Peritoneal dialysis challenges and solutions for continuous quality improvement.

Heat sterilization of peritoneal dialysis solutions influences ingestive behavior in non-uremic rats

Conventional peritoneal dialysis (PD) solutions elicit vasodilation, which is implicated in the variable rate of solute transport during the dwell. The components causing such vasoactivity are still controversial. This study was conducted to define the vasoactive components of conventional and new PD solutions. Three visceral peritoneal microvascular levels were visualized by intravital video microscopy of the terminal ileum of anesthetized rats. Anesthesia-free decerebrate conscious rats served as control. Microvascular diameter and blood flow by Doppler measurements were conducted after topical peritoneal exposure to 4 clinical PD solutions and 6 prepared solutions designed to isolate potential vasoactive components of the PD solution. All clinically available PD solutions produced a rapid and generalized vasodilation at all intestinal microvascular levels, regardless of the osmotic solute. The pattern and magnitude of this dilation was not affected by anesthesia but was determined by arteriolar size, the osmotic solute, and the solution's buffer anion system. The greatest dilation occurred in the small precapillary arterioles and was elicited by conventional PD solution and heat re-sterilized solution containing low glucose degradation products (GDPs). Hypertonic mannitol solutions produced a dilation that was approximately 50% less than the dilation obtained with glucose solutions with identical osmolarity and buffer. Increasing a solution's osmolarity did not produce a parallel increase in the magnitude of dilation, suggesting a nonlinear relationship between the two variables. Lactate dissolved in an isotonic solution was completely non-vasoactive unless the solution's H(+) concentration was increased. At low pH, isotonic lactate produced a rapid but transient vasodilation. This vascular reactivity was similar in magnitude and pattern to that obtained with the isotonic 7.5% icodextrin solution (Extraneal; Baxter Healthcare, Deerfield, Illinois, USA). (1) Hyperosmolarity is the major vasoactive component of PD solution. (2) Hyperosmolarity and active intracellular glucose uptake account together for approximately 75% of PD solution-induced dilation, whereas GDPs contribute to approximately 25%. (3) Lactate is vasoactive only at low pH (high [H(+)]). (4) The magnitude of PD solution-mediated vasodilation is partially dependent on the nature of the osmotic solute, the GDP contents, and the [H(+)], which determine the vasoactivity of the lactate-buffer anion system. Studies are required to define the molecular mechanisms of PD-induced vasodilation and to determine the vasoactive properties of these solutions after chronic infusion.

Objective To explore the potential mechanisms of low density lipoprotein receptor (LDLr) in high glucose peritoneal dialysis solution (PDS)-induced peritoneal fibrosis. Methods Human peritoneal mesothelial cells (PMCs) were applied. In pre-experiment, human PMCs were cultured with 1.5% PDS, 2.5% PDS and 4.25% PDS for 6 h, 12 h and 24 h. 4.25% mannitol was used as high osmotic pressure control. In formal experiment, PMCs were divided into the control group(treated with phosphate buffer saline) and the high glucose PDS group (treated with 4.25% PDS for 24 h). Morphological change of PMCs was observed by inverted microscope. The mRNA and protein expressions of extracellular matrix proteins such as α-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1) and collagenⅠ in PMCs were respectively measured by real-time PCR and Western blotting. The lipid accumulation was observed by oil red O staining and filipin staining, and the content of intracellular cholesterol ester was detected by high-performance liquid chromatography. The co-expression of the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) with golgin was observed with immunofluorescent staining. The mRNA and protein expressions of LDLr, SREBP-2 and SCAP were respectively detected by real-time PCR and Western blotting. The mRNA and protein expressions of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and p70 S6 kinase (S6K1) were respectively detected by real-time PCR and Western blotting. Results (1) Compared with the 1.50% PDS stimulation, 4.25% PDS for 24 h intervention significantly increased the expression of LDLr in PMCs (P 0.05). (2) Compared with those in the control group, in high glucose PDS group PMCs showed notable elongation consistent with the morphology of myofibroblasts, the expressions of α-SMA, FSP-1 and collagen Ⅰ were increased (all P<0.05), and the intracellular cholesterol were enhanced (P<0.05). Meanwhile, the co-expression of SCAP with golgin was enhanced, and the mRNA and protein expressions of LDLr, SREBP-2 and SCAP were up-regulated in high glucose PDS group (all P<0.05). Further, the mRNA and protein phosphorylation of mTOR, 4EBP1 and S6K1 were increased (all P<0.05). Conclusions The disruption of LDLr feedback regulation is involved in high glucose PDS-mediated cholesterol accumulation in PMCs by mammalian target of rapamycin complex 1 (mTORC1) pathway, which promotes the accumulation of extracellular matrix and peritoneal fibrosis. Key words: Peritoneal dialysis; Receptors, LDL; Intracellular signaling peptides and proteins; Retroperitoneal fibrosis; Mechanistic target of rapamycin complex 1

