function, and use of glucose-sparing solutions like icodextrin to optimize volume control are important. PD patients whose BP is consistently >140/90 mm Hg should be treated to maintain SBP at <140 mm Hg and DBP at <90 mm Hg. There are no randomized studies examining different BP targets in relation to clinical outcomes in PD patients. As a perspective, evidence for BP control in PD patients is awaited.

Peritoneal dialysis: from bench to bedside and bedside to bench.

For patients with end-stage kidney disease unable to receive a kidney transplant, replacement of kidney function with dialysis is necessary to extend life. Peritoneal dialysis (PD) and hemodialysis (HD) are the two major forms of dialysis therapy. HD involves the passage of blood via an extracorporeal circuit whereby removal of small solutes, toxins, and water is achieved across a synthetic, semipermeable dialysis membrane. In contrast, in PD, the dialysis membrane is the highly vascularized internal lining of the peritoneal cavity. Intraperitoneal installation of hypertonic high glucose PD solution creates a transmembrane osmotic and diffusive gradient that facilitates water removal [ultrafiltration (UF)], convection, and diffusion of uremic toxins. Insight into the physiology of solute and water transport across the peritoneal membrane has been enhanced by the proposal of the ''three-pore model'' of peritoneal membrane transport. Transport characteristics and UF capacity of the peritoneal membrane vary among individuals, and deleterious changes in the membrane may ensue over time. The degree to which these changes are a direct consequence of the type and composition of currently available PD solutions, recurrent infectious episodes, genetic differences among individuals, or a combination thereof is the subject of intense study. Adverse consequences resulting from the systemic and local metabolic effects of intraperitoneal glucose exposure, infection of the PD fluid, PD catheter dysfunction, and patient burnout from self-care often limit the long-term success of the therapy. Research aimed at addressing these challenges will examine the use of more biocompatible PD solutions and strategies aimed at attenuating progressive peritoneal membrane injury.

Compare the effects of intravenous and intraperitoneal mesenchymal stem cell transplantation on ultrafiltration failure in a rat model of chronic peritoneal dialysis

Aim: The purpose of this study was to compare the possible healing effects of intraperitoneal (IP) and intravenous (IV) mesenchymal stem cell (MSC) transplantation on ultrafiltration failure (UFF) in a chronic rat model of peritoneal dialysis (PD). Methods: Rats were initially divided into two groups. The UFF-group received once-daily IP injections of 20 mL of 3.86% glucose PD solution for six weeks to stimulate the development of UFF, and a control group received no injections. The UFF group was sub-divided into four groups: an UFF-C group, a MSC-IP group, a MSC-IV group and a placebo (P) group. Peritoneal equilibration tests (PETs) and peritoneal biopsies were performed in the control and UFF-C groups. MSCs were administered by IP injection in the MSC-IP group and by IV injection in the MSC-IV group. The P group received IP injection of placebo. PETs and peritoneal biopsies were performed in the MSC-IP, MSC-IV and P groups at the three weeks after receiving MSCs or placebo. Results: When compared with the control group, ultrafiltration capacity significantly decreased, and the submesothelial thickness increased in the UFF-C and P group, but there were no differences between the control and MSC-IP and MSC-IV groups. The rate of glucose transport was high in the UFF-C and P group compared with the control group, and D/PCr rates in the UFF-C and P group were lower than in the control group. However, D/D0glucose was higher and D/PCr was lower in the MSC-IP group than in the UFF-C and P groups, but D/D0glucose rate of MSC-IV group similar to UFF-C and P groups and there was no difference between MSC-IV group and the other groups in terms of D/PCr rates. The MSC-IP, MSC-IV and P groups had significantly decreased tumor necrosis factor α concentrations compared with the UFF-C group. MSC-IP group had lower levels of TGF-β1 compared with the P group; MSC-IP group had also lower levels of interleukin-6 compared with UFF-C group. Conclusion: The UFF group had a high permeability UFF. These results showed that IV and IP MSC transplantation exerted positive effects on UFF in a chronic rat model of PD. However, healing effect of small solute transport in MSC-IP group was better than MSC-IV group. IP MSC transplantation may be more effective than IV MSC transplantation for the renewal of the peritoneum in chronic PD patients with UFF.

