Glucose-based Peritoneal Dialysis Solutions Research Articles

#2490 Analyzing the morphology of mesothelial cells when exposed to peritoneal dialysis solutions

Abstract Background and Aims Glucose remains the predominant osmotic agent in peritoneal dialysis (PD), yet its prolonged use is associated with an inevitable decline in peritoneal filtration capacity. Persistent contact with glucose during dialysis can induce significant morphological and functional changes in the peritoneum. In this study, we explore the morphological alterations in mesothelial cells exposed to both conventional glucose-based PD solutions and an innovative biocompatible PD solution (XyloCore) containing L-carnitine and Xylitol. Method Met5A mesothelial cells were seeded and cultured on a polyester filter (with a pore size of 0.4 micrometers, Transwell, 12 well type, Millipore) utilizing a full medium. The impact of PD solutions, differentiating between glucose-based and XyloCore, was assessed on cells cultivated on transwells. These cells were exposed to PD solutions on the apical side and to culture medium on the basal side. The cells were then employed for proteomic and metabolomic assessments and were also fixed and scrutinized through scanning electron microscopy (SEM). Results Through unsupervised hierarchical clustering analysis, discernable proteomic distinctions emerged between wild-type (WT) cells (control) and cells exposed to either glucose-based PD solution or XyloCore. In SEM analysis, control cells exhibited a distinct flat epithelial appearance. Contrastingly, subjecting WT cells to treatment with a glucose-based PD solution induced significant alterations in cellular morphology. Notably, cells displayed elongated shapes, loosening of cell-cell contacts, and a consistent denuding of the culture surface. In contrast, XyloCore maintained a better cellular morphology and mitigated cell detachment. Conclusion Preserving the integrity of the mesothelial barrier is crucial for maintaining peritoneal ultrafiltration capacity. The findings suggest that glucose-based PD solutions trigger early morphological changes in cell shape and cell-cell contacts, likely stemming from alterations in cytoskeleton or adhesion molecules. The exploration of new osmotic agents in clinical practice holds paramount significance for the future of peritoneal dialysis.

Effects of sodium-glucose co-transporter 2 inhibitors on ultrafiltration in patients with peritoneal dialysis: a protocol for a randomized, double-blind, placebo-controlled, crossover trial (EMPOWERED)

BackgroundVolume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium–glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD.MethodsThe EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters.ConclusionsThis trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.

Influence of peritoneal residual volume on the results of the peritoneal equilibration test. Prospective study

BackgroundCategorization of the capacity of ultrafiltration during a peritoneal equilibration test (PET) is a usual step during the monitoring of peritoneal transport characteristics of Peritoneal Dialysis (PD) patients. Quantifying the peritoneal residual volume (Vr) after the dwell preceding the PET (Vrpre) and at the end of the test (Vrpost) could help to improve the accuracy of the estimation of this variable. MethodFollowing a prospective design, we calculated Vrpre and Vrpost in 116 patients, incident or prevalent on DP, who underwent one or two (n = 27) PET with 3,86/4,25% glucose-based PD solutions and complete drainage at 60 min. We evaluated the consistency of Vr by comparing Vrpre and Vrpost, as also these two parameters in repeated tests. We scrutinized potential associations between demographic and clinical factors, on one side, and the amount of Vr on the other, as also the impact of correcting ultrafiltration during PET for Vr on the categorization of the capacity of ultrafiltration. ResultsAs a mean, Vrpost was larger than Vrpre. Consequently, correction of ultrafiltration for Vr resulted in significantly higher values than those obtained according to the standard procedure (494 vs. 449 mL, p < 0,0005). We disclosed marked inconsistencies for different estimations of Vr in the same patients (Vrpre vs Vrpost and repeated PET studies). Moreover, no demographic or clinical variable was able to predict the amount of Vr. We observed a significant deviation (>200 mL) between both methods of estimation of the capacity of utrafiltration in only 12,9% of the patients. However, 21,1% of the patients categorized as cases of ultrafiltration failure according to the standard procedure did not maintain this condition after correction for Vr. ConclusionsCorrection for Vr of the capacity of ultrafiltration during a PET carries, as a mean, a minor impact on the categorization of this parameter. However, the results of the test can be significantly affected in 12,9% of the cases. We have been unable to detect demographic or clinical predictors of Vr, which suggests a random component for the mechanics of single peritoneal exchanges. We suggest that Vr should be estimated at the time of categorizing the capacity of ultrafiltration, whenever inconsistencies during serial PET studies are detected.