Update on Peritoneal Dialysis: Core Curriculum 2016

BackgroundRepeated exposure to peritoneal dialysis (PD) solutions contributes to cumulative intraperitoneal inflammation and peritoneal injury. The present study aimed to explore the capacity of dialysate interleukin-6(IL-6) to a) predict peritoneal membrane function and peritonitis in incident PD patients, and b) to evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solution on dialysate IL-6 levels.MethodsThe study included 88 incident participants from the balANZ trial who had completed 24-months of follow-up. Change in peritoneal solute transport rate (PSTR) and peritonitis were primary outcome measures, and the utility of IL-6 and IL-6 appearance rate (IL-6 AR) in predicting these outcomes was analyzed using multilevel linear regression and Cox proportional hazards models, respectively. Sensitivity analyses were performed by analyzing outcomes in a peritonitis-free cohort (n = 56).ResultsDialysate IL-6 concentration significantly increased from baseline to 24 months (mean difference 19.07 pg/mL; P < 0.001) but was not affected by the type of PD solution received (P = 0.68). An increase in PSTR from baseline was associated with higher levels of IL-6 (P = 0.004), the use of standard solutions (P = 0.005) and longer PD duration (P < 0.001). Baseline IL-6 level was not associated with a shorter time to first peritonitis (adjusted hazard ratio 1.00, 95% CI 0.99-1.00, P = 0.74). Analysis of IL-6 AR as well as sensitivity analyses in a peritonitis-free cohort yielded comparable results.ConclusionDialysate IL-6 concentration increased with longer PD duration and was a significant, independent predictor of PSTR. The use of biocompatible PD solutions exerted no significant effect on dialysate IL-6 levels but did abrogate the increase in PSTR associated with standard PD solutions. This is the first study to examine the impact of biocompatible solutions on the utility of IL-6 in predicting PSTR and peritonitis.

This article reviews current knowledge on the usefulness of glycylglycine in preparing single stable hemodialysis (HD) and peritoneal dialysis (PD) solutions containing bicarbonate. The coexistence of bicarbonate and glycylglycine in a dialysis solution renders it a potent, stable buffer in which the well known reactions between bicarbonate and calcium and magnesium, and the subsequent formation of insoluble neutral calcium and magnesium carbonate salts, are avoided. Single stable bicarbonate-glycylglycine (BiGG) solutions for HD and PD have been successfully prepared and studied, both experimentally and clinically. These studies have demonstrated the advantages of BiGG solutions in terms of simplicity, stability, convenience, tolerance, biocompatibility, protection of the peritoneum, and higher ultrafiltration, compared to standard acetate or lactate solutions, and on-line prepared bicarbonate solutions. Progressive accumulation of glycylglycine or glycine, even after prolonged use, side effects, or signs of toxicity were not observed. In conclusion, BiGG solutions ensure a physiologic dialysis both from the theoretic and practical points of view.