Solubleform of (pro)renin receptor is excreted from mesothelial cells to peritoneal dialysis effluent of peritoneal dialysis patients (1173.5)

Renin angiotensin system (RAS) is associated with peritoneal injury in peritoneal dialysis (PD). Angiotensin II dependent and independent role of (pro) renin receptor ((P)RR) to the cellular injury has been demonstrated. Thus, the present study determined the expression of (P)RR in drained PD effluent (PDE) and human peritoneal mesothelial cells (HPMCs) of the PD patients.PDE drained after 2.5% glucose PD solution during peritoneal equivalent test (0hours, 2hours, 4hours) was collected from PD patients. Human soluble from of (P)RR level was measured by ELISA. The expression of (P)RR on cultured HPMCs and media isolated from PDE were investigated by Western blot analysis and/or flow cytometry. HPMCs was specified by cytokeratin positive cells in flow cytometry. Full length or soluble (P)RR was identified by the molecular weight compared to the full length and soluble (P)RR synthesized in vitro from the expression vectors.Soluble (P)RR was detected in both plasma and PDE of PD patients. Time dependent increase in soluble (P)RR was observed in PDE. Expression of (P)RR was observed in cytokeratin positive mesothelial cells. Full length (P)RR was detected in HPMCs while soluble from of (P)RR was detected in concentrated cultured medium.These results indicate that full length (P)RR is expressed in HPMCs and excrete soluble (P)RR in drained PDE. The role of full length (P)RR in HPMCs and soluble (P)RR in plasma and PDE of PD patients requires further investigation.

Effect of high glucose peritoneal dialysis solution on PGC-1α expression and mitochondria related oxidative injury in human peritoneal mesothelial cells

To investigate the mechanism of mitochondrial oxidative injury induced by high glucose peritoneal dialysis solution (PDS) and the protective effect of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α) in the mitochondria of human peritoneal mesothelial cells (HPMC) in the high glucose ambience. HPMC was cultured in a PDS containing 1.5%, 2.5% and 4.25% glucose for 24 hours. Western blot analysis was used to detect PGC-1α expression. MitoSOX? Red staining, respiratory chain complexes and antioxidant enzyme activities were determined. The activities of respiratory chain complex III and antioxidant enzymes decreased significantly in a concentration- and time-dependent manner, along with the increased production of mitochondrial reactive oxygen species (ROS) and cellular apoptosis. In addition, protein expression of PGC-1α was also decreased in the high glucose PDS ambience. High glucose PDS might inhibit PGC-1α expression, resulting in the inhibition of mitochondrial function and increase of mitochondrial ROS and cellular apoptosis.

Functional and structural alterations of peritoneum and secretion of fibrotic cytokines in rats caused by high glucose peritoneal dialysis solutions

Objective: To determine functional and structural alterations of peritoneum and fibrotic cytokines expression in peritoneal dialysis (PD) rats. Methods: 28 Sprague–Dawley (S-D) rats were randomly divided into four groups and dialyzed with various solutions daily for four weeks: (1) no solution (CON group), (2) 0.9% Saline solution (NS group), (3) 1.5% Dianeal (LG group), (4) 4.25% Dianeal (HG group). Peritoneal equilibration tests, ultrafiltration function and effluent protein quantification were measured. Peritoneum morphology was studied and immunohistochemistry were performed for detection of transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), and fibronectin (FN) proteins. Reverse transcriptional-polymerase chain reaction was used to analyze the expression of TGF-β1, CTGF mRNA. Results: Administration of 4.25% Dianeal caused functional and structural changes of peritoneum, including protein loss through the transport process, decrease of peritoneal solute transport rate and ultrafiltration capacity. The collagen of peritoneum in the HG group was thicker than the other groups. The levels of CTGF, TGF-β1, and FN proteins were significantly the highest in the HG group, followed by the LG group. The liner correlation analysis showed positive correlations between the levels of CTGF, TGF-β1, and FN proteins and the collagen thickness. The expression of TGF-β1 and CTGF mRNA in the HG group were significantly higher than those in the other groups and were indicated positive correlation. Conclusion: Using high glucose peritoneal dialysis solutions in rats may not only lead to processing of peritoneal fibrosis, which is promoted by ectopic expression of TGF-β1, but also increase the expression of CTGF. CTGF is an important fibrotic media of peritoneal fibrosis in PD rats.

Mesenchymal stem cell transplantation may provide a new therapy for ultrafiltration failure in chronic peritoneal dialysis

