Concentrations Of Glucose Degradation Products Research Articles

#6062 EFFECT OF KIDNEY TRANSPLANTATION ON ARTERIOLAR MOLECULAR PATHWAYS IN CHILDREN WITH PRECEDING PERITONEAL DIALYSIS

Abstract Background and Aims Patients on peritoneal dialysis suffer from progressive peritoneal membrane transformation and accelerated vascular disease, underlying molecular machineries have recently been described. Molecular effects of kidney transplantation (KTx) on vascular and peritoneal pathophysiology following PD are hardly understood. Method Fat surrounded omental arterioles (i.e. not directly exposed to PD fluids) from age-matched (median 6,5 years) children with chronic kidney disease (CKD5, n = 8), 5 children on PD [neutral pH, low glucose degradation product content, median PD duration 22 (5,50) months] and 6 children, who underwent successful KTx 4-5 weeks after a median 22 (12, 36) months of PD were analyzed by digital histomorphometry. Following microdissection from fat tissue, arterioles underwent transcriptome and proteome analyses, followed by Gene Set Enrichment Analysis (GSEA), weighted gene co-expression network analysis (WGCNA), gene ontology (GO) and protein interaction analysis (string-db.org). Key pathways were validated in independent, matched cohorts by quantitative immunohistochemistry (n = 15/group) and in vitro. Results 5000 most variable arteriolar transcripts (cut off p-value<0.05 and |r| >0.5) were grouped into 23 modules by WGCNA, of which 8 significantly differed between CKD5, PD and KTx. Seven were specifically related to KTx and one module to PD. Four out of seven KTx specific modules resulted in significant GO terms summarized as fatty acid biosynthesis, negative regulation of RNA metabolism, cell cycle arrest, and apoptosis. The PD specific module was associated with muscle cell proliferation, detoxification and complement activation (with thrombospondin as most interconnected gene). Multi-omics analysis of KTx vs. PD demonstrated concordant upregulation of lipid and fatty acid biosynthesis with the hub gene fatty acid synthase (FASN) and downregulation of positive cell cycle regulation. In independent, matched cohorts, arteriolar abundance of thrombospondin and terminal complement complex were higher in children on PD, arterioles from children after KTx had levels comparable to arterioles from children with CKD5. Key drivers of fibrotic process, arteriolar TGF-ß and pSMAD2/3, were also higher in PD arterioles compared to CKD5 and persistently high after KTx. Arteriolar cell cycle arrest marker p16 and apoptosis marker cleaved Casp3 were higher after KTx as compared to PD and CKD5. FASN was abundant in intima and media layers of all arterioles, and three-fold higher after KTx then in children with PD and CKD5, respectively. Neutral lipids (oil red staining) were present in all three groups, more abundant in the media than in the intima, and two-fold increased in the media of children after KTx compared to children on PD (p = 0.018) and with CKD5 (p = 0.002). In vitro, methylprednisolone and tacrolimus, but not mycophenolate mofetil increased FASN abundance and activity in human umbilical arterial endothelial and vascular smooth muscle cells compared to media controls. Conclusion We for the first time comprehensively describe molecular pathways activated after KTx in children following a standard immunosuppressive regime. After KTx, arteriolar fatty acid biosynthesis, apoptosis and cell cycle arrest markers are increased as compared to arterioles from children with PD and CKD5; profibrotic pathways induced by PD are persistently activated. Arteriolar hubgene FASN is three-fold more abundant after KTx and neutral lipid deposition is increased, presumably due to the induction of FASN activity by methylprednisolone and tacrolimus.