Chronic exposure to sterile peritoneal dialysis (PD) solutions is associated with microvascular and interstitial changes within the blood-peritoneal barrier (peritoneum). These changes are commonly linked to loss of peritoneal function over time, presumably because of angiogenesis-related increased vascular area. However, the effects on peritoneal microvascular function of chronic peritoneal exposure to PD solutions are unknown. The present study examined peritoneal microvascular function after chronic exposure to sterile PD solution. Six rats underwent permanent catheter insertion under anesthesia. Three rats were treated with approximately 16 mL conventional PD solution daily for 6 weeks; catheter insertion controls received 1 mL saline daily. At 6 weeks, visceral peritoneal microvascular function was assessed in vivo using intravital microscopy. Endothelial cell functions were assessed using messenger RNA (mRNA) gene microarray analysis. In both groups, significant angiogenesis was seen, predominantly in the base of the mesentery. Sensitivity and reactivity of the intestinal visceral peritoneal pre-capillary arterioles (A3 arterioles, 8 - 15 microm in diameter) were decreased in the catheter controls, but not in the chronic PD infusion rats. Chronic catheter presence increased the expression of 18 genes in the controls as compared with 12 genes in the chronic infusion rats. In both groups, expression of fibronectin, integrin-beta, integrin-alpha5, collagen type XVIII-alpha1, and matrix metalloproteinase was enhanced. Endothelial expression of proinflammatory genes (interleukin-1beta, tissue pathway inhibitor, chemokine ligand 2) was enhanced by chronic catheter insertion, but not after chronic PD fluid infusion. Increased expression of genes encoding proteins involved in inflammation and tissue remodeling results from peritoneal catheter-related endothelial cell activation. Chronic exposure of the nonuremic peritoneum to sterile PD solutions overrides the catheter-related endothelial cell proinflammatory phenotype to restore peritoneal microvascular function.

To determine the biocompatibility of a peritoneal dialysis (PD) solution containing amino acids compared to PD solutions containing glucose. The biocompatibility of three dialysis solutions containing 1.1% amino acids, 1.36% glucose, and 3.86% glucose, respectively, was evaluated in vivo in rabbits. After 60 days of PD, peritoneal histological changes in rabbits were investigated by light and transmission electron microscopy. The parameters investigated were: (1) mesothelial damage; (2) submesothelial edema; (3) submesothelial cell infiltration; (4) submesothelial fibrosis; and (5) vascular alterations. Semiquantitative evaluations were performed for all the above alterations; quantitative morphometric evaluation was performed for mesothelial damage (cubic transformation of the mesothelium, areas devoid of mesothelium, submesothelial edema) and thickness of peritoneal arteriole walls. (1) Mesothelial damage was practically nonexistent in rabbits dialyzed with the solution containing amino acids, and intermediate and severe with low-glucose and high-glucose solutions, respectively. Both controls and rabbits dialyzed with amino acid solution showed flat continuous mesothelium; rabbits dialyzed with low-glucose solution showed cubic continuous mesothelium; and rabbits dialyzed with high-glucose solution showed cubic discontinuous mesothelium. Cytopathic mesothelial effects were slight with the solution containing amino acids and severe with both the low- and high-glucose solutions. Duplication and thickening of mesothelial basement membrane were never observed. (2) Submesothelial edema showed a worsening trend from controls to rabbits dialyzed with solution containing amino acids, low glucose, and high glucose. (3) No difference in submesothelial infiltration was found between groups. (4) Submesothelial fibrosis was never observed. (5) Vascular alterations were never observed. These results are evidence that PD solution with amino acids is more biocompatible than high- and also low-glucose solutions.

♦ The longitudinal trends of lipid parameters and the impact of biocompatible peritoneal dialysis (PD) solutions on these levels remain to be fully defined. The present study aimed to a) evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solutions on serum lipid parameters, and b) explore the capacity of lipid parameters (total cholesterol [TC], triglyceride [TG], high density lipoprotein [HDL], TC/HDL, low density lipoprotein [LDL], very low density lipoprotein [VLDL]) to predict cardiovascular events (CVE) and mortality in PD patients. ♦ The study included 175 incident participants from the balANZ trial with at least 1 stored serum sample. A composite CVE score was used as a primary clinical outcome measure. Multilevel linear regression and Poisson regression models were fitted to describe the trend of lipid parameters over time and its ability to predict composite CVE, respectively. ♦ Small but statistically significant increases in serum TG (coefficient 0.006, p < 0.001), TC/HDL (coefficient 0.004, p = 0.001), and VLDL cholesterol (coefficient 0.005, p = 0.001) levels and a decrease in the serum HDL cholesterol levels (coefficient -0.004, p = 0.009) were observed with longer time on PD, whilst the type of PD solution (biocompatible vs standard) received had no significant effect on these levels. Peritoneal dialysis glucose exposure was significantly associated with trends in TG, TC/HDL, HDL and VLDL levels. Baseline lipid parameter levels were not predictive of composite CVEs or all-cause mortality. ♦ Serum TG, TC/HDL, and VLDL levels increased and the serum HDL levels decreased with increasing PD duration. None of the lipid parameters were significantly modified by biocompatible PD solution use over the time period studied or predictive of composite CVE or mortality.

