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Este artículo de investigación se encuentra disponible en la siguiente URL: https://www.revistanefrologia.com/es-pdf-S0211699521001570 En este artículo de investigación también participan: Ramón A. García-Trabanino, Miguel Hueso, Pedro Trinidad, Aquiles Jara, Mónica Furlano, Rosana Gelpi, Ana Vila-Santandreu, César A. Restrepo, Maya Sánchez-Baya, Carolt Arana, Marián Goicoechea, Verónica Coll, Julián Segura, Orlando Gutiérrez, Kamyar Kalantar-Zadeh, Emilio Sánchez y Alejandro Ferreiro.

Background Some studies reveal that obesity is associated with a decrease in mortality in haemodialysis (HD) patients. However, few studies have addressed the association between body mass index (BMI) and peritoneal dialysis (PD) patients. Methods We performed this longitudinal, retrospective study to evaluate the impact of obesity on PD patients, using data from the Catalan Registry of Renal Patients from 2002 to 2015 (n = 1573). Obesity was defined as BMI ≥30; low weight: BMI Results Obesity was observed in 20% of patients starting PD. We did not find differences in sex or PD modality, with the obesity group being older (65.9% are ≥55 years versus 59% non-obese, P = 0.003) and presenting more diabetes mellitus and cardiovascular disease (CVD) (47.9% obese versus 25.1% non-obese and 41.7% versus 31.5%, respectively). We did not observe differences in haemoglobin, albumin and Kt/V in obese patients. Regarding peritonitis rate, we did not find any difference between groups, presenting more peritonitis patients on continuous ambulatory peritoneal dialysis and aged ≥65 years [sub-hazard ratio (SHR) = 1.75, P = 0.000 and SHR = 1.56, P = 0.009]. In relation to technique survival, we found higher transfer to HD in the obese group of patients in the univariate analysis, which was not confirmed in the multivariate analysis (SHR = 1.12, P = 0.4), and we did not find differences in mortality rate. In relation to being transplanted, the underweight group, elderly and patients with CVD or diabetic nephropathy presented less probability to undergo kidney transplantation (SHR = 0.65, 0.24, 0.5 and 0.54, P Conclusions Obese and non-obese patients starting on PD had similar outcomes.

Objective: To determine whether miR-125b regulates cholesterol efflux in vivo and in vitro through the regulation of scavenger receptor type B1 (SR-B1). Approach and results: We demonstrated that miR-125b is up-regulated in the human aortas of patients with CAD and is located in macrophages and vascular smooth muscle cells (VSMCs). We identified SCARB1 as a direct target of miR-125b by repressing the activity of the SCARB1 3'-untranslated region reporter construct. Moreover, the overexpression of miR-125b in both human and mouse macrophages as well as VSMCs was found to downregulated the expression of the SCARB1 and the SR-B1 protein levels, thereby impairing alpha-HDL-mediated macrophage cholesterol efflux in vitro. The in vivo reverse cholesterol transport (RCT) rate from non-cholesterol-loaded macrophages transfected with miR-125b to feces was also found to be decreased when compared with that of control mimic-transfected macrophages. Conclusions: Together, these results provide evidence that miR-125b downregulates SCARB1 and SR-B1 in both human and mouse macrophages as well as VSMCs, thereby impairing macrophage cholesterol efflux in vitro and the whole macrophage-specific RCT pathway in vivo.

For many years, the RNA world of eukaryotic cells remained stable and predictable, organized by a few families of functionally different molecules [...]

This paper concerns 3′-untranslated regions (3′UTRs) of mRNAs, which are non-coding regulatory platforms that control stability, fate and the correct spatiotemporal translation of mRNAs. Many mRNAs have polymorphic 3′UTR regions. Controlling 3′UTR length and sequence facilitates the regulation of the accessibility of functional effectors (RNA binding proteins, miRNAs or other ncRNAs) to 3′UTR functional boxes and motifs and the establishment of different regulatory landscapes for mRNA function. In this context, shortening of 3′UTRs would loosen miRNA or protein-based mechanisms of mRNA degradation, while 3′UTR lengthening would strengthen accessibility to these effectors. Alterations in the mechanisms regulating 3′UTR length would result in widespread deregulation of gene expression that could eventually lead to diseases likely linked to the loss (or acquisition) of specific miRNA binding sites. Here, we will review the mechanisms that control 3′UTR length dynamics and their alterations in human disorders. We will discuss, from a mechanistic point of view centered on the molecular machineries involved, the generation of 3′UTR variability by the use of alternative polyadenylation and cleavage sites, of mutually exclusive terminal alternative exons (exon skipping) as well as by the process of exonization of Alu cassettes to generate new 3′UTRs with differential functional features.

