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Long-term peritoneal dialysis is associated with alterations in peritoneal function, like the development of high small solute transfer rates and impaired ultrafiltration. Also, morphologic changes can develop, the most prominent being loss of mesothelium, vasculopathy, and interstitial fibrosis. Current research suggests peritoneal inflammation as the driving force for these alterations. In this review, the available evidence for inflammation is examined and a new hypothesis is put forward consisting of high glucose-induced pseudohypoxia. Hypoxia of cells is characterized by a high (oxidized-reduced nicotinamide dinucleotide ratio) NADH-NAD+ ratio in their cytosol. Pseudohypoxia is similar but occurs when excessive amounts of glucose are metabolized, as is the case for peritoneal interstitial cells in peritoneal dialysis. The glucose-induced high NADH-NAD+ ratio upregulates the hypoxia-inducible factor-1 gene, which stimulates not only the glucose transporter-1 gene but also many profibrotic genes like TGFβ, vascular endothelial growth factor, plasminogen activator inhibitor-1, and connective tissue growth factor, all known to be involved in the development of peritoneal fibrosis. This review discusses the causes and consequences of pseudohypoxia in peritoneal dialysis and the available options for treatment and prevention. Reducing peritoneal exposure to the excessively high dialysate glucose load is the cornerstone to avoid the pseudohypoxia-induced alterations. This can partly be done by the use of icodextrin or by combinations of low molecular mass osmotic agents, all in a low dose. The addition of alanyl-glutamine to the dialysis solution needs further clinical investigation.

Several studies have been published in the last decade on the effects of low glucose degradation product (GDP) neutral pH (L-GDP/N-pH) dialysis solutions on peritoneal morphology and function during the long-term PD treatment. Compared to conventional solutions, the impact of these solutions on the morphological and functional alterations of the peritoneal membrane is discussed, including those of effluent proteins that reflect the status of peritoneal tissues. Long-term PD with conventional solutions is associated with the loss of mesothelium, submesothelial and interstitial fibrosis, vasculopathy, and deposition of advanced glycosylation end products (AGEs). L-GDP/N-pH solutions mitigate these alterations, although vasculopathy and AGE deposition are still present. Increased vascular density was found in some studies. Small solute transport increases with PD duration on conventional solutions. Initially, higher values are present on L-GDP/N-pH treatment, but these may be reversible and remain stable with PD duration. Consequently, ultrafiltration (UF) is lower initially but remains stable thereafter. At 5 years, UF and small pore fluid transport are higher, while free water transport decreased only slightly during follow-up. Cancer antigen 125 was initially higher on L-GDP/N-pH solutions, suggesting better mesothelial preservation but decreased during follow-up. Therefore, L-GDP/N-pH solutions may not prevent but reduce and retard the peritoneal alterations induced by continuous exposure to glucose-based dialysis fluids.

The peritoneal dialysis membrane is subject to remodelling in the course of peritoneal dialysis. In the absence of longitudinal morphological studies, this process is mainly studied indirectly by the investigation of changes in peritoneal transport. Non-invasive assessment of the peritoneum is also possible by assessment of substances that originate from peritoneal tissues and can be determined either as their gene expression in peritoneal effluent cells and/or as proteins in peritoneal effluent. Three of these biomarkers will be discussed, because longitudinal data are available. Cancer antigen 125 (CA 125) is present on the mesothelium,while its gene (MUC 16) is expressed in peritoneal effluent cells and is related to dialysate CA 125 protein. The constitutive production and the small intra-individual variability of 15% indicate its usefulness as a follow-up marker of mesothelial cell mass. Dialysate appearance rate is higher on biocompatible than on conventional solutions, but both decrease during long-term follow-up. Interleukin-6 (Il-6) is present in peritoneal effluent due to both transport from the circulation and local intraperitoneal production. Its appearance rate is unrelated to its gene expression in peritoneal cells. The intra-individual variation of effluent Il-6 averages 28%, hampering the interpretation of cross-sectional values. The relationships between effluent Il-6 and peritoneal transport have been interpreted as microinflammation, but are difficult to interprete due to mathematical coupling. Plasminogen activator inhibitor-1 (PAI-1) is encoded by the SERPINE 1 gene. A relationship is present between effluent concentration and gene expression. PAI-1 production is stimulated by glucose. PAI-1 appearance rate increases with PD duration. The sensitivity of effluent PAI-1 for the diagnosis of encapsulating peritoneal sclerosis was 100% one year prior to the diagnosis and the specificity 56%. It can be concluded that the discussed biomarkers are useful extensions to transport in assessment of the peritoneum during dialysis., Bulletin de la Dialyse à Domicile, Vol. 3 No 3 (2020): Bulletin de la Dialyse à Domicile