MO714: PARK7—A Novel Therapeutic Target for Peritoneal Dialysis Induced Peritoneal Membrane and Vascular Transformation

Abstract BACKGROUND AND AIMS Patients with chronic kidney disease (CKD) suffer from increased oxidative stress, which is further aggravated in patients on peritoneal dialysis (PD). Parkinson disease protein 7 (PARK7) has antioxidant and antiapoptotic activity; its role in PD is unknown. METHOD Transcriptome and proteome data sets from microdissected omental arterioles obtained from age-matched non-CKD children, children with CKD5 and children on PD with fluids containing low or high concentrations of glucose degradation products (GDP; n = 6/group) underwent PARK7 related gene set analysis (FDR < 0.05). Respective parietal peritoneal tissues (n = 60) underwent digital histomorphometry analyses. PARK7 western blotting was performed in effluents of eight children on high-GDP PD. Human umbilical endothelial cells (HUVEC) viability (MTT assay) and transepithelial electrical resistance (TER, Transwells) and 4-, 10- and 70-kDa dextran transport were measured (n = 6–12/group). As an extreme phenotype approach of PD toxicity, C57/BL6J mice were treated with chlorhexidine digluconate (CG) and PARK7 activator for 7 days and parietal peritoneal damage was quantitated (n = 6–8/group). RESULTS Arteriolar transcriptome analyses in children on low-GDP PD demonstrated the enrichment of PARK7 related GO terms of oxidant detoxification as compared to CKD5 and in children on high-GDP PD that of reactive oxygen species-, mitochondria- and apoptosis-related processes. On the proteome level the DNA repair/organization, catabolic and mitochondria associated processes were enriched in children on low-GDP PD, and mitochondrial processes in children on high-GDP PD. PARK7 was detected in the parietal peritoneal tissues in mesothelial, endothelial and inflammatory cells, in myocytes and fibroblasts and was present in the PD effluents. Total peritoneal and submesothelial PARK7 abundance was similar in controls, patients with CKD5 and in patients on low-GDP PD, but 2-fold increased in patients on high GDP PD compared to controls and CKD5. Mesothelial PARK7 was 2-fold increased in children on low-GDP PD versus CKD5, endothelial PARK7 abundance was similar in all four groups. In low-GDP PD patients endothelial PARK7 abundance correlated with vessel lumen/vessel diameter ratio (r = 0.53, P = 0.06), i.e. inversely with lumen obliteration. Submesothelial PARK7 correlated with microvessel density (r = 0.55, P = 0.05), with submesothelial hypoxia inducible factor-1 and angiopoietin-1 and -2 (ρ = 0.63, P = 0.023; r = 0.91, P < 0.0001; r = 0.60, P = 0.03) but not with VEGF. Submesothelial and endothelial PARK7 correlated with respective caspase 3 abundances (r = 0.74/0.68, P = 0.009/0.015). In HUVEC methylglyoxal (MG) dose- and time-dependently reduced viability, coincubation with PARK7 activator partially preserved endothelial cell viability. In Transwells, MG treatment decreased TER and increased dextran transport, but none of them was improved by PARK7 activation. In mice treated with CG submesothelial thickness was 2-fold increased, microvessel density was unchanged; PARK7 protein abundance was 5-fold reduced. Co-treatment of CG with PARK7 activator prevented the submesothelial thickening. CONCLUSION PD modifies arteriolar PARK7 related biological processes of oxidant detoxification, mitochondria- and apoptosis-related processes. PARK7 is ubiquitously expressed in the parietal peritoneum and regulated by the GDP content of PD fluids. In patients on low-GDP PD, PARK7 abundance correlated with the degree of arteriolar lumen narrowing, and VEGF-independent angiogenesis. Activation of PARK7 preserves endothelial cell viability in vitro and prevents CG induced peritoneal membrane damage in mice and thus represents a potential novel therapeutic approach.

Degradation and de novo formation of nine major glucose degradation products during storage of peritoneal dialysis fluids