#4950 CARNITINE ACETYLTRANSFERASE (CRAT) MODULATES MESOTHELIAL CELL RESPONSE TO FIBROTIC STRESS

Abstract Background and Aims It has been shown that long-term exposure to the high glucose load of peritoneal dialysis (PD) fluids can induce peritoneal fibrosis causing loss of peritoneal ultrafiltration capacity. TGF-beta is a master regulator factor in the onset of peritoneal fibrosis and recent findings suggest that production of it is dependent on a hyper-glycolytic state caused by glucose-based PD solutions. Currently, a different class of bio-compatible PD solutions are under development; they are based on two synergistic strategies: reducing the amount of glucose, and using osmotic-metabolic agents that may provide metabolic benefits able to mitigate local and systemic glucose over-exposure [1, 2]. One such is L-carnitine [1]. The aim of the present study is to explore the role of L-carnitine and carnitine acetyltransferase (CrAT, a key enzyme in L-carnitine metabolism) on the modulation of TGF-beta pro-fibrotic effects. Method CrAT proved overexpressed in the human mesothelial cell line Met5A. Plasmid-coding CrAT ORF (Origene RG21296) was transfected by Lipofectamine 3000 and subsequently cells underwent antibiotic selection. Single clones were isolated, and CrAT expression was measured at the gene and protein level by real-time PCR and WB respectively. Metabolomic analyses were performed on WT and CrAT overexpressing mesothelial cells. WT and CrAT-overexpressing mesothelial cells were also treated with and without TGF-beta in the presence of physiological and supra-physiological L-carnitine concentrations (50 μM and 2 mM, respectively). The expression of fibrosis and inflammatory markers was analyzed. Results Gene and protein expression analyses confirmed CrAT overexpression in several clones and the two with the highest expression rate were used in subsequent analyses. WT and CrAT-overexpressing mesothelial cells displayed a different metabolic profile, as gleaned by unsupervised hierarchical clustering analysis of the top 50 significant metabolites employing ANOVA and partial least square-discriminant analysis (Figure 1). Most interestingly, they showed a different behavior in response to TGF-beta (Figure 2). In detail: treatment with TGF-beta significantly increased the expression of fibrotic markers alpha-smooth muscle actin (alpha-SMA) and vimentin (VIM) as well as that of pro-inflammatory markers interleukine-6 (IL-6) and interleukine-1β (IL-1β) at a physiological L-carnitine concentration (50 μM). Treatment with supra-physiological L-carnitine levels (2 mM) significantly reduced the up-regulation of the markers analyzed. Similarly, TGF-b was unable to modulate the expression of alpha-SMA, VIM, IL-6 and IL-1β in CrAT-overexpressing cells. Conclusion Studying CrAT-overexpressing mesothelial cells may prove to be a useful tool in elucidating how L-carnitine metabolism manages to keep in check the development of fibrosis and inflammation during PD. The use of L-carnitine as an osmo-metabolic agent in PD solutions could significantly slow down the progression of fibrosis in PD therapy.

Dialysis Duration and Glucose Exposure Amount Do Not Increase Mortality Risk in Peritoneal Dialysis Patients: A Population-Based Cohort Study From 2004 to 2012.