Long-term peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane. Inflammation may be the key moment, and, consequently, fibrosis may be the end result of chronic inflammatory reaction. The objective of the present study was to identify genes involved in peritoneal alterations during PD by comparing the transcriptome of peritoneal cells in patients with short- and long-term PD. Peritoneal effluent of the long dwell of patients with stable PD was centrifuged to obtain peritoneal cells. The gene expression profiles of peritoneal cells using microarray between patients with short- and long-term PD were compared. Based on microarray analysis, 31 genes for quantitative RT-PCR validation were chosen. A 4-h peritoneal equilibration test was performed on the day after the long dwell. Transport parameters and protein appearance rates were assessed. Genes involved in the immune system process, immune response, cell activation, and leukocyte and lymphocyte activation were found to be substantially upregulated in the long-term group. Quantitative RT-PCR validation showed higher expression of CD24, lymphocyte antigen 9 ( LY9), TNF factor receptor superfamily member 4 ( TNFRSF4), Ig associated-α ( CD79A), chemokine (C-C motif) receptor 7 ( CCR7), carcinoembryonic antigen-related cell adhesion molecule 1 ( CEACAM1), and IL-2 receptor-α ( IL2RA) in patients with long-term PD, with CD24 having the best discrimination ability between short- and long-term treatment. A relationship between CD24 expression and genes for collagen and matrix formation was shown. Activation of CD24 provoked by pseudohypoxia due to extremely high glucose concentrations in dialysis solutions might play the key role in the development of peritoneal membrane alterations.

Lipoprotein apheresis (LA) is a well-established therapy for lowering lipid levels in serious cases of dyslipidaemia, including high levels of lipoprotein(a) [Lp(a)]. This method lowers both LDL cholesterol and Lp(a) by more than 60% in most of patients; however, because randomized clinical studies could be extremely difficult, also other markers of the effect of this procedures on vascular health are of importance. Therefore, in addition to changes in plasma lipids and Lp(a) during LA, we also analysed the response of biomarkers associated with vascular integrity: small non-coding microRNAs (miRNAs).We analysed the changes in miRNAs in two women (age 70 and 72 years) with clinically manifest extensive and progressive atherosclerotic disease and high levels of Lp(a) and with different clinical course who were treated by LA. In both women we analysed changes of 175 circulating plasma miRNAs using pre-defined serum/plasma focus panels at the beginning of and one year after the therapy.In addition to reduced levels of plasma lipids and Lp(a), circulating plasma levels of miR-193a-5p; -215-5p; -328-3p; -130a-3p; -362-3p; -92b-3p decreased, and levels of miR-125a-5p; -185-5p; -106a-5p; -320b; -19a increased (all P 0.05) in both women. Moderate differences were found between both women with regard to the different course of atherosclerotic disease.Long-term LA substantially changes circulating plasma miRNAs associated with vascular integrity reflected different clinical course in both women. If confirmed, this approach could improve the assessment of the effectiveness of this therapy on an individual basis.

Permanent irritation of the peritoneum during peritoneal dialysis (PD) treatment leads to local chronic inflammation and subsequently activation of processes driving fibrogenesis in the long-term. The aim of the study was to compare the peritoneal effluent transcriptome of 20 patients treated less and 13 patients treated more than 2 years using microarray analysis. An increased expression of genes associated with an immune response was observed in long-term treated patients with well preserved peritoneal function, when compared to patients treated less than 2 years. From 100 genes highly expressed in long-term patients, a significant up-regulation of six was found by RT-qPCR: LY9 (lymphocyte antigen 9), TNSFR4 (tumor necrosis factor receptor superfamily, member 4), CD 79A (CD79a molecule), CCR7 (chemokine C-C receptor 7), CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) and IL2RA (interleukin 2 receptor alpha chain). Furthermore, the effluent cell population was analysed. A positive relationship between the number of granulocytes and NK cells on one hand, and duration of PD treatment on the other, was shown. We conclude, that the mechanisms of adaptive immunity promoting T helper 2 cells response are activated in the long-term before functional alterations develop. It consequently might trigger the fibrosis promoting processes.