Reactive glucose degradation products (GDPs) are formed during heat sterilization of glucose-containing peritoneal dialysis fluids (PDFs) and may induce adverse clinical effects. Long periods of storage and/or transport of PDFs before use may lead to de novo formation or degradation of GDPs. Therefore, the present study quantified the GDP profiles of single- and double-chamber PDFs during storage. Glucosone, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal, methylglyoxal (MGO), acetaldehyde, formaldehyde, and 5-hydroxymethylfurfural (5-HMF) were quantified by two validated UHPLC-DAD methods after derivatization with o-phenylenediamine (dicarbonyls) or 2,4-dinitrophenylhydrazine (monocarbonyls). The PDFs were stored at 50 °C for 0, 1, 2, 4, 13, and 26 weeks. The total GDP concentration of single-chamber PDFs did not change considerably during storage (496.6 ± 16.0 µM, 0 weeks; 519.1 ± 13.1 µM, 26 weeks), but individual GDPs were affected differently. 3-DG (− 82.6 µM) and 3-DGal (− 71.3 µM) were degraded, whereas 5-HMF (+ 161.7 µM), glyoxal (+ 32.2 µM), and formaldehyde (+ 12.4 µM) accumulated between 0 and 26 weeks. Acetaldehyde, glucosone, MGO, and 3,4-DGE showed time-dependent formation and degradation. The GDP concentrations in double-chamber fluids were generally lower and differently affected by storage. In conclusion, the changes of GDP concentrations during storage should be considered for the evaluation of clinical effects of PDFs.

Safety of electrooxidation for urea removal in a wearable artificial kidney is compromised by formation of glucose degradation products

A major challenge for the development of a wearable artificial kidney (WAK) is the removal of urea from the spent dialysate, as urea is the waste solute with the highest daily molar production and is difficult to adsorb. Here we present results on glucose degradation products (GDPs) formed during electrooxidation (EO), a technique that applies a current to the dialysate to convert urea into nitrogen, carbon dioxide, and hydrogen gas. Uremic plasma and peritoneal effluent were dialyzed for 8 hours with a WAK with and without EO‐based dialysate regeneration. Samples were taken regularly during treatment. GDPs (glyoxal, methylglyoxal, and 3‐deoxyglucosone) were measured in EO‐ and non‐EO‐treated fluids. Glyoxal and methylglyoxal concentrations increased 26‐ and 11‐fold, respectively, in uremic plasma (at [glucose] 7 mmol/L) and 209‐ and 353‐fold, respectively, in peritoneal effluent (at [glucose] 100 mmol/L) during treatment with EO, whereas no change was observed in GDP concentrations during dialysate regeneration without EO. EO for dialysate regeneration in a WAK is currently not safe due to the generation of GDPs which are not biocompatible.

Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis.

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FC 102PD INDUCED ARTERIOLAR AND PERITONEAL PATHOMECHANISMS ARE PARTIALLY REVERSED AFTER KIDNEY TRANSPLANTATION

Abstract Background and Aims Due to the unphysiological composition of PD fluids, chronic peritoneal dialysis (PD) induces progressive peritoneal fibrosis, hypervascularization, and vasculopathy. The evolution of the PD membrane and vasculopathy following kidney transplantation (KTx) is largely unknown. Method Arteriolar and peritoneal tissues were obtained from 107 children with chronic kidney disease (CKD5), 72 children on PD (treated with neutral pH PD fluids, with low glucose degradation product content, GDP) and 21 children, who underwent KTx 4-5 weeks after a median 21 months of PD. Specimen underwent standardized digital quantitative histomorphometry. Molecular mechanisms were studied in omental arterioles microdissected from surrounding fat by multi-omics followed by Gene Set Enrichment Analysis (GSEA); key findings were validated in parietal tissues of independent, matched cohorts by quantitative immunohistochemistry (n=15/group). Results Arteriolar transcriptome and proteome GSEA revealed suppression of leucocyte migration and T-cell activation / secretory pathways regulation, of sprouting angiogenesis biological processes and of epithelial proliferation and cell cycle after KTx as compared to PD. Lipid / fatty acid metabolism, autophagy and ATP synthesis pathways were activated. Transcriptome analysis including KTx, PD and CKD5 specifically attributed regulation of arteriolar lipid and fatty acid metabolism to transplantation and comprised 140 transcripts; their regulation was confirmed on the proteome level. Hub gene fatty acid synthase was identified by protein interaction analysis (string-db.org). 15 arteriolar genes activated by PD were inactivated after KTx and included glucose metabolisms and cytoskeleton related transcripts. 24 transcripts and 10 corresponding proteins induced by PD were still active after KTx and associated with biological processes related to TGF-ß signaling, fibrosis and mineral absorption. In line with arteriolar multi-omics findings, peritoneal hypervascularization induced by chronic PD was reversed after Tx to CKD5 level. CD45 positive tissue infiltrating leucocytes count was reduced by 40% and was independently associated with microvessel density in multivariable analysis including PD vintage, daily GDP exposure and recent KTx. Peritoneal lymphatic vessel density, submesothelial thickness, activated fibroblast, fibrin deposit, macrophage and EMT cell counts remained unchanged after KTx compared to PD. Arteriolar lumen to vessel ratios (a marker of vasculopathy) were similar in both groups. Vessel-homeostasis-related proteins in independent, matched cohorts demonstrated increased caspase-3 abundance in peritoneal arterioles after KTx. Arteriolar VEGF-A, thrombospondin, angiopoietin1/2, and hypoxia-inducible factor-1 (HIF-1a) were unchanged, while submesothelial HIF-1a and angiopoietin1/2 were decreased after Tx, favoring vessel maturation. The abundance of the key driver of fibrosis, TGF-ß-effector pSMAD2/3, was unchanged in the peritoneum and arterioles after Tx. Conclusion Our multi-omics analyses of fat covered omental arterioles, not directly exposed to PD fluids, demonstrate inhibition of PD induced immune response and angiogenesis pathways, of glucose metabolism and cytoskeleton regulation to levels similar as seen in children with CKD5. Arteriolar lipid and fatty acid metabolism is selectively altered after KTx. Reversal of low GDP PD induced hypervascularization and inflammation of the parietal peritoneum after KTx, mirror molecular changes in omental arterioles, while profibrotic activity persists after KTx in omental arterioles and in the parietal peritoneum.