BackgroundAlthough the bio-incompatibility of glucose-based peritoneal dialysis (PD) solution is well documented, it is used worldwide. How PD duration and the amount of dialyzate glucose exposure affect survival in patients with end-stage renal disease remain inconclusive due to improper study designs in the extant literature.MethodsAll incident patients with PD from 2004 to 2007 who were older than 18 years in Taiwan were included. Patients were censored when they received a transplant or at the end of 2012. Glucose exposure through PD solution was calculated by the mean glucose contained per liter when receiving PD. For those who had already shifted to hemodialysis (HD) and survived longer than 2, 3, and 4 years (the index dates), the cause-specific Cox regression model was used to make the survival comparison by PD duration and mean glucose concentration in these three cohorts, respectively. The model was adjusted by demographics, case-mix, time cohort (2004–2005 vs. 2006–2007), peritonitis episode (none vs. ≥once), and mean PD solution glucose exposure (tertile).ResultsA total of 3,226 patients were included, with a mean age of 53.4 ± 15.2 years, 44.6% being male, and 34.2% having diabetes mellitus. The 1, 2, 3, and 4-year survival rates were 94, 87, 80, and 74%, while technical survival rates were 86, 70, 56, and 45%, respectively. The overall transplant events were 309 (9.6%) only. There were 389, 495, and 553 incident patients with PD shifting to HD included in 2-, 3-, and 4-year cohort, respectively. The population with moderate glucose concentration exposure had the highest mortality, and the high glucose concentration exposure had non-significant lower mortality in each cohort. In various fixed time-window cohorts, the duration of PD treatment did not increase mortality risk after adjustments. In addition, glucose exposure did not affect the mortality rate.ConclusionFor incident PD patients with PD duration no longer than 4 years, neither PD duration nor glucose exposure amount increases the long-term mortality risk.

Influencia del volumen peritoneal residual en los resultados de la prueba de equilibrio peritoneal. Estudio prospectivo

BackgroundCategorization of the capacity of ultrafiltration during a peritoneal equilibration test (PET) is a usual step during the monitoring of peritoneal transport characteristics of peritoneal dialysis (PD) patients. Quantifying the peritoneal residual volume (Vr) after the dwell preceding the PET (Vrpre) and at the end of the test (Vrpost) could help to improve the accuracy of the estimation of this variable. MethodFollowing a prospective design, we calculated Vrpre and Vrpost in 116 patients, incident or prevalent on DP, who underwent one or two (n=27) PET with 3.86/4.25% glucose-based PD solutions and complete drainage at 60min. We evaluated the consistency of Vr by comparing Vrpre and Vrpost, as also these two parameters in repeated tests. We scrutinized potential associations between demographic and clinical factors, on one side, and the amount of Vr on the other, as also the impact of correcting ultrafiltration during PET for Vr on the categorization of the capacity of ultrafiltration. ResultsAs a mean, Vrpost was larger than Vrpre. Consequently, correction of ultrafiltration for Vr resulted in significantly higher values than those obtained according to the standard procedure (494 vs 449mL, p<0.0005). We disclosed marked inconsistencies for different estimations of Vr in the same patients (Vrpre vs Vrpost and repeated PET studies). Moreover, no demographic or clinical variable was able to predict the amount of Vr. We observed a significant deviation (>200mL) between both methods of estimation of the capacity of utrafiltration in only 12.9% of the patients. However, 21.1% of the patients categorized as cases of ultrafiltration failure according to the standard procedure did not maintain this condition after correction for Vr. ConclusionsCorrection for Vr of the capacity of ultrafiltration during a PET carries, as a mean, a minor impact on the categorization of this parameter. However, the results of the test can be significantly affected in 12.9% of the cases. We have been unable to detect demographic or clinical predictors of Vr, which suggests a random component for the mechanics of single peritoneal exchanges. We suggest that Vr should be estimated at the time of categorizing the capacity of ultrafiltration, whenever inconsistencies during serial PET studies are detected.

How to Improve the Biocompatibility of Peritoneal Dialysis Solutions (without Jeopardizing the Patient's Health).

Peritoneal dialysis (PD) is an important, if underprescribed, modality for the treatment of patients with end-stage kidney disease. Among the barriers to its wider use are the deleterious effects of currently commercially available glucose-based PD solutions on the morphological integrity and function of the peritoneal membrane due to fibrosis. This is primarily driven by hyperglycaemia due to its effects, through multiple cytokine and transcription factor signalling—and their metabolic sequelae—on the synthesis of collagen and other extracellular membrane components. In this review, we outline these interactions and explore how novel PD solution formulations are aimed at utilizing this knowledge to minimise the complications associated with fibrosis, while maintaining adequate rates of ultrafiltration across the peritoneal membrane and preservation of patient urinary volumes. We discuss the development of a new generation of reduced-glucose PD solutions that employ a variety of osmotically active constituents and highlight the biochemical rationale underlying optimization of oxidative metabolism within the peritoneal membrane. They are aimed at achieving optimal clinical outcomes and improving the whole-body metabolic profile of patients, particularly those who are glucose-intolerant, insulin-resistant, or diabetic, and for whom daily exposure to high doses of glucose is contraindicated.