Non-coding RNAs (ncRNAs) are emerging therapeutic tools but there are barriers to their translation to clinical practice. Key issues concern the specificity of the targets, the delivery of the molecules, and their stability, while avoiding “on-target” and “off-target” side effects. In this “ncRNA in therapeutics” issue, we collect several studies of the differential expression of ncRNAs in cardiovascular diseases, bone metabolism-related disorders, neurology, and oncology, and their potential to be used as biomarkers or therapeutic targets. Moreover, we review recent advances in the use of antisense ncRNAs in targeted therapies with a particular emphasis on their basic biological mechanisms, their translational potential, and future trends.

Haemodialysis (HD) patients present more morbidity and mortality risk in coronavirus disease 2019 (COVID-19). In patients who may develop severe symptoms, the process called ‘viral sepsis’ seems to be a crucial mechanism. In those cases, the HD procedure provides an excellent tool to explore the benefit of some extracorporeal therapies. We reported the outcome of four HD patients with severe COVID-19 treated with Seraph®100 haemoperfusion (HP) device. Three of the four cases presented a good clinical response after HP. In conclusion, the treatment with Seraph®100 device may be a simultaneous treatment to improve HD patients with severe acute respiratory syndrome coronavirus 2.

Completion of the human genome sequencing project highlighted the richness of the cellular RNA world, and opened the door to the discovery of a plethora of short and long non-coding RNAs (the dark transcriptome) with regulatory or structural potential, which shifted the balance of pathological gene alterations from coding to non-coding RNAs. Thus, disease risk assessment currently has to also evaluate the expression of new RNAs such as small micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), competing endogenous RNAs (ceRNAs), retrogressed elements, 3′UTRs of mRNAs, etc. We are interested in the pathogenic mechanisms of atherosclerosis (ATH) progression in patients suffering Chronic Kidney Disease, and in this review, we will focus in the role of the dark transcriptome (non-coding RNAs) in ATH progression. We will focus in miRNAs and in the formation of regulatory axes or networks with their mRNA targets and with the lncRNAs that function as miRNA sponges or competitive inhibitors of miRNA activity. In this sense, we will pay special attention to retrogressed genomic elements, such as processed pseudogenes and Alu repeated elements, that have been recently seen to also function as miRNA sponges, as well as to the use or miRNA derivatives in gene silencing, anti-ATH therapies. Along the review, we will discuss technical developments associated to research in lncRNAs, from sequencing technologies to databases, repositories and algorithms to predict miRNA targets, as well as new approaches to miRNA function, such as integrative or enrichment analysis and their potential to unveil RNA regulatory networks.

Cardiovascular mortality increases with decreasing renal function although the cause is yet unknown. Here, we have investigated whether low chronic inflammation in chronic kidney diseases (CKD) could contribute to increased risk for coronary artery diseases (CAD). Thus, a prospective case&ndash, control study was conducted in patients with CAD and CKD undergoing coronary artery bypass graft surgery with the aim of detecting differences in cardiovascular outcomes, epicardial adipose tissue volume, and inflammatory marker activity associated with renal dysfunction. Expression of membrane CD14 and CD16, inflammatory cytokines and chemokines, mitogen-activated protein (MAP) kinases and hsa-miR-30a-5p were analyzed in peripheral blood mononuclear cells (PBMCs). Epicardial fat volume and tissue inflammation in perivascular adipose tissue and in the aorta were also studied. In the present study, 151 patients were included, 110 with CAD (51 with CKD) and 41 nonCAD controls (15 with CKD). CKD increased the risk of cardiac surgery&ndash, associated acute kidney injury (CSA-AKI) as well as the 30-day mortality after cardiac surgery. Higher counts of CD14++CD16+ monocytes were associated with vascular inflammation, with an increased expression of IL1&beta, and with CKD in CAD patients. Expression of hsa-miR-30a-5p was correlated with hypertension. We conclude that CKD patients show an increased risk of CSA-AKI and mortality after cardiovascular surgery, associated with the expansion of the CD14++CD16+ subset of proinflammatory monocytes and with IL1&beta, expression. We propose that inflammation associated with CKD may contribute to atherosclerosis (ATH) pathogenesis.