Metal cations promote \u03b1-dicarbonyl formation in glucose-containing peritoneal dialysis fluids

Heat sterilization of peritoneal dialysis fluids (PDFs) leads to the formation of glucose degradation products (GDPs), which impair long-term peritoneal dialysis. The current study investigated the effects of metal ions, which occur as trace impurities in the fluids, on the formation of six major α-dicarbonyl GDPs, namely glucosone, glyoxal, methylglyoxal, 3-deoxyglucosone, 3-deoxygalactosone, and 3,4-dideoxyglucosone-3-ene. The chelation of metal ions by 2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA) during sterilization significantly decreased the total GDP content (585 μM vs. 672 μM), mainly due to the decrease of the glucose-oxidation products glucosone (14 μM vs. 61 μM) and glyoxal (3 μM vs. 11 μM), but also of methylglyoxal (14 μM vs. 31 μM). The glucose-dehydration products 3-deoxyglucosone, 3-deoxygalactosone, and 3,4-dideoxyglucosone-3-ene were not significantly affected by chelation of metal ions. Additionally, PDFs were spiked with eleven different metal ions, which were detected as traces in commercial PDFs, to investigate their influence on GDP formation during heat sterilization. Iron(II), manganese(II), and chromium(III) had the highest impact increasing the formation of glucosone (1.2–1.5 fold increase) and glyoxal (1.3–1.5 fold increase). Nickel(II) and vanadium(III) further promoted the formation of glyoxal (1.3 fold increase). The increase of the pH value of the PDFs from pH 5.5 to a physiological pH of 7.5 resulted in a decreased formation of total GDPs (672 μM vs 637 μM). These results indicate that the adjustment of metal ions and the pH value may be a strategy to further decrease the content of GDPs in PDFs.

Production of Glucose from Waste Bark Acacia Mangium Using Delifnification and Chemical Hydrolysis Process