MO717EFFECT ON BLOOD PRESSURE OF UNCOMPENSATED 130 MM SODIUM DIALYSATE IN CAPD PATIENT WITH RESISTANT HYPERTENSION

Abstract Background and Aims In peritoneal dialysis (PD) blood pressure (BP) control is largely unsatisfied mainly due to sodium retention. Currently, sodium removal in PD patients depends substantially on ultrafiltration. Lowering sodium in PD solution might improve sodium removal by diffusion, though the real benefit of low PD solution remains still undetermined. Method In this case report, we used a novel uncompensated glucose-based PD solution (DextroCore LS, Iperboreal Pharma, Italy) containing 130 mM sodium to treat resistant hypertension in 78-year-old female treated by CAPD (3 dwells glucose 1.5% a day, Na 132). Results At baseline, Ambulatory BP monitoring (ABPM) showed 24h-BP (152/81 mmHg), diurnal BP (151/83 mmHg) and nocturnal BP (153/75 mmHg), with inversion of circadian rhythm in systolic BP (systolic night/day ratio: 1.02), despite the use of three anti-hypertensive (doxazosin 4mg, amlodipine 10 mg, telmisartan 80 mg) and diuretic (furosemide 250 mg) at adequate doses. She had no signs of hypervolemia. We switched from standard PD (132 mM/L) to low sodium PD solution using 1.5% glucose bags with sodium concentration of 130 mM. CAPD schedule was confirmed. Second ABPM after six months reported a reduction 24h BP (131/73 mmHg), diurnal (134/75 mmHg) and nocturnal BP (122/67 mmHg), with restoring of circadian BP rhythm. No change in body weight, UF and residual diuresis was found. Diet and therapy prescriptions were unmodified. No side effects were reported. Conclusion Six-months PD treatment with uncompensated glucose-based PD solution containing 130 mM sodium in all daily dwells has allowed to reduce systolic BP (-16 mmHg) in a CAPD patient affected by resistant hypertension, with no change in ultrafiltration and residual diuresis.

MO900ENHANCED EXPRESSION OF THIOREDOXIN-INTERACTING PROTEIN (TXNIP) RESULTS IN REDUCED TRX ACTIVITY AND INCREASED OXIDATIVE DNA-DAMAGE IN PERITONEAL DIALYSIS PATIENTS*