The purpose of this study was to investigate possible healing effects of intraperitoneal (IP) mesenchymal stem cell (MSC) transplantation on ultrafiltration failure (UFF) in a chronic rat model of peritoneal dialysis (PD). Rats were initially divided into two groups. The APUF group received once-daily IP injections of 20 mL of 3.86% glucose PD solution for 6 weeks to stimulate the development of UFF and a control group received noinjections. The PUF group was sub-divided into three groups: a PUF-C group, an MSC group and a Placebo (P) group. Peritoneal equilibration tests (PETs) and peritoneal biopsies were performed in the control and PUF-C groups. MSCs were administered by IP injection in the MSC group and the PUF-C and P groups received IP injection of placebo. PETs and peritoneal biopsies were performed in the MSC and P groups at the first [P-1 (and MSC-1 groups] and second [P-2 and MSC-2 groups] week after receiving MSCs or placebo. When compared with the control group, ultrafiltration capacity significantly decreased and the submesothelial thickness increased in the PUF-C and P groups (P-1, P-2) (P < 0.05), but there were no differences between the control and MSC groups (MSC-1, MSC-2). The rate of glucose transport was high in the PUF-C and P-2 groups compared with the control group, and D/PCr rates in the PUF-C and P-2 groups were lower than in the control group (P < 0.05). However, D/D0(glucose) was higher and D/P(Cr)was lower in the MSC-2 group than in the PUF-C and P-2 groups (P < 0.05). Transforming growth factor-β (TGF-β) levels were lower in the MSC groups than in the P and PUF-C groups (P < 0.05). The PUF-C group had a high permeability UFF. These results showed that MSC transplantation exerted positive effects on UFF in a chronic rat model of PD. MSC transplantation may provide new options for the renewal of the peritoneum in chronic PD patients with UFF.

Hyperbranched Polyglycerol is an Efficacious and Biocompatible Novel Osmotic Agent in a Rodent Model of Peritoneal Dialysis

To enhance the effectiveness of peritoneal dialysis (PD), new biocompatible PD solutions may be needed. The present study was designed to test the efficacy and biocompatibility of hyperbranched polyglycerol (HPG)-a nontoxic, nonimmunogenic water-soluble polyether polymer-in PD. Adult Sprague-Dawley rats were instilled with 30 mL HPG solution (molecular weight 3 kDa; 2.5% - 15%) or control glucose PD solution (2.5% Dianeal: Baxter Healthcare Corporation, Deerfield, IL, USA), and intraperitoneal fluid was recovered after 4 hours. Peritoneal injury and cellular infiltration were determined by histologic and flow cytometric analysis. Human peritoneal mesothelial cells were assessed for viability in vitro after 3 hours of PD fluid exposure. The 15% HPG solution achieved a 4-hour dose-related ultrafiltration up to 43.33 ± 5.24 mL and a dose-related urea clearance up to 39.17 ± 5.21 mL, results that were superior to those with control PD solution (p < 0.05). The dialysate-to-plasma (D/P) ratios of urea with 7.5% and 15% HPG solution were not statistically different from those with control PD solution. Compared with fluid recovered from the control group, fluid recovered from the HPG group contained proportionally fewer neutrophils (3.63% ± 0.87% vs 9.31% ± 2.89%, p < 0.0001). Detachment of mesothelial cells positive for human bone marrow endothelial protein 1 did not increase in the HPG group compared with the stain control (p = 0.1832), but it was elevated in the control PD solution group (1.62% ± 0.68% vs 0.41% ± 0.31%, p = 0.0031). Peritoneal biopsies from animals in the HPG PD group, compared with those from control PD animals, demonstrated less neutrophilic infiltration and reduced thickness. Human peritoneal mesothelial cell survival after HPG exposure was superior in vitro (p < 0.0001, 7.5% HPG vs control; p < 0.01, 15% HPG vs control). Exposure to glucose PD solution induced cytoplasmic vacuolation and caspase 3-independent necrotic cell death that was not seen with HPG solution. Our novel HPG PD solution demonstrated effective ultrafiltration and waste removal with reduced peritoneal injury in a rodent model of PD.

Role of mitochondrial respiratory chain complex III in high glucose peritoneal dialysate-induced hyperpermeability of HPMCs

Background: High-glucose-based peritoneal dialysis solution (PDS) is considered to be one of the primary causes for the increase of ionic permeability in peritoneum as detected by transmesothelial electrical resistance (TER) measurements and claudin-1 expression. However, the mechanism is not clear. The aim of this study is to test the hypothesis that high-glucose PDS induces hyperpermeability in human peritoneal mesothelial cell (HPMC) monolayer by mitochondrial respiratory chain complex III pathway. Methods: HPMCs were cultured in a 1 : 1 mix of Dulbecco's modified Eagle's medium (DMEM) and PDS containing 1.5% and 4.25% glucose for 24 h. A 1 : 1 mixture of 160 mg/L glutathione and 4.25% glucose PDS was also added as an antioxidant group. TER measurement and immunostaining and western blot analysis of claudin-1 expression were examined for detection of permeability damage in HPMCs. MitoSOX™ Red staining and respiratory chain complexes' activities were determined for detection of mitochondrial reactive oxygen species (ROS) production and mitochondrial complexes' activities. Results: TER decreased in a time- and concentration-dependent manner after culture with high-glucose PDS for 24 h. Claudin-1 was also downregulated. Complex III activity was inhibited accompanied by increasing mitochondrial ROS generation. These changes were partially prevented by glutathione. Conclusion: These findings demonstrate that mitochondrial respiratory complex III pathway has crucial importance in maintaining permeability of HPMCs, which might reveal a valuable target for novel therapies to fight hyperpermeability of peritoneum during the prolonged PD treatment.