The bark of Acacia mangium is lignocellulosic biomass from waste pulp which can be recovered by means of hydrolyse to produce simple sugar called glucose. To produce glucose, there are two stages of the process performed is process using solvent delignification NaOH and KOH. The parameters analyzed were the biomass with a solvent ratio (1:6, 1:8, 1:10, 1:12). The second stage cellulose is then hydrolyzed to see the influence of sulfuric acid concentration of the resulting glucose content (0.1; 0.25; 0.40; 0.55% (v/v)).Lignin removal efficiency using NaOH and KOH solvent that is almost equal to 62.39%. Decrease hemicellulose using KOH solvent (36%) are more efficient than solvent only 29.3% NaOH. Efficiency increased levels of cellulose using NaOH or KOH solvent almost equal approximately 85.5%, but with KOH the lower alkaline properties provide a more stable rise. Solvent delignification process with NaOH provide large enough glucose content at a ratio of 1: 6 and 1: 8 with sulfuric acid concentration in the range of 0.1 to 0.4 and 0.5% v/v. Increased glucose content in the solvent of NaOH at a ratio of 1:6 reached 69.88 ppm for sulfuric acid concentration of 0.55% v/v, whereas the content of glucose degradation products of cellulose with delignification process using KOH solvent is in the range of 3.25 ppm to 77.67 ppm. The highest value is produced by the hydrolysis of cellulose to the sulfuric acid concentration of 0.4% v/v, and the KOH solvent ratio is 1:10. The higher the ratio, the lower the KOH solvent content of glucose produced.

New peritoneal dialysates, for which benefits ?

The ideal peritoneal dialysis solution should allow efficient withdrawal of waste products of the metabolism and water and solutes equilibrium with minimal side effects for the patient and the peritoneal membrane. Glucose degradation products (GDP) resulting from the manufacturing process play a major toxic role and new biocompatible PD solutions with low GDP content and a more physiological bicarbonate or bicarbonate/lactate buffer have brought a clear benefit in experimental studies; however, in clinical cohorts and meta-analysis, the benefits of these solutions appear limited to better preservation of residual renal function and of diuresis. Glucose is the principal osmotic agent although hypertonic glucose solutions have a deleterious effect on PD, and their use should be restrained. Dialysate concentrations of sodium, calcium and magnesium are close to plasma; their diffusive transport is thus limited and their net peritoneal transport mainly depends on the ultrafiltration volume. A dialysate calcium concentration above 1.25 mmol/l generates a calcium load which may contribute to the high prevalence of adynamic bone disease in PD patients; this should be avoided. Low sodium dialysis solutions experimentally improve sodium diffusive transport and extraction in PD patients; the clinical benefit of this approach has to be confirmed.

Associations Between Peritoneal Glucose Exposure, Glucose Degradation Product Exposure, and Peritoneal Membrane Transport Characteristics in Peritoneal Dialysis Patients: Secondary Analysis of the balANZ Trial.

Glucose is the most commonly used osmotic medium in peritoneal dialysis (PD) solutions, and its use has been associated with both local and systemic adverse effects. Previous, single-center, observational cohort studies have reported conflicting findings regarding whether a relationship exists between peritoneal glucose exposure and peritoneal small solute transport rate. In this secondary analysis of the balANZ multicenter, multinational, randomized controlled trial of a neutral pH, ultra-low glucose degradation product (biocompatible) versus conventional PD solutions over a 2-year period, the relationship between time varying peritoneal glucose exposure and change in peritoneal solute transport rate, (measured as dialysate to plasma creatinine ratio at 4 hours [D:PCr4h]), was evaluated using multivariable, multilevel linear regression. Baseline peritoneal glucose exposure was also assessed as either a continuous or categorical variable. The study included 165 patients (age 58.1 ± 14.2 years, 55% male, 33% diabetic). Peritoneal glucose exposure increased over time (coefficient 1.49, 95% confidence interval [CI] 1.07 - 1.92 and was not significantly associated with change in D:PCr4h (coefficient 0.00004, 95% CI -0.0001 - 0.0002, p = 0.68). Similar results were found when peritoneal glucose exposure was examined as a baseline continuous or categorical variable. A significant 2-way interaction was observed with PD solution type, whereby a progressive increase in D:PCr4h was seen in the patients receiving conventional PD solution, but not in those receiving biocompatible solution. Increases in peritoneal solute transport rate in PD patients over time were not associated with peritoneal glucose exposure, although a strong and positive association with PD solution glucose degradation product content was identified. Peritoneal glucose exposure may be a less important consideration than peritoneal glucose degradation product exposure with respect to peritoneal membrane function over time.