Abstract Background and Aims Peritoneal dialysis (PD) is an effective method of renal replacement therapy (RRT). The long-term use of PD as a RRT is limited due to adverse effects of high glucose-based PD solutions to the structure and function of the peritoneal membrane. PD patients show excessive oxidative stress compared to healthy controls. However, there are only scare information on pathophysiological mechanisms leading to oxidative DNA-damage in PD patients. Therefore, the aim of this study was to elucidate the mechanism leading to excessive oxidative stress in human samples of the peritoneal membrane. Method Human peritoneal biopsies of healthy controls, PD patients and patients with EPS were collected. Protein expression of TXNIP was analysed by ELISA using plasma samples and by immunohistochemistry of peritoneal biopsies using a Histo-Score. Protein expression of TRX was examined by immunohistochemistry. To measure TRX activity a kit based on the reduction of insulin by reduced TRX was used. The resulting oxidative DNA-damage was investigated by immunohistochemistry using a Histo-Score or by ELISA using plasma samples of patients. Results Biopsies from the peritoneum of 8 healthy controls, 11 uremic patients, 22 patients on PD &amp;lt; 12 months or 29 patients on PD &amp;gt; 12 months and of 13 patients with EPS were collected. The age of the uremic patients was higher (median 65.0 years, IQR: 49.0-75.0) than in the other subgroups (PD &amp;lt; 12 months: median 62.0 years, IQR: 52.25-68.25, PD &amp;gt; 12 months: median 60.0 years, IQR: 39.5-70.5 and EPS: median 51.00 years, IQR: 40.0-57.5). In general, there were more female participants in the control-group (75 %) compared to all other groups (uremic group: 27%, PD &amp;lt; 12 months: 18 %, PD &amp;gt;12 months: 41% and EPS group 33 %). Time on PD was longer in EPS patients (median 72.0 months) than in PD patients (PD &amp;lt;12 months: median 10.0 months and PD &amp;gt; 12 months: 39.0 months). The ELISA study of plasma samples showed that TXNIP is upregulated in all groups compared to healthy controls. Immunohistochemically studies of peritoneal biopsies showed also an upregulation of TXNIP upon exposure to high glucose-based dialysis fluids (PD and EPS group). Interestingly, a glucose-related change in protein expression of its interacting partner and cellular anti-oxidant TRX was only observed in EPS samples. TRX activity in uremic patients was almost unchanged compared to healthy controls except for one patient. However, enhanced TXNIP expression correlated with a reduced activity of TRX in samples of PD as well as EPS patients. Reduced TRX activity resulted in an increase of produced ROS. Therefore, the effect on the generation of oxidative damage was analysed by ELISA of plasma samples and by immunohistochemistry on peritoneal sections. Both analysis showed an increase in the oxidative DNA-damage marker 8-Hydroxydesoxyguanosin (8-OHdG) in all PD samples and samples of EPS patients compared to the control group. Conclusion Here, we show that high glucose-based peritoneal dialysis solutions lead to an upregulation of TXNIP expression in human peritoneal samples. This increase in TXNIP expression reduces the activity of its interacting partner an antioxidant TRX leading to an increase in ROS production and enhanced levels of DNA-damage. In this study, we elucidate for the first time a novel mechanism showing that glucose-dependent upregulation of TXNIP induces a perturbation of the intracellular redox equilibrium leading to alterations of the peritoneal membrane. Therefore, manipulation of TXNIP expression may be a promising therapeutic target to improve peritoneal membrane function.

A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with l-Carnitine Improves Biocompatibility on Human Mesothelial Cells.

The main reason why peritoneal dialysis (PD) still has limited use in the management of patients with end-stage renal disease (ESRD) lies in the fact that the currently used glucose-based PD solutions are not completely biocompatible and determine, over time, the degeneration of the peritoneal membrane (PM) and consequent loss of ultrafiltration (UF). Here we evaluated the biocompatibility of a novel formulation of dialytic solutions, in which a substantial amount of glucose is replaced by two osmometabolic agents, xylitol and l-carnitine. The effect of this novel formulation on cell viability, the integrity of the mesothelial barrier and secretion of pro-inflammatory cytokines was evaluated on human mesothelial cells grown on cell culture inserts and exposed to the PD solution only at the apical side, mimicking the condition of a PD dwell. The results were compared to those obtained after exposure to a panel of dialytic solutions commonly used in clinical practice. We report here compelling evidence that this novel formulation shows better performance in terms of higher cell viability, better preservation of the integrity of the mesothelial layer and reduced release of pro-inflammatory cytokines. This new formulation could represent a step forward towards obtaining PD solutions with high biocompatibility.

P1146ENHANCED EXPRESSION OF THIOREDOXIN-INTERACTING-PROTEIN (TXNIP) MAY REGULATE OXIDATIVE DAMAGE IN PERITONEAL DIALYSIS PATIENTS