Establishment of colonic dialysis model in uremic rats by right nephrectomy and left partial nephrectomy

BackgroundThe balANZ trial recently reported that neutral pH, low glucose degradation product (biocompatible) peritoneal dialysis (PD) solutions significantly delayed anuria and reduced peritonitis rates compared with conventional solutions. This article reports a secondary outcome analysis of the balANZ trial with respect to peritoneal membrane function.MethodsAdult, incident PD patients with residual renal function were randomized to receive either biocompatible or conventional (control) PD solutions for 2 years. Peritoneal equilibration tests were performed at 1, 6, 12, 18 and 24 months. Peritoneal small solute clearances and ultra-filtration (UF) were measured at 3, 6, 9, 12, 18 and 24 months.ResultsOf the 185 patients recruited into the trial, 85 patients in the Balance group and 82 patients in the control group had peritoneal membrane function evaluated. Mean 4-h dialysate:plasma creatinine ratios (D:P Cr 4h) at 1 month were significantly higher in the Balance group compared with controls (0.67 ± 0.10 versus 0.62 ± 0.10, P = 0.002). Over the 2-year study period, mean D:P Cr 4 h measurements remained stable in the Balance group but increased significantly in controls [difference −0.004 per month, 95% confidence interval (95% CI) −0.005 to −0.002, P < 0.001]. Similar results were obtained for dialysate glucose ratios (D/D0 glucose). Peritoneal UF was significantly lower in the Balance group than in controls at 3 and 6 months. Over the 2-year study period, peritoneal UF increased significantly in the Balance group but remained stable in controls (difference 24 mL/day/month, 95% CI 9–39, P = 0.002). No differences in peritoneal small solute clearances, prescribed dialysate fill volumes or peritoneal glucose exposure were observed between the two groups.ConclusionsBiocompatible and conventional PD solutions exert differential effects on peritoneal small solute transport rate and UF over time. Adequately powered trials assessing the impact of these differential membrane effects on PD technique and patient survival rates are warranted.

Background: Peritoneal dialysis (PD) solutions contribute to peritoneal membrane damage. We investigated how conventional and biocompatible PD solutions with different glucose concentrations affect morphological and functional signs of peritoneal fibrosis as well as the TGF-β1/Smad signaling pathway in a chronic PD rat model. Methods: Non-uremic male Wistar rats (n = 28) were dialyzed thrice daily for 28 days with 20 ml of a conventional solution (Dianeal® 1.36%, D1, or 3.86%, D3) or a biocompatible solution (Physioneal® 1.36%, P1, or 3.86%, P3). A peritoneal equilibration test was performed. Six rats without dialysis served as controls. Results: The use of conventional solutions, particularly D3, resulted in expansion of the submesothelial compact zone, loss of mesothelial cell layer integrity, hypercellularity, accumulation of collagen I, increased vessel numbers and increased TGF-β1/Smad expression, but this did not significantly change fluid and solute peritoneal transport characteristics. In comparison with D1 and D3, the use of P1 and P3 was associated with less TGF-β1/Smad expression and less expansion of the submesothelial cell layer. Conclusions: Our findings indicate that biocompatible solutions with less glucose may decrease the rate of peritoneal fibrosis. The TGF-β1/Smad pathway is stimulated by PD solutions, representing a plausible pathophysiological mechanism.