The Banff 2019 kidney allograft pathology update excluded isolated tubulitis without interstitial inflammation (ISO-T) from the category of borderline (suspicious) for acute T cell-mediated rejection due to its proposed benign clinical outcome. In this study, we explored the molecular assessment of ISO-T. ISO-T or interstitial inflammation with tubulitis (I + T) was diagnosed in indication biopsies within the first 14 postoperative days. The molecular phenotype of ISO-T was compared to I + T either by using RNA sequencing (n = 16) or by Molecular Microscope Diagnostic System (MMDx, n = 51). RNA sequencing showed lower expression of genes related to interferon-y (p = 1.5 *10–16), cytokine signaling (p = 2.1 *10–20) and inflammatory response (p = 1.0*10–13) in the ISO-T group than in I + T group. Transcripts with increased expression in the I + T group overlapped significantly with previously described pathogenesis-based transcript sets associated with cytotoxic and effector T cell transcripts, and with T cell-mediated rejection (TCMR). MMDx classified 25/32 (78%) ISO-T biopsies and 12/19 (63%) I + T biopsies as no-rejection. ISO-T had significantly lower MMDx scores for interstitial inflammation (p = 0.014), tubulitis (p = 0.035) and TCMR (p = 0.016) compared to I + T. Fewer molecular signals of inflammation in isolated tubulitis suggest that this is also a benign phenotype on a molecular level.

LDL/Lp(a) apheresis therapy is a well-established method of aggressively lowering LDL and Lp(a). Recently, miRNAs have been discussed as markers of vascular status including atherosclerosis. MiRNAs inhibit post-transcriptional processes through RNA duplex formation resulting in gene silencing or regulation of gene expression.We measured a profile of 175 plasma-circulating miRNAs using pre-defined Serum/Plasma Focus Human microRNA PCR Panels in pooled samples of 11 subjects with familial hypercholesterolaemia under long-term apheresis treatment. Subsequently we analysed expressions of ten pre-selected miRNAs potentially involved in lipid homeostasis in the same group of subjects. We compared plasma-circulating miRNA levels isolated from peripheral blood collected immediately before and after apheresis.The greatest differences in plasma levels were found in miR-451a, miR-16, miR-19a/b, miR-223 and miR-185. In subsequent individual miRNA assay we detected a significant increase in miR-33b levels after apheresis (P 0.05). Additionally, correlations between plasma lipids and miR-33a (P 0.04) and miR-122 (P 0.01) have been determined. Moreover, miR-122 levels in LDLR homozygotes were higher compared to heterozygotes after, but not before, apheresis treatment (P 0.04).LDL/Lp(a) apheresis has an impact on miRNAs associated with lipid homeostasis and vascular status.

Background Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection. Methods Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry. Results In the case of genes involved in immune response-related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups. Conclusions Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.

The Banff 2019 kidney allograft pathology update excluded isolated tubulitis without interstitial inflammation (ISO-T) from the category of borderline (suspicious) for acute T cell-mediated rejection due to its proposed benign clinical outcome. In this study, we explored the molecular assessment of ISO-T. ISO-T or interstitial inflammation with tubulitis (I + T) was diagnosed in indication biopsies within the first 14 postoperative days. The molecular phenotype of ISO-T was compared to I + T either by using RNA sequencing (n = 16) or by Molecular Microscope Diagnostic System (MMDx, n = 51). RNA sequencing showed lower expression of genes related to interferon-y (p = 1.5 *10

Background and objectives There is a paucity of large longitudinal studies on the time course of peritoneal fluid transport. The aim of the present study was to longitudinally analyze changes in fluid transport and relevant solute transport parameters in patients treated with a conventional peritoneal dialysis (PD) fluid and, to mimic clinical reality, not selected for the presence or absence of ultrafiltration (UF) failure. Methods This prospective single-center cohort study followed 138 consecutive incident PD patients from July 1994 until censoring in August 2004. The design was longitudinal, with repeated measures over time in each patient. Patients had undergone at least 1 and a maximum of 5 annual standard peritoneal permeability analyses (SPAs) using 3.86% glucose dialysate. A linear mixed model was used to analyze the longitudinal data. Results No differences in patient characteristics were present at baseline in relation to the number of available SPAs. There were also no differences in patient withdrawal during the years of follow-up. A gradual decline in fluid transport, expressed as free water transport (FWT), small-pore fluid transport (SPFT), and transcapillary UF (TCUF), was observed with duration of PD. The decline was mainly attributable to patients who developed UF failure. The time courses for the determinants of fluid transport, such as the reflection coefficient (σ) and the UF coefficient (LpA), were not different. However, they were associated with an increase in the mass transfer area coefficient of creatinine, reflecting the peritoneal vascular surface area. Conclusions Fluid profiles for FWT and SPFT during a dwell can be explained by current knowledge of the three-pore model. Fluid transport declines with the duration of PD because of an increase in the vascular surface area, leading to a rapid dissipation of glucose as the osmotic agent. The absence of a trend in the time course of osmotic conductance and its constituents-that is, LpA and σ-suggests that, in an unselected population, these parameters are affected only late in the time course of PD.