Biocompatibility of a new PD solution for Japan, Reguneal\u2122, measured as in vitro proliferation of fibroblasts

BackgroundThe aim of this study was to investigate in vitro biocompatibility of Reguneal™, a new bicarbonate containing peritoneal dialysis fluid (PDF) for Japan, and compare it with other PDFs available in that country.MethodsWe assessed basal cytotoxicity using in vitro proliferation of cultured fibroblasts, L-929, determining the quantity of living cells by the uptake of Neutral Red. Levels of ten glucose degradation products (GDPs) were measured by a validated ultrahigh-performance liquid chromatography method in combination with an ultraviolet detector. We compared inhibition of fibroblast cell growth between brands of PDF, adjusting for dextrose and GDP concentrations using random-effects mixed models.ResultsThe results demonstrate that cytotoxicity of Reguneal™ is comparable to a sterile-filtered control and is less cytotoxic than most of the other PDFs, most of which significantly inhibited cell growth. As a “class effect”, increasing dextrose and GDP concentrations were non-significantly but positively associated with cytotoxicity. As a “brand effect”, these relationships varied widely between brands, and some PDFs had significant residual effects on basal cytotoxicity through mechanisms that were unassociated with either dextrose or GDP concentration.ConclusionOur study suggests that Reguneal™ is a biocompatible PDF. The results of our study also highlight that dextrose and GDPs are important for biocompatibility, but alone are not a complete surrogate. The results of our study need to be confirmed in other tissue culture models, and should lead to further research on determinants of biocompatibility and the effect of such PDFs on clinical outcomes.

Neuronal damage and shortening of lifespan in C. elegans by peritoneal dialysis fluid: Protection by glyoxalase-1.

Glucose and glucose degradation products (GDPs), contained in peritoneal dialysis (PD) fluids, contribute to the formation of advanced glycation end-products (AGEs). Local damaging effects, resulting in functional impairment of the peritoneal membrane, are well studied. It is also supposed that detoxification of AGE precursors by glyoxalase-1 (GLO1) has beneficial effects on GDP-mediated toxicity. The aim of the current study was to analyze systemic detrimental effects of PD fluids and their prevention by glyoxlase-1. Wild-type and GLO1-overexpressing Caenorhabditis elegans (C. elegans) were cultivated in the presence of low- and high-GDP PD fluids containing 1.5 or 4% glucose. Lifespan, neuronal integrity and neuronal functions were subsequently studied. The higher concentrations of glucose and GDP content resulted in a decrease of maximum lifespan by 2 (P<0.01) and 9 days (P<0.001), respectively. Exposure to low- and high-GDP fluids caused reduction of neuronal integrity by 34 (P<0.05) and 41% (P<0.05). Cultivation of animals in the presence of low-GDP fluid containing 4% glucose caused significant impairment of neuronal function, reducing relative and absolute head motility by 58.5 (P<0.01) and 56.7% (P<0.01), respectively; and relative and absolute tail motility by 55.1 (P<0.05) and 55.0% (P<0.05), respectively. Taken together, GLO1 overexpression protected from glucose-induced lifespan reduction, neurostructural damage and neurofunctional damage under low-GDP-conditions. In conclusion, both glucose and GDP content in PD fluids have systemic impact on the lifespan and neuronal integrity of C. elegans. Detoxification of reactive metabolites by GLO1 overexpression was sufficient to protect lifespan, neuronal integrity and neuronal function in a low-GDP environment. These data emphasize the relevance of the GLO1 detoxifying pathway as a potential therapeutic target in the treatment of reactive metabolite-mediated pathologies.

Bicarbonate buffered peritoneal dialysis fluid upregulates angiopoietin-1 and promotes vessel maturation.