Background: Glucose-free dialysis solutions may be more biocompatible owing to the physiological pH and the lack of glucose degradation products, and the effects can be reflected by the changes in some markers of peritoneal mesothelial cells (PMC). Method: Peritoneal effluents were collected in 17 CAPD patients after one daily exchange of glucose-containing dialysate to Nutrineal (1.1% amino acid-based PDF), and human PMC were cultured from peritoneal effluent and treated with various peritoneal dialysis (PD) solutions. Results: The level of cancer antigen 125 (CA125) in peritoneal effluent increased significantly after using Nutrineal® for 3 months (p = 0.045), whereas that of procollagen I peptide (PICP) remained unaltered. Production of CA125 by human PMC showed a time-responsive increase after stimulation with Nutrineal and Extraneal (icodextran-based PDF). An increased expression of CA125 was observed in cultured human PMC treated with various PD solutions, and the increase induced by Nutrineal was lower than that induced by 4.25% Dianeal® and Extraneal®. A lower increase was also observed for lactate dehydrogenase (LDH). The levels of heat shock protein 70 (HSP70), however, were not altered. Conclusion: Nutrineal is more biocompatible to the peritoneal membrane than the conventional PD solutions tested herein, reflected by both the in vivo and in vitro response of CA125.

The objective of this study was to investigate the stability of ceftazidime and cephazolin in a 7.5% icodextrin or pH neutral peritoneal dialysis (PD) solution. Ceftazidime and cephazolin were injected into either a 7.5% icodextrin or pH neutral PD bag to obtain the concentration of 125 mg/L of each antibiotic. A total of nine 7.5% icodextrin or pH neutral PD bags containing ceftazidime and cephazolin were prepared and stored at 1 of 3 different temperatures: 4°C in a domestic refrigerator; 25°C at room temperature; or 37°C (body temperature) in an incubator. An aliquot was withdrawn immediately before (0 hour) or after 12, 24, 48, 96, 120, 144, 168 and 336 hours of storage. Each sample was analyzed in duplicate for the concentration of ceftazidime and cephazolin using a stability-indicating high-performance liquid chromatography technique. Ceftazidime and cephazolin were considered stable if they retained more than 90% of their initial concentration. Samples were also assessed for pH, colour changes and evidence of precipitation immediately after preparation and on each day of analysis. Ceftazidime and cephazolin in both types of PD solution retained more than 90% of their initial concentration for 168 and 336 hours respectively when stored at 4°C. Both of the antibiotics lost more than 10% of the initial concentration after 24 hours of storage at 25 or 37°C. There was no evidence of precipitation at any time under the tested storage conditions. Change in the pH and color was observed at 25 and 37°C, but not at 4°C. Premixed ceftazidime and cephazolin in a 7.5% icodextrin or pH neutral PD solution is stable for at least 168 hours when refrigerated. This allows the preparation of PD bags in advance, avoiding the necessity for daily preparation. Both the antibiotics are stable for at least 24 hours at 25 and 37°C, permitting storage at room temperature and pre-warming of PD bags to body temperature prior to its administration.

Peritoneal dialysis (PD) solutions using glucose as osmotic agent have been used for more than two decades as effective treatment for patients with end-stage renal disease. Although alternative osmotic agents such as amino acids and macromolecular solutions, including polypeptides and glucose polymers, are now available, glucose is still the most widely used osmotic agent in PD. It has been shown to be safe, effective, readily metabolized, and inexpensive. On the other hand, it is widely assumed that exposure of the peritoneal membrane to high glucose concentrations contributes to both structural and functional changes in the dialyzed peritoneal membrane. As in diabetes, glucose, either directly or indirectly through the generation of glucose degradation products or the formation of advanced glycation end products, may contribute to peritoneal membrane failure. Although efforts to reduce glucose toxicity have been made for years, only a few suggestions, such as dual-bag systems with bicarbonate as buffer system, have found broader acceptance. Recently, some interesting new approaches to the problem of glucose-related toxicity have been made, but further investigations will be necessary before they can be used clinically. This review will focus on adverse effects of glucose in PD solutions and summarize different aspects of glucotoxicity and potential therapeutic interventions.