Abstract Background and Aims Glucose-based solutions used as peritoneal dialysis fluids influence the peritoneal membrane. Exposure to high glucose-based peritoneal dialysis solutions induces reactive oxygen species (ROS) production due to upregulation of TXNIP as shown by several studies in rats as well as in human primary cells. Enhanced expression of TXINP also regulates oxidative damage. Therefore the aim of this study was to investigate the expression of TXNIP and the extent of oxidative damage in human peritoneal biopsies. Method Human peritoneal biopsies of healthy controls, PD patients and patients with EPS were collected. TXNIP and thioredoxin-1 (TRX) mRNA expression was determined by qPCR. Protein expression and the extent of oxidative damage were examined by immunohistochemistry. Results Biopsies from the peritoneum of 7 healthy controls, 36 patients on PD without signs of EPS as well as of 12 patients with EPS were collected. The age of the healthy controls was higher (median 64.00 years, IQR: 53.00-70.00) than in the other subgroups (PD: median 60.50 years, IQR: 46.00-69.00 and EPS: median 51.00 years, IQR: 38.00-58.75). Furthermore, compared to the PD- (39 %) and EPS-group (33 %), there were more female participants in the control-group (86 %). Time on PD was longer in EPS patients (median 70.00 months) than in PD patients (median 33.50 months). In a preliminary study, exposure to high glucose-based peritoneal dialysis solutions did not markedly influence the mRNA expression of TXNIP and TRX. However, on protein level a significant glucose-related upregulation of TXNIP could be observed especially in PD patients. Interestingly, there was no glucose-related change in protein expression of its interacting partner and cellular anti-oxidant TRX. To study the effect of TXNIP expression on the generation of oxidative damage, pH2AX positive nuclei were counted on peritoneal membrane sections. A slight increase of pH2AX positive nuclei upon exposure to dialysis solutions could be observed in the cohort analysed. Conclusion Here, we show for the first time a clear tendency for upregulation TXNIP in human peritoneal tissue after exposure to high glucose-based peritoneal dialysis solutions especially in PD patients. This increase in TXNIP expression may correlate with the accumulation of oxidative damage of macromolecules. Therefore, manipulation of TXNIP expression may be a promising therapeutic target to improve peritoneal membrane function.

Removal of Protein-Bound Uremic Toxins by Liposome-Supported Peritoneal Dialysis.

Background:Protein-bound uremic toxins (PBUTs) are poorly cleared by peritoneal dialysis (PD). This study aimed to enhance PBUT removal in PD by adding a binder to the peritoneal dialysate and to evaluate the feasibility and efficacy of liposome-supported PD (LSPD) to increase the removal of PBUTs compared with albumin PD.Methods:Removal of p-cresyl sulfate (PCS), indoxyl sulfate (IS), and indole-3-acetic acid (3-IAA) was first evaluated in an in vitro PD model using artificial plasma preloaded with test solutes. Male Sprague-Dawley rats (n = 24) were then subjected to 5/6 nephrectomy and fed for 16 weeks to establish end-stage renal failure, after which they were treated with either conventional glucose-based PD, albumin-based PD, or liposome-based PD. Removal of PBUTs and small water-soluble solutes was determined during a 6-hour PD dwell.Results:In vitro experiments showed that adding albumin as a toxin binder to the dialysate markedly increased the removal of PCS, IS, and 3-IAA compared with the control. The uptake capacity of liposomes was comparable with that of albumin for PCS and 3-IAA, though slightly inferior for IS. In vivo PD in uremic rats demonstrated that LSPD resulted in higher intraperitoneal concentrations and more total mass removal for PBUTs than the conventional glucose-based PD, which was comparable with albumin PD.Conclusions:Supplementing conventional glucose-based PD solutions with a binder could efficiently increase the removal of PBUTs. This preliminary study suggested that LSPD may be a promising alternative to albumin PD for increasing PBUT removal in the development of next-generation PD solutions for PD patients.

The effect of high glucose-based peritoneal dialysis fluids on thioredoxin-interacting protein expression in human peritoneal mesothelial cells

BackgroundIt has been demonstrated that thioredoxin-interacting protein (TXNIP) interacted with NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and participated in the NLRP3 inflammasome activation. Our previous study has demonstrated that in human peritoneal mesothelial cells (HPMCs), exposure to high glucose-based peritoneal dialysis (PD) solutions induced mitochondrial reactive oxygen species (ROS) production, activation of NLRP3 inflammasome and IL-1β expression. This study aimed to investigate the effect of high glucose-based PD fluids on the TXNIP expression and the underlying mechanisms by which TXNIP-NLRP3 interaction mediates the inflammatory injury to HPMCs in high glucose-based PD fluids conditions. MethodsTXNIP gene and protein expression was detected by real-time polymerase chain reaction (RT-PCR) and immunoblot. Immunoprecipitation was used to evaluate the interaction between TRX1 and TXNIP, TXNIP and NLRP3. ROS production and IL-1β expression was examined by flow cytometry and immunoblot and enzyme-linked immunosorbent assay (ELISA) respectively. ResultsIt was identified that high glucose-based PD solutions enhance the level of TXNIP gene and protein in cultured HPMCs and a rat-based PD model. We also found that ROS generation induced by high glucose-based PD solutions disrupts the TRX1-TXNIP association, while promoting the binding of TXNIP to NLRP3 in HPMCs. Furthermore, the application of a ROS inhibitor (APDC) to HPMCs blocked the high glucose-based PD solution-induced TXNIP-NLRP3 binding, in addition to ROS production and IL-1β expression. ConclusionThe results of the present study revealed a novel mechanism underlying high glucose-containing PD-mediated peritoneal inflammatory injury, supporting the attenuation of ROS generation as a potential therapeutic strategy to alleviate such pathology.