This article deals with the positive and negative consequences of foreign labour migration in Russia. The authors emphasize that Russia is not a homogeneous country. The socio-economic implications for regions diff er. This study has found foreign labour migration to be a complicated socio-economic phenomenon, which has a dual eff ect on the labor market in Russia: on the one hand it is filling the gap in the labour force caused by the demographic crisis; on the other hand it increases the tension on the labour market because of migrants.

♦ Background and Objectives In automated peritoneal dialysis (APD), a patient's peritoneal membrane is more intensively exposed to fresh dialysate than it is in continuous ambulatory peritoneal dialysis (CAPD). Our aim was to study, in incident peritoneal dialysis (PD) patients, the influence of APD—compared with that of CAPD—on peritoneal transport over 4 years. ♦ Design, Setting, Participants, and Measurements Patients were included if at least 2 annual standard permeability analyses (SPAs) performed with 3.86% glucose were available while the patient was using the same modality with which they had started PD (APD or CAPD). Patients were followed until their first modality switch. Differences in the pattern of SPA outcomes over time were tested using repeated-measures models adjusted for age, sex, comorbidity, primary kidney disease, and year of PD start. ♦ Results The 59 CAPD patients enrolled were older than the 47 APD patients enrolled (mean age: 58 ± 14 years vs 49 ± 14 years; p < 0.01), and they had started PD earlier (mean start year: 2000 vs 2002). Over time, no differences in solute ( p > 0.19) or fluid transport ( p > 0.13) were observed. Similarly, free water transport ( p = 0.43) and small-pore transport ( p = 0.31) were not different between the modalities. Over time, patients on APD showed a faster decline in effective lymphatic absorption rate (ELAR: p = 0.02) and in transcapillary ultrafiltration (TCUF: p = 0.07, adjusted p = 0.05). Further adjustment did not change the results. ♦ Conclusions Compared with patients starting on CAPD, those starting on APD experienced a faster decline in ELAR and TCUF. Other transport parameters were not different over time between the groups.

Background Water transport in peritoneal dialysis (PD) patients occurs through the small pores and water channels, the latter allowing free water transport (FWT). The osmotic gradient is known to be one of the major determinants of water transport. The objective of the study was to analyse the relation between each transport route and the osmotic gradient. Methods The 4-h standard peritoneal permeability analyses of 80 stable PD patients were studied. Small pore transport (SPT) was calculated based on the transported amount of sodium. FWT was calculated by subtracting SPT from transcapillary ultrafiltration (TCUF). Water transport rates were determined. The osmotic gradient was calculated. The slope of the relation between FWT rate and osmotic gradient (slope(FWT)), and the elimination constant (K(e)) of the exponential relation between SPT rate and osmotic gradient (K(SPT)) were calculated for every patient. Results The FWT rate was related to the osmotic gradient (P = 0.001). A similar correlation was also found between the SPT rate and osmotic gradient when fitted exponentially (P = 0.005). The rates of FWT decreased significantly between each time point during the whole dwell. The SPT rates decreased significantly within the first half of the dwell and levelled off thereafter. No correlations were found between the slope(FWT), K(SPT) and PD duration. The slope(FWT) of the relationship between the FWT and the osmotic gradient is an indirect measurement of the amount of functioning water channels. Similarly, the K(SPT) value represents the number of functioning small pores. The absence of a relationship of these parameters with the duration of PD suggests opposing mechanisms, for instance a lower number of functioning pores in combination with an increased vascular surface area. Conclusion. The curves of the relationship between FWR, SPT and OG support the assumption that FWR is much more dependent on the OG than SPT. Non-osmotic determinants are likely to be important in small pore fluid transport.