Background: The 2019 Science for Dialysis Meeting at Bellvitge University Hospital was devoted to the challenges and opportunities posed by the use of data science to facilitate precision and personalized medicine in nephrology, and to describe new approaches and technologies. The meeting included separate sections for issues in data collection and data analysis. As part of data collection, we presented the institutional ARGOS e-health project, which provides a common model for the standardization of clinical practice. We also pay specific attention to the way in which randomized controlled trials offer data that may be critical to decision-making in the real world. The opportunities of open source software (OSS) for data science in clinical practice were also discussed. Summary: Precision medicine aims to provide the right treatment for the right patients at the right time and is deeply connected to data science. Dialysis patients are highly dependent on technology to live, and their treatment generates a huge volume of data that has to be analysed. Data science has emerged as a tool to provide an integrated approach to data collection, storage, cleaning, processing, analysis, and interpretation from potentially large volumes of information. This is meant to be a perspective article about data science based on the experience of the experts invited to the Science for Dialysis Meeting and provides an up-to-date perspective of the potential of data science in kidney disease and dialysis. Key messages: Healthcare is quickly becoming data-dependent, and data science is a discipline that holds the promise of contributing to the development of personalized medicine, although nephrology still lags behind in this process. The key idea is to ensure that data will guide medical decisions based on individual patient characteristics rather than on averages over a whole population usually based on randomized controlled trials that excluded kidney disease patients. Furthermore, there is increasing interest in obtaining data about the effectiveness of available treatments in current patient care based on pragmatic clinical trials. The use of data science in this context is becoming increasingly feasible in part thanks to the swift developments in OSS.

Background: Renal transplantation is the treatment of choice for chronic kidney disease (CKD) patients, but the shortage of kidneys and the disabling medical conditions these patients suffer from make dialysis essential for most of them. Since dialysis drastically affects the patients’ lifestyle, there are great expectations for the development of wearable artificial kidneys, although their use is currently impeded by major concerns about safety. On the other hand, dialysis patients with hemodynamic instability do not usually tolerate intermittent dialysis therapy because of their inability to adapt to a changing scenario of unforeseen events. Thus, the development of novel wearable dialysis devices and the improvement of clinical tolerance will need contributions from new branches of engineering such as artificial intelligence (AI) and machine learning (ML) for the real-time analysis of equipment alarms, dialysis parameters, and patient-related data with a real-time feedback response. These technologies are endowed with abilities normally associated with human intelligence such as learning, problem solving, human speech understanding, or planning and decision-making. Examples of common applications of AI are visual perception (computer vision), speech recognition, and language translation. In this review, we discuss recent progresses in the area of dialysis and challenges for the use of AI in the development of artificial kidneys. Summary and Key Messages: Emerging technologies derived from AI, ML, electronics, and robotics will offer great opportunities for dialysis therapy, but much innovation is needed before we achieve a smart dialysis machine able to analyze and understand changes in patient homeostasis and to respond appropriately in real time. Great efforts are being made in the fields of tissue engineering and regenerative medicine to provide alternative cell-based approaches for the treatment of renal failure, including bioartificial renal systems and the implantation of bioengineered kidney constructs.

Background: CD34+ Endothelial Progenitor Cells (EPCs) play an important role in the recovery of injured endothelium and contribute to atherosclerosis (ATH) pathogenesis. Previously we described a potential atherogenic role for miR-125 that we aimed to confirm in this work. Methods: Microarray hybridization, TaqMan Low Density Array (TLDA) cards, qPCR, and immunohistochemistry (IHC) were used to analyze expression of the miRNAs, proteins and transcripts here studied. Results: Here we have demonstrated an increase of resident CD34-positive cells in the aortic tissue of human and mice during ATH progression, as well as the presence of clusters of CD34-positive cells in the intima and adventitia of human ATH aortas. We introduce miR-351, which share the seed sequence with miR-125, as a potential effector of CD34. We show a splicing event at an internal/cryptic splice site at exon 8 of the murine Cd34 gene (exonic-switch) that would regulate the differential accession of miRNAs (including miR-125) to the coding region or to the 3’UTR of Cd34. Conclusions: We introduce new potential mediators of ATH progression (CD34 cell-clusters, miR-351), and propose a new mechanism of miRNA action, linked to a cryptic splicing site in the target-host gene, that would regulate the differential accession of miRNAs to their cognate binding sites.