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.

"Biocompatible" Neutral pH Low-GDP Peritoneal Dialysis Solutions: Much Ado About Nothing?

Adverse outcomes in peritoneal dialysis (PD), including PD related infections, the loss of residual kidney function (RKF), and longitudinal, deleterious changes in peritoneal membrane function continue to limit the long-term success of PD therapy. The observation that these deleterious changes occur upon exposure to conventional glucose-based PD solutions fuels the search for a more biocompatible PD solution. The development of a novel PD solution with a neutral pH, and lower in glucose degradation products (GDPs) compared to its conventional predecessors has been labeled a "biocompatible" solution. While considerable evidence in support of these novel solutions' biocompatibility has emerged from cell culture and animal studies, the clinical benefits as compared to conventional PD solutions are less clear. Neutral pH low GDP (NpHLGDP) PD solutions appear to be effective in reducing infusion pain, but their effects on other clinical endpoints including peritoneal membrane function, preservation of RKF, PD-related infections, and technique and patient survival are less clear. The literature is limited by studies characterized by relatively few patients, short follow-up time, heterogeneity with regards to the novel PD solution type under study, and the different patient populations under study. Nonetheless, the search for a more biocompatible PD solution continues with emerging data on promising non glucose-based solutions.

Evidence for Biocompatible Peritoneal Dialysis Solutions.

Glucose-based peritoneal dialysis (PD) solutions are the mainstay of therapy for PD patients, yet are accompanied by a number of adverse effects and potential complications. The high glucose content can cause both systemic effects, such as hyperglycaemia, as well as local effects on the peritoneal membrane, which can interfere with its function. In addition, glucose degradation products (GDPs) generated during heat sterilization of the solutions and the acidic pH at which these solutions are kept have been shown to cause peritoneal membrane injury and precipitate inflow pain, respectively. As a result, biocompatible PD solutions, characterized by neutral pH and low GDP concentrations, have been developed. However, the published evidence supporting their use has often been conflicting and of variable methodological quality. This review aims to discuss the relevant literature and up-to-date evidence for the use of biocompatible PD solutions.

Hyperbranched polyglycerol is superior to glucose for long-term preservation of peritoneal membrane in a rat model of chronic peritoneal dialysis.

BackgroundReplacing glucose with a better biocompatible osmotic agent in peritoneal dialysis (PD) solutions is needed in PD clinic. We previously demonstrated the potential of hyperbranched polyglycerol (HPG) as a replacement for glucose. This study further investigated the long-term effects of chronic exposure to HPG as compared to a glucose-based conventional PD solution on peritoneal membrane (PM) structure and function in rats.MethodsAdult male Wistar rats received once-daily intraperitoneal injection of 10 mL of HPG solution (1 kDa, HPG 6%) compared to Physioneal™ 40 (PYS, glucose 2.27%) or electrolyte solution (Control) for 3 months. The overall health conditions were determined by blood chemistry analysis. The PM function was determined by ultrafiltration, and its injury by histological and transcriptome-based pathway analyses.ResultsHere, we showed that there was no difference in the blood chemistry between rats receiving the HPG and the Control, while PYS increased serum alkaline phosphatase, globulin and creatinine and decreased serum albumin. Unlike PYS, HPG did not significantly attenuate PM function, which was associated with smaller change in both the structure and the angiogenesis of the PM and less cells expressing vascular endothelial growth factor, α-smooth muscle actin and MAC387 (macrophage marker). The pathway analysis revealed that there were more inflammatory signaling pathways functioning in the PM of PYS group than those of HPG or Control, which included the signaling for cytokine production in both macrophages and T cells, interleukin (IL)-6, IL-10, Toll-like receptors, triggering receptor expressed on myeloid cells 1 and high mobility group box 1.ConclusionsThe results from this experimental study indicate the superiority of HPG to glucose in the preservation of the peritoneum function and structure during the long-term PD treatment, suggesting the potential of HPG as a novel osmotic agent for PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1098-z) contains supplementary material, which is available to authorized users.