BackgroundUltrafiltration decline is a progressive issue for patients on chronic peritoneal dialysis (PD) and can be caused by peritoneal angiogenesis induced by PD fluids. A recent pediatric trial suggests better preservation of ultrafiltration with bicarbonate versus lactate buffered fluid; underlying molecular mechanisms are unknown.MethodsAngiogenic cytokine profile, tube formation capacity and Receptor Tyrosine Kinase translocation were assessed in primary human umbilical vein endothelial cells following incubation with bicarbonate (BPDF) and lactate buffered (LPDF), pH neutral PD fluid with low glucose degradation product content and lactate buffered, acidic PD fluid with high glucose degradation product content (CPDF). Peritoneal biopsies from age-, PD-vintage- and dialytic glucose exposure matched, peritonitis-free children on chronic PD underwent automated histomorphometry and immunohistochemistry.ResultsIn endothelial cells angiopoietin-1 mRNA and protein abundance increased 200% upon incubation with BPDF, but decreased by 70% with LPDF as compared to medium control; angiopoietin-2 remained unchanged. Angiopoietin-1/Angiopoietin-2 protein ratio was 15 and 3-fold increased with BPDF compared to LPDF and medium. Time-lapse microscopy with automated network analysis demonstrated less endothelial cell tube formation with BPDF compared to LPDF and CPDF incubation. Receptor Tyrosine Kinase translocated to the cell membrane in BPDF but not in LPDF or CPDF incubated endothelial cells. In children dialyzed with BPDF peritoneal vessels were larger and angiopoietin-1 abundance in CD31 positive endothelium higher compared to children treated with LPDF.ConclusionBicarbonate buffered PD fluid promotes vessel maturation via upregulation of angiopoietin-1 in vitro and in children on dialysis. Our findings suggest a molecular mechanism for the observed superior preservation of ultrafiltration capacity with bicarbonate buffered PD fluid with low glucose degradation product content.

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.

The Trio Trial - A Randomized Controlled Clinical Trial Evaluating the Effect of a Biocompatible Peritoneal Dialysis Solution on Residual Renal Function.

♦ Residual renal function (RRF) correlates with mortality and morbidity rates in patients receiving peritoneal dialysis (PD). We examined the effect of a biocompatible PD solution (Gambrosol Trio; Gambro Lundia AB, Lund, Sweden) with lower concentrations of glucose degradation products on rates of decline in RRF. ♦ Incident patients at 2 centers in Canada and 1 in Hong Kong were randomized (by minimization) in an open-label parallel group trial to receive Gambrosol Trio or standard PD solution (Dianeal; Baxter Healthcare, Mississauga, Canada) for 2 years. Primary outcome was slope of RRF. Secondary outcomes were urine volumes, fluid and nutrition indices, PD and membrane characteristics, peritonitis rates, adverse events, and PD technique survival. ♦ Residual renal function declined by 0.132 mL/minute/1.73 m(2)/month in 51 patients allocated to biocompatible, and 0.174 mL/minute/1.73 m(2)/month in 50 patients allocated to standard PD solution (difference 0.042 mL/minute/1.73 m(2)/month, p = 0.001). Urine volume, body mass index, normalized protein catabolic rates, and fat mass were higher; total body water, peritoneal ultrafiltration, and D/P creatinine did not differ; and serum phosphate, rates of icodextrin, and automated cycler use were lower with Gambrosol Trio use. There were more peritonitis events with Gambrosol Trio use, while PD technique survival did not differ between groups. ♦ The use of the biocompatible PD solution Gambrosol Trio was associated with slower rates of decline in RRF, fluid and nutrition benefits, and increased peritonitis rates. ISRCTN26252543.

We Use Bioincompatible Peritoneal Dialysis Solutions.

Despite advances in peritoneal dialysis (PD) technique and therapy over the last 40 years, PD therapy for end-stage renal disease (ESRD) in the United States remains underutilized. One of the major factors contributing to this underutilization involves concerns about technique failure. More physiologic PD solutions, with a lower concentration of glucose degradation products and a neutral pH, exist and are readily available in Europe, Asia, and Australia. Several benefits of these biocompatible solutions exist over the conventional solutions including a slower decline in residual renal function and better maintenance of urine volumes. There may also be a beneficial effect of the biocompatible solutions in limiting the increase in peritoneal transport that is characteristic of patients maintained on conventional solutions. It should be of concern to the US nephrology community that biocompatible PD solutions are unavailable in the United States.

Update on Peritoneal Dialysis: Core Curriculum 2016

Update on Peritoneal Dialysis: Core Curriculum 2016

Increased peritoneal damage in glyoxalase 1 knock-down mice treated with peritoneal dialysis.