Data presented in this Data in Brief article correspond to the article "in vivo" silencing of CD40 reduces progression of experimental atherogenesis through a NFκB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis" (M. Hueso, L. De Ramon, E. Navarro, E. Ripoll, J.M. Cruzado, J.M. Grinyo, J. Torras, 2016) [1]. Here, we describe the validation of the silencing of CD40 expression with a specific siRNA in ApoE−/− mouse aortas, and its systemic effects on splenic lymphocytic subpopulations as well as on the infiltration of aortic intima by F4/80+, galectin-3+ macrophages or by NF-κB+ cells. We also show the output of a Gene Ontology and TLDA analysis which allowed the detection of potential mediators of atherosclerosis progression. We provide the scientific community with a set of genes whose expression is increased during atherosclerosis progression but downregulated upon CD40 silencing.

Atherosclerosis (ATH) and coronary artery disease (CAD) are chronic inflammatory diseases with an important genetic background; they derive from the cumulative effect of multiple common risk alleles, most of which are located in genomic noncoding regions. These complex diseases behave as nonlinear dynamical systems that show a high dependence on their initial conditions; thus, long-term predictions of disease progression are unreliable. One likely possibility is that the nonlinear nature of ATH could be dependent on nonlinear correlations in the structure of the human genome. In this review, we show how chaos theory analysis has highlighted genomic regions that have shared specific structural constraints, which could have a role in ATH progression. These regions were shown to be enriched with repetitive sequences of the Alu family, genomic parasites that have colonized the human genome, which show a particular secondary structure and are involved in the regulation of gene expression. Here, we show the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms via which the Alu elements alter the inflammatory response. We devote special attention to their relationship with the long noncoding RNA (lncRNA); antisense noncoding RNA in the INK4 locus (ANRIL), a risk factor for ATH; their role as microRNA (miRNA) sponges; and their ability to interfere with the regulatory circuitry of the (nuclear factor kappa B) NF-κB response. We aim to characterize ATH as a nonlinear dynamic system, in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

Background: Current dialysis devices are not able to react when unexpected changes occur during dialysis treatment or to learn about experience for therapy personalization. Furthermore, great efforts are dedicated to develop miniaturized artificial kidneys to achieve a continuous and personalized dialysis therapy, in order to improve the patient’s quality of life. These innovative dialysis devices will require a real-time monitoring of equipment alarms, dialysis parameters, and patient-related data to ensure patient safety and to allow instantaneous changes of the dialysis prescription for the assessment of their adequacy. The analysis and evaluation of the resulting large-scale data sets enters the realm of “big data” and will require real-time predictive models. These may come from the fields of machine learning and computational intelligence, both included in artificial intelligence, a branch of engineering involved with the creation of devices that simulate intelligent behavior. The incorporation of artificial intelligence should provide a fully new approach to data analysis, enabling future advances in personalized dialysis therapies. With the purpose to learn about the present and potential future impact on medicine from experts in artificial intelligence and machine learning, a scientific meeting was organized in the Hospital Universitari Bellvitge (L’Hospitalet, Barcelona). As an outcome of that meeting, the aim of this review is to investigate artificial intel ligence experiences on dialysis, with a focus on potential barriers, challenges, and prospects for future applications of these technologies. Summary and Key Messages: Artificial intelligence research on dialysis is still in an early stage, and the main challenge relies on interpretability and/or comprehensibility of data models when applied to decision making. Artificial neural networks and medical decision support systems have been used to make predictions about anemia, total body water, or intradialysis hypotension and are promising approaches for the prescription and monitoring of hemodialysis therapy. Current dialysis machines are continuously improving due to innovative technological developments, but patient safety is still a key challenge. Real-time monitoring systems, coupled with automatic instantaneous biofeedback, will allow changing dialysis prescriptions continuously. The integration of vital sign monitoring with dialysis parameters will produce large data sets that will require the use of data analysis techniques, possibly from the area of machine learning, in order to make better decisions and increase the safety of patients.

A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: “Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients” (Arbiol-Roca et al. [1] ). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients. This article analyzes the Hardy-Weinberg disequilibrium of each studied SNP, and the linkage disequilibrium between them.

Item does not contain fulltext BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, >/=60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m(2) of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m(2) were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m(2) (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m(2) (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m(2); 95% CI, 0.86 to 1.68; P3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS: Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).