Comparative in vitro Study of Different Peritoneal Dialysis Solutions on Cytokine Production by Peripheral Blood Mononuclear Cells

Background/Aims: Peritoneal dialysis solutions (PDS), new and conventional, do not yet have a clinical biocompatibility profile. We aimed at a comparative laboratory profile based on the effect of PDS on peripheral blood mononuclear cell (PBMC) cytokine release. Method: PBMCs from 19 healthy volunteers were incubated at a concentration of 10⁶/ml in fresh PDS and control medium (RPMI 1640), and stimulated or not with 10μg/ml Escherichia coli lipopolysaccharide. The tested PDS were glucose/lactate 1.5 and 4.25%, glucose/pyruvate 1.0 and 4.0%, icodextrin and amino acid solutions. The initial incubation in culture flasks for 15 min was followed by 1:1 dilution with RPMI and by additional incubation for 22 h as a ‘recovery period’. At the end, the supernatants were tested for cytokines IL-6 and TNFα by ELISA. Results: The hypertonic glucose solutions, irrespective of the buffer, had the most adverse effect on PBMC cytokine release. The icodextrin and amino acid solutions seemed close to the isotonic glucose PDS. The substitution of pyruvate for lactate buffer seemed to offer an advantage only for the hypertonic glucose-based solutions. Conclusions: Icodextrin and amino acid solutions seem to offer an advantage only compared to hypertonic glucose PDS.

Insulin Resistance and Glucose Homeostasis in Peritoneal Dialysis

Cardiovascular disease (CVD) is the main cause of death in peritoneal dialysis (PD) patients, a situation that can be explained by a combination of traditional and nontraditional risk factors for CVD in these patients. Glucose and insulin homeostasis are altered in chronic kidney disease (CKD) patients even in the early stages of CKD, leading to insulin resistance by various pathways. Several factors have been implicated in the pathogenesis of insulin resistance, including anemia, dyslipidemia, uremia, malnutrition, excess of parathyroid hormone, vitamin D deficiency, metabolic acidosis, and increase in plasma free fatty acids and proinflammatory cytokines. Insulin resistance and dyslipidemia are observed and increase with the progression of CKD, playing an important role in the pathogenesis of hypertension and atherosclerosis. Particularly in PD patients, exposure to glucose from dialysis fluid accentuates the foregoing metabolic abnormalities. In conclusion, insulin resistance and altered glucose metabolism are frequently observed in CKD, and although dialysis partly corrects those disturbances, the use of glucose PD solutions intensifies a series of harmful metabolic consequences. New therapeutic measures aimed at reducing metabolic disorders are urgently needed and perhaps will improve PD patient survival.

Overnight Mesothelial Cell Exfoliation: A Magic Tool for Predicting Future Ultrafiltration Failure in Patients on Continuous Ambulatory Peritoneal Dialysis

Continuous exposure of the peritoneal membrane to dialysis solutions during long-term dialysis results in mesothelial cell loss, peritoneal membrane damage, and thereby, ultrafiltration (UF) failure, a major determinant of mortality in patients on continuous ambulatory peritoneal dialysis (CAPD). Unfortunately, none of tests available today can predict long-term UF decline. Here, we propose a new tool to predict such a change. Mesothelial cells from 8-hour overnight effluents (1.36% glucose dialysis solution) were harvested, co-stained with cytokeratin (a mesothelial marker) and TUNEL (an apoptotic marker), and were counted using flow cytometry in 48 patients recently started on CAPD. Adequacy of dialysis, UF, nutrition status, dialysate cancer antigen 125 (CA125), and a peritoneal equilibration test (3.86% glucose peritoneal dialysis solution) were simultaneously assessed and were re-evaluated 1 year later. The numbers of total and apoptotic mesothelial cells were 0.19 +/- 0.19 million and 0.08 +/- 0.12 million cells per bag, respectively. Both numbers correlated well with the levels of end dialysate-to-initial dialysate (D/D(0)) glucose, dialysate-to-plasma (D/P) creatinine, and sodium dipping. Notably, the counts of cells of both types in patients with diabetes or with high or high-average transport were significantly greater than the equivalent counts in nondiabetic patients or those with low or low-average transport. A cut-off of 0.06 million total mesothelial cells per bag had sensitivity of 1 and a specificity of 0.75 in predicting a further decline in D/D(0) glucose and a sensitivity of 0.86 and a specificity of 0.63 to predict a further decline in UF over a 1-year period. In contrast, dialysate CA125 and other measured parameters had low predictive values. The greater the loss of exfoliated cells, the worse the expected decline in UF. The ability of a count of mesothelial cells to predict a future decline in UF warrants further investigation in clinical practice.