Antibody-mediated rejection of solid-organ allografts

To the editor: the comprehensive review article by Loupy and Lefaucheur (Sept. 20 issue)1 on antibody-mediated rejection describes major advances in understanding the pathophysiological process and diagnosis of antibody-mediated rejection, but successful treatment is still limited to the acute forms of antibody-mediated rejection.2 Allograft loss eventually occurs in the majority of patients in whom true pathogenic donor-specific anti-HLA antibodies develop.3 This is frustrating for both clinicians and patients because even treatments administered at early stages of the disease are not effective. It is quite obvious that the best strategy to minimize the risk of donor-specific antibodies is to improve the level of HLA matching between the donor and recipient.4 This point was omitted in the article

Paleoneuroanatomy of the European lambeosaurine dinosaur Arenysaurus ardevoli

The neuroanatomy of hadrosaurid dinosaurs is well known from North America and Asia. In Europe only a few cranial remains have been recovered that include the braincase. Arenysaurus is the first European endocast for which the paleoneuroanatomy has been studied. The resulting data have enabled us to draw ontogenetic, phylogenetic and functional inferences. Arenysaurus preserves the endocast and the inner ear. This cranial material was CT scanned, and a 3D-model was generated. The endocast morphology supports a general pattern for hadrosaurids with some characters that distinguish it to a subfamily level, such as a brain cavity that is anteroposteriorly shorter or the angle of the major axis of the cerebral hemisphere to the horizontal in lambeosaurines. Both these characters are present in the endocast of Arenysaurus. Osteological features indicate an adult ontogenetic stage, while some paleoneuroanatomical features are indicative of a subadult ontogenetic stage. It is hypothesized that the presence of puzzling mixture of characters that suggest different ontogenetic stages for this specimen may reflect some degree of dwarfism in Arenysaurus. Regarding the inner ear, its structure shows differences from the ornithopod clade with respect to the height of the semicircular canals. These differences could lead to a decrease in the compensatory movements of eyes and head, with important implications for the paleobiology and behavior of hadrosaurid taxa such as Edmontosaurus, Parasaurolophus and Arenysaurus. The endocranial morphology of European hadrosaurids sheds new light on the evolution of this group and may reflect the conditions in the archipelago where these animals lived during the Late CretaceousPeer ReviewedPostprint (published version

Management of post-transplant diabetes mellitus: an opportunity for novel therapeutics

Post-transplant diabetes mellitus (PTDM) is a common problem after kidney transplantation (KT), occurring in 50% of high-risk recipients. The clinical importance of PTDM lies in its impactas a significant risk factor for cardiovascular and chronic kidney disease (CKD) after solid organ transplantation. Kidney Disease: Improving Global Outcomes (KDIGO) has recently updated the treatment guidelines for diabetes management in CKD with emphasis on the newer antidiabetic agents such as dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors as add-on therapy to metformin. Given all these new diabetes treatments and the updated KDIGO guidelines, it is necessary to evaluate and give guidance on their use for DM management in KT recipients. This review summarizes the scarce published literature about the use of these new agents in the KT field. In summary, it is absolutely necessary to generate evidence in order to be able to safely use these new treatments in the KT population to improve blood glucose control, but specially to evaluate their potential cardiovascular and renal benefits that would seem to be independent of blood glucose control in PTDM patients

An exonic switch regulates differential accession of microRNAs to the Cd34 transcript in aterosclerosis progression

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

Design and methodology of the screening for CKD among older patients across Europe (SCOPE) study: a multicenter cohort observational study

Background: Decline of renal function is common in older persons and the prevalence of chronic kidney disease (CKD) is rising with ageing. CKD affects different outcomes relevant to older persons, additionally to morbidity and mortality which makes CKD a relevant health burden in this population. Still, accurate laboratory measurement of kidney function is under debate, since current creatinine-based equations have a certain degree of inaccuracy when used in the older population. The aims of the study are as follows: to assess kidney function in a cohort of 75+ older persons using existing methodologies for CKD screening; to investigate existing and innovative biomarkers of CKD in this cohort, and to align laboratory and biomarker results with medical and functional data obtained from this cohort. The study was registered at ClinicalTrials.gov, identifier NCT02691546, February 25th 2016. Methods/design: An observational, multinational, multicenter, prospective cohort study in community dwelling persons aged 75 years and over, visiting the outpatient clinics of participating institutions. The study will enroll 2450 participants and is carried out in Austria, Germany, Israel, Italy, the Netherlands, Poland and Spain. Participants will undergo clinical and laboratory evaluations at baseline and after 12 and 24 months-follow-up. Clinical evaluation also includes a comprehensive geriatric assessment (CGA). Local laboratory will be used for 'basic' parameters (including serum creatinine and albumin-to-creatinine ratio), whereas biomarker assessment will be conducted centrally. An intermediate telephone follow-up will be carried out at 6 and 18 months. Discussion: Combining the use of CGA and the investigation of novel and existing independent biomarkers within the SCOPE study will help to provide evidence in the development of European guidelines and recommendations in the screening and management of CKD in older people

Kidney regeneration and repair after transplantation

PURPOSE OF REVIEW: To briefly show which are the mechanisms and cell types involved in kidney regeneration and describe some of the therapies currently under study in regenerative medicine for kidney transplantation. RECENT FINDINGS: The kidney contains cell progenitors that under specific circumstances have the ability to regenerate specific structures. Apart