Contemporary medical science heavily relies on the use of technology. Part of this technology strives to im- prove examination and measurement of the human body, with some of the most impressive technical breakthroughs to be found in the development of non-invasive proce- dures. Another part focuses on the development of de- vices that support therapies for specific pathologies. An example of this is the artificial kidney, which has become the target of intensive research from many directions and generates great expectations for dialysis patients. Re- search on the artificial kidney is still incipient though, and there are many challenges that must be overcome before it will become a reality and part of clinical practice in ne- phrology. One of these non-trivial challenges concerns the safety of users of these new dialysis devices. Safety risks make effective monitoring systems mandatory.

Background and aims CD40/CD40L signaling exerts a critical role in the development of atherosclerosis, and microRNAs (miRNAs) are key regulators in vascular inflammation and plaque formation. In this work, we investigated mRNA/miRNA expression during progression of atherosclerotic lesions through CD40 silencing. Methods : We silenced CD40 with a specific siRNA in ApoE −/− mice and compared expression of mRNA/miRNA in ascending aorta with scrambled treated mice. Results siRNA- CD40 treated mice significantly reduced the extension and severity of atherosclerotic lesions, as well as the number of F4/80 + , galectin-3 + macrophages and NF-κB + cells in the intima. Genome-wide mRNA/miRNA profiling allowed the identification of transcripts, which were significantly upregulated during atherosclerosis; among them, miR-125b and miR-30a, Xpr1 , a regulator of macrophage differentiation, Taf3 , a core transcription factor and the NF-κB activator Ikkβ, whereas, the NF-κB inhibitor Ikbα was downregulated during disease progression. All those changes were reversed upon CD40 silencing. Interestingly, TAF3 , XPR1 and miR-125b were also overexpressed in human atherosclerotic plaques. Murine Taf3 and Xpr1 were detected in the perivascular adipose tissue (PVAT), and Taf3 also in intimal foam cells. Finally, expression of miR-125b was regulated by the CD40-NF-κB signaling axis in RAW264.7 macrophages. Conclusions CD40 silencing with a specific siRNA ameliorates progression of experimental atherosclerosis in ApoE −/− mice, and evidences a role for NF-κB , Taf3 , Xpr1 , and miR-125b in the pathogenesis of atherosclerosis.

Background Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Single nucleotide polymorphisms (SNPs) in ANRIL gene have been associated with higher cardiovascular morbidity and mortality in general population. The main objective was to ascertain whether ANRIL polymorphisms could identify risk of major adverse cardiovascular event (MACE) in patients starting on hemodialysis (HD). Methods This was a prospective observational cohort study. 284 CKD patients starting on HD were included in the study and followed until achievement of the primary end-point (MACE) or end of the study. All patients were genotyped for four ANRIL SNPs (rs10757278, rs4977574, rs10757274 and rs6475606). Kaplan-Meier curves and multivariate Cox survival analyses, together with multiple logistic regression were used to analyze the association between ANRIL SNPs and MACE. Results We found that ANRIL SNP rs10757278 was a representative SNP of a strong linkage disequilibrium block and showed significant genotypic associations with MACE in hemodialysis patients. Homozygous patients for the risk allele (GG) showed 2.17 (1.05–4.49) fold increased risk of MACE during hemodialysis than carriers of the protective allele (AA or AG). Diabetes mellitus was a strong enhancer of this effect. Conclusions Our results indicate that ANRIL polymorphisms may confer risk to development of MACE in incident patients on hemodialysis.

Background: Chronic Kidney Disease (CKD) and inflammation are risk factors for atherosclerotic vascular disease (ASVD). In inflammatory conditions, Nuclear Factor-kappa B (NF-kappa B) is frequently activated and it has been detected in human ASVD. In this work, we investigated if the degree of inflammation and of NF-kappa B activation were increased in the aorta of patients with CKD. Methods: This is a case-control pilot study performed on 30 abdominal aorta samples from 10 human autopsies. Cases were patients with CKD and controls patients with normal glomerular filtration rate (eGFR). Infiltrating mononuclear cells (S100(+), CD3(+), CD40(+), CD40L(+)) and activation of NF-kappa B were identified by immunohistochemistry. Findings: The number of cells in the intima which showed activated nuclear NF-.B correlated with severity of ASVD lesions (r = 0.56, p = 0.003), with numbers of CD3(+) lymphocytes in adventitia (r = 0.50, p = 0.008), with numbers of CD40(+) cells in the intima (r = 0.59, p = 0.002) or in the adventitia (r = 0.45, p = 0.02), and with numbers of CD40L(+) cells in the intima (r = 0.51, p = 0.011). Increased numbers of S100(+) Intimal Dendritic cells (IDCs) were associated with ASVD (p = 0.03) and CKD (p = 0.01). Conclusions: Number of CD3(+) cells, of CD40(+) cells, of CD40L(+) cells and the degree of NF-kappa B activation were increased in ASVD lesions suggesting a role for the adaptive T cell in the development of ASVD lesions. IDCs were associated both with ASVD and CKD suggesting a role of these cells in the pathogenesis of ASVD in CKD.