Peritoneal dialysis (PD) is limited by peritoneal fibrosis and ultrafiltration failure. This is in part caused by the high concentration of glucose degradation products (GDPs) present in PD fluids (PDF) as a consequence of heat sterilization. Existing research in long-term PD has mainly dealt with the toxicity induced by GDPs and the development of therapeutic strategies to reduce the cellular burden of GDPs. Currently, there are few data regarding the potential role of detoxification systems of GDP in PD. In this study, the role of glyoxalase 1 (Glo1), the major detoxification pathway for dicarbonyl-derived GD such as methylglyoxal (MG) and glyoxal (Gx), was investigated in vivo using heterozygous knock-down mice for Glo1 (Glo1(-/+)). Wild-type (WT) and Glo1(-/+) mice were repeatedly treated with PDF containing low and high amounts of GDP, particularly with respect to the content of dicarbonyls. After 12 weeks of treatment with PDF, peritoneal damage and function were evaluated. Glo1(-/+) mice treated with PDF showed increased formation of advanced glycation endproduct (AGE) when compared with WT mice, particularly the Gx-derived AGE, carboxymethyl-lysine. This was associated with increased inflammation, neovascularization, increased peritoneal fibrosis and impaired peritoneal function. This study suggests a pivotal and underestimated role for Glo1 as a detoxifying enzyme in GDP-associated peritoneal toxicity in PD. The indirect and direct modulation of Glo1 may therefore offer a new therapeutic option in prevention of GDP-induced peritoneal damage in PD.

3,4-DGE is cytotoxic and decreases HSP27/HSPB1 in podocytes

Hyperglycemia is the key driver of diabetic complications and increased concentrations of glucose degradation products. The study of peritoneal dialysis solution biocompatibility has highlighted the adverse biological effects of glucose degradation products. Recently, 3,4-dideoxyglucosone-3-ene (3,4-DGE) was identified as the most toxic glucose degradation product in peritoneal dialysis fluids. In addition, 3,4-DGE is present in high-fructose corn syrup, and its precursor 3-deoxyglucosone is increased in diabetes. The role of 3,4-DGE in glomerular injury had not been addressed. We studied the effects of 3,4-DGE on cultured human podocytes and in vivo in mice. 3,4-DGE induced apoptosis in podocytes in a dose- and time-dependent manner. 3,4-DGE promoted the release of cytochrome c from mitochondria and activation of caspase-3. While high glucose concentrations increased the levels of the podocyte intracellular antiapoptotic protein HSP27/HSPB1, 3,4-DGE decreased the expression of podocyte HSP27/HSPB1. Apoptosis induced by 3,4-DGE was caspase-dependent and could be prevented by the broad-spectrum caspase inhibitor zVAD-fmk. Antagonism of Bax by a Ku-70-derived peptide also prevented apoptosis. Intravenous administration of 3,4-DGE to healthy mice resulted in a decreased expression of HSP27/HSPB1 and caspase-3 activation in whole kidney and in podocytes in vivo. In conclusion, 3,4-DGE induces apoptotic cell death in cultured human podocytes, suggesting a potential role in glomerular injury resulting from metabolic disorders.

Peritonealdialyse gestern und heute: welche Entwicklungen und Erkenntnisse waren in den letzten Jahrzehnten bedeutend?

During the past years new developments in peritoneal dialysis (PD) technique have resulted in continuous improvement of patient outcome. The importance of salt and fluid balance, residual renal function and peritoneal glucose load are of increasing interest, whereas small solute clearances have lost importance. In patients with high peritoneal transport rates automated PD (APD) is indicated. However, APD can also be chosen as initial PD treatment since recent studies show comparable or even better survival as compared to continuous ambulatory PD patients. Alternative PD solutions improve peritoneal ultrafiltration (icodextrin), reduce peritoneal glucose load (amino acid solution, icodextrin) and protect the peritoneal membrane (solutions with low concentration of glucose degradation products). Infection risk can be reduced when using antibiotic creams, but resistances should be considered. Ongoing studies will clarify if non-antibiotic agents, e.g. medihoney, are effective in preventing PD-associated infections. Due to these improvements PD and hemodialysis have become equivalent treatments.