The role of Resveratrol-induced mitophagy/autophagy in peritoneal mesothelial cells inflammatory injury via NLRP3 inflammasome activation triggered by mitochondrial ROS

It has been suggested that continuous exposure of peritoneal mesothelial cells (PMCs) to high glucose-containing peritoneal dialysis (PD) solutions may result in peritoneal inflammatory injury and impairment of local peritoneal host defence. Here, we investigated the effect of glucose-based PD solutions on mitochondrial reactive oxygen species (ROS) and nod-like receptor 3 (NLRP3) inflammasome activation in human PMCs (HPMCs). Exposure of HPMCs to high glucose-based PD solutions resulted in ROS production, which can trigger NLRP3 activation, leading to IL-1β secretion. Additionally, resveratrol (RSV) treatment induced mitophagy/autophagy via adenosine monophosphate-activated protein kinase (AMPK) activation. Increased mitochondrial ROS concentrations and IL-1β upregulation were confirmed following inhibition (siRNA against Beclin1 and ATG5 or autophagy inhibitor 3MA), but not induction (RSV), of mitophagy/autophagy. Furthermore, we observed that ATG5 and Beclin1 downregulation sensitised cells to IL-1β release induced by MSU or nigericin, which is an NLRP3 inflammasome activator. RSV treatment attenuated this effect. Taken together, this study may provide a potential therapeutic strategy for peritoneal inflammatory injury via NLRP3 inflammasome activation triggered by mitochondrial ROS.

Therapeutic mechanisms of adjunct peritoneal resuscitation for the early hepatic injury in rats after hemorrhagic shock

Objective To investigate the therapeutic effect of adjunct peritoneal resuscitation (APR) on the early hepatic injury in rats with hemorrhagic shock in order to explore its possible mechanisms. Methods Ninety-six male Wistar rats were assigned randomly (random number) into control group, shock group, APR1 group and APR2 group. Each group was further divided into 3 subgroups (n=8 in each) as per the animals sacrificed separately at 1 h, 2 h, and 6 h after resuscitation. The rat model of hemorrhagic shock was made by exsanguination under amytal anesthesia and heparinization. The rats in shock group received shed blood plus twice amount of normal saline as conventional intravenous resuscitation (CIR). Besides CIR, at the beginning of resuscitation, those rats in APR1 and APR2 groups were administered intra-peritoneally with 100 mL/kg of Ringer's solution or 2.5% glucose-based peritoneal dialysis solution, respectively. The shock rats in the four groups were sacrificed separately at above mentioned intervals after resuscitation. Liver enzymes and wet/dry weight ratio (W/D) of liver tissue were measured, and pathological changes of liver tissue were observed under optic microscope. The expressions of NF-κB and hot shock protein-70 (HSP70) mRNA in the liver tissue of rats were detected with RT-PCR. All data were statistically analyzed using SPSS 16.0 software. Results Compared with the shock group and APR1 group, the expressions of HSP70 mRNA in the liver tissue of rats at all given intervals after resuscitation in APR2 group increased significantly (P <0.05) , but the W/D ratios of liver tissue at 2 h, 6 h, the degree of pathological changes of liver tissue in 6 h, serum levels of ALT and AST at all given intervals and the expressions of NF-κB mRNA at all given intervals decreased significantly (P <0.05). Conclusions APR with 2.5% glucose-based peritoneal dialysis solution can significantly mitigate the early hepatic injury secondary to hemorrhagic shock, and the mechanisms may be associated with enhancement the expressions of HSP70 mRNA and inhibition the expressions of NF-κB mRNA. Key words: Adjunct peritoneal resuscitation; Hemorrhagic shock; Nulear factor kappa B; Heat- shock protein 70; Hepatic lesion; Peritoneal dialysis fluid; Liver function; Wet/dry weight ratio (W/D) of liver tissue

Update on Peritoneal Dialysis: Core Curriculum 2016

Update on Peritoneal Dialysis: Core Curriculum 2016