After transplantation, glomerular volumes increases and large glomerular volume at 4 months is associated with better renal function. The aim is to characterize glomerular adaptation after the fourth month in two serial protocol biopsies and its relationship with subclinical rejection and chronic allograft nephropathy (CAN). Mean glomerular volume (Vg) was estimated according to the Weibel and Gomez method in a 4-month and 1-year serial protocol biopsies in 61 stable grafts. Glomerular enlargement (deltaVg) was calculated as the Vg difference between both biopsies. Banff schema was used to evaluate renal biopsies. Vg increased from 4.4+/-2.4 to 5.7+/-2.6 x 10(6) microm3 (P0.001). Mean deltaVg was 1.0 x 10(6) microm3. Patients with deltaVg1 were considered as patients with impaired glomerular enlargement (n=29). Impaired glomerular enlargement was associated with increased acute index score in the 4-month (1.83+/-1.56 vs 1.06+/-1.48; P0.05) and 1-year protocol biopsies (1.52+/-1.59 vs 0.62+/-1.07; P0.05). Impaired glomerular enlargement was also associated with increased progression of chronic lesions between the 4-month and 1-year biopsy in the glomerular (0.17+/-0.38 vs 0.55+/-0.63; P0.01), tubular (0.38+/-0.56 vs 0.83+/-0.85; P0.01), and interstitial compartment (0.41+/-0.57 vs 0.90+/-0.86; P0.01). The proportion of sclerotic glomeruli between both biopsies increased in patients with impaired glomerular enlargement (1.5+/-3.9 to 5.3+/-10.1, P0.05) while it did not modify in patients with glomerular enlargement (2.1+/-7.3 vs 2.6+/-4.5; P=NS). During the first year, glomeruli enlarge but this adaptation mechanism is impaired in patients with subclinical rejection. Moreover, impaired glomerular enlargement is associated with progression of CAN.

Introduction. The presence of chronic allograft nephropathy (CAN) in protocol biopsies is negatively associated with graft survival. Although recent studies have indicated that the resistive index (RI) is a predictor of graft failure, it does not correlate with CAN in stable grafts. We therefore studied the relationship between RI and CAN and examined the predictive value of both parameters on graft outcome. Methods. Included were patients transplanted between 1997 and 2002 and who had protocol biopsies and RI determinations. Renal lesions were blindly evaluated according to Banff 97 criteria. Mean glomerular volume, cortical interstitial volume fraction and intimal arterial volume fraction were estimated using a point counting technique. RI was determined before biopsy in at least two different renal locations. The outcome variable was defined as graft failure or a 30% serum creatinine increase between protocol biopsy and last follow-up. Results. Eighty-seven patients were included. RI correlated with recipient age (R ¼ 0.52, P

Protein kinase Emk1/Par1 (GenBank accession no. X97630) has been identified as a regulator of the immune system homeostasis. Since immunological factors are critical for the development of chronic allograft nephropathy (CAN), we reasoned that expression of Par1/Emk1 could be altered in kidney allografts undergoing CAN. In this paper, we have analysed the association among renal allograft lesions and expression of Par1/Emk1, studied by RT-PCR on total RNA from 51 protocol biopsies of transplanted kidneys, five normal kidneys, and five dysfunctional allografts. The most significant result obtained has been the detection of alterations in the normal pattern of alternative splicing of the Par1/Emk1 transcript, alterations that included loss of expression of constitutively expressed isoforms, and the inclusion of a cryptic exon to generate a new Emk1 isoform (Emk1C). Expression of Emk1C was associated with an increase in the extension of the interstitial infiltrate (0.88+/-0.33 in Emk1C([+]) vs. 0.41+/-0.50 in Emk1C([-]); P0.011), and with a trend to display higher interstitial scarring (0.66+/-0.70 vs. 0.29+/-0.52; P=0.09) in protocol biopsies when evaluated according to the Banff schema. Moreover, a higher mean arterial pressure (MAP) was also observed (110+/-11 vs. 99+/-11 mm Hg; P=0.012). From these results we propose that Par1/Emk1 could have a role in the development of CAN in kidney allografts.

Endothelin (ET) is known to play a role in the pathogenesis of warm ischaemic renal damage, however, little is known about its involvement in renal cold ischaemia. This study was designed to investigate the response of ET after kidney cold ischaemia, and to assess the potential protective effect of bosentan, a dual, non-selective ET(A)/ET(B) receptor antagonist, against cold ischaemia reperfusion injury in a rat model of syngeneic renal transplantation.Kidneys from Lewis rats were transplanted, either immediately or after 5 h of cold preservation. After 48 h, contralateral nephrectomy was performed. Rats were organized into three groups: Tr-NoISC, no cold ischaemia; Tr-ISC, 5 h cold ischaemia; and Tr-BOS, 5 h cold ischaemia plus bosentan (100 mg/kg/day, from the day before transplantation until the seventh day post-transplantation). On day 7, plasma and tissue immunoreactive ET (irET), as well as ET mRNA tissue expression, were evaluated. Renal function was measured by means of serum creatinine on days 3, 4, 5 and 7, and by creatinine clearance on day 7. Conventional histology was performed.The ischaemic group had significantly higher plasma irET levels than the non-ischaemic group and significantly lower levels than the bosentan group. Tissue irET levels and ET mRNA expression were similar in the ischaemic and bosentan groups and were higher than in the non-ischaemic group. Throughout the follow-up, serum creatinine was significantly higher in the ischaemic group than in the bosentan group. Moreover, creatinine decreased rapidly in the bosentan group after nephrectomy, whereas it continued to increase for 48 h in the ischaemic group. Kidneys from the ischaemic group showed a higher degree of tubular-cell necrosis and epithelial-cell detachment than kidneys from the bosentan group.We conclude that cold ischaemia and preservation damage induces an increase in renal ET mRNA and irET expression in the reperfusion phase, contributing both to the deterioration of renal function and to tubular necrosis. Bosentan is effective in protecting kidneys from this cold ischaemia reperfusion damage. Non-selective ET(A)/ET(B) receptor antagonists might be potentially useful in clinical renal transplantation.

Background. Cyclosporine (CsA) nephrotoxicity can be identified by functional changes and chronic renal damage. CsA-associated renal fibrosis has been related to the overproduction of transforming growth factor (TGF)-β 1 , a fibrogenic cytokine. Mycophenolate mofetil (MMF) may allow CsA dose reduction without increasing the risk of rejection. Methods. We studied the impact of CsA dose reduction in association with MMF on renal function and TGF-β 1 production in 16 long-term renal allograft recipients with suspected CsA nephrotoxicity. Two grams/day of MMF were introduced, and CsA dose was reduced to reach whole-blood levels between 40 and 60 ng/ml within 1 month. CsA dose and levels, renal function parameters, and platelet-poor plasma TGF-β 1 levels were evaluated before and 6 months thereafter. Results. MMF allowed a decrease in both the mean dose of CsA (3.8±1.35 vs. 2.2±0.73 mg/kg/day; P

Background: Patients undergoing conventiona l hemodialysis (C-HD) present a greater immuno-inflam- matory state probably related to uremia, sympathetic nervous system (SNS) activation and /or membrane bioincompat ibility, which could improve with a technique-switch ing to online hemodiafiltration (OL-HD). The antigen-indep endent pathway activation of this modified immunologic state turns dendritic cells (DC) into an accurate cell model to study these patients. The aim of this study is to further evaluate the immune-inflammat ory state of patients in C-HD assessed by DC maturation. Methods: 31 patients were submitted to C-HD and after 4 months switched to the OL-HD technique. Monocytes-derive d DCs from HD patients were cultured in the presence of IL-4/GM-CSF. DC-maturation was evaluated by assessing the maturation phenotype by flow cytometry (FACs). DCs-functiona l capacity to elicit T-cell alloresponse was studied by mixed leuco- cyte reaction. Cytokine release was assessed by FACs and SNS was evaluated measuring renalase levels by ELISA. Results: An up-regulation of maturation markers was observed in C-HD DCs which induced two fold more T cells proliferation than OL-HD DCs. Also, C-HD-mDCs presented with over-produc- tion of pro-inflammatory cytokines (IL-6, IL-1 β , IL-8, IL-10 and TNF- α ) compared with OL- HD-mDC (P < 0·05). Results were correlated with clinical data. When SNS was evaluated, hypotension events and blood pressure were significantly lower and renalase levels were significantly higher after conversion to OL-HD. Diabetes mellitus type 2 patients also found beneficial reduction of mDC when converted to OL-HD compared to non-diabetics. Conclusions: OL-HD could interfere with immuno-inflammatory state in HD patients with an improvement of renalase levels as potential key mediators in the mechanistic pathway of down-regulation of DC maturation

Protocol biopsies performed in stable renal allografts show different degrees of acute and chronic lesions. Histologic findings in protocol biopsies have been related to graft outcome. We evaluated histologic lesions observed in protocol biopsies performed in patients under different immunosuppression therapies. From June 1988 a protocol biopsy was performed at approximately 4 months in patients who fulfilled the following criteria: serum creatinine

Background Subclinical rejection and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies are associated with outcome. We study the relationship between histologic lesions in early protocol biopsies and histologic diagnoses in late biopsies for cause. Materials and methods Renal transplants with a protocol biopsy performed within the first 6 months posttransplant between 1988 and 2006 were reviewed. Biopsies were evaluated according to Banff criteria, and C4d staining was available in biopsies for cause. Results Of the 517 renal transplants with a protocol biopsy, 109 had a subsequent biopsy for cause which showed the following histological diagnoses: chronic humoral rejection (CHR) (n=44), IF/TA (n=42), recurrence of the primary disease (n=11), de novo glomerulonephritis (n=7), T-cell-mediated rejection (n=4), and polyoma virus nephropathy (n=1). The proportion of retransplants (15.9% vs. 2.3%, P=0.058) and the prevalence of subclinical rejection were higher in patients with CHR than in patients with IF/TA (52.3% vs. 28.6%, P=0.0253). Demographic donor and recipient characteristics and clinical data at the time of protocol biopsy were not different between groups. Logistic regression analysis showed that subclinical rejection (relative risk, 2.52; 95% confidence interval, 1.1-6.3; P=0.047) but not retransplantation (relative risk, 6.7; 95% confidence interval, 0.8-58.8; P=0.085) was associated with CHR. Conclusion Subclinical rejection in early protocol biopsies is associated with late appearance of CHR.

BACKGROUND Detection of markers predicting allograft rejection is important for risk assessment before kidney transplantation, as well as to minimize posttransplantation immunosuppression. METHODS We studied the expression of CD25, HLA-DR, CD134, CD62L, and CD44 by flow cytometry in CD4, CD8, and CD3 cells, from pretransplant blood samples from 91 transplanted patients accounting for 16 episodes of acute renal rejection in the first month after transplantation. RESULTS None of the activation markers showed a significant association to acute rejection. Early rejectors showed less pretransplant CD3CD25 cells than nonrejectors (0.79%±0.50% vs. 1.51%±0.79% of CD3 cells; P=0.001) and a lower CD3CD25/CD3HLA-DR ratio (0.043±0.034 vs. 0.111±0.079; P

Grafts with subclinical rejection associated with interstitial fibrosis and tubular atrophy (SCR+IF/TA) show poorer survival than grafts with subclinical rejection without IF/TA (SCR). Aiming to detect differences among SCR+IF/TA and SCR, we immunophenotyped the inflammatory infiltrate (CD45, CD3, CD20, CD68) and used a low-density array to determine levels of T(H)1 (interleukin IL-2, IL-3, gamma-interferon, tumor necrosis factor-alpha, lymphotoxin-alpha, lymphotoxin-beta, granulocyte-macrophage colony-stimulating factor) and T(H)2 (IL-4, IL-5, IL-6, IL-10, and IL-13) transcripts as well as of IL-2R (as marker for T-cell activation) in 31 protocol biopsies of renal allografts. Here we show that grafts with early IF/TA and SCR can be distinguished from grafts with SCR on the basis of the activation of IL-10 gene expression and of an increased infiltration by B-lymphocytes in a cellular context in which the degree of T-cell activation is similar in both groups of biopsies, as demonstrated by equivalent levels of IL-2R mRNA. These results suggest that the up-regulation of the IL-10 gene expression, as well as an increased proportion of B-lymphocytes in the inflammatory infiltrates, might be useful as markers of early chronic lesions in grafts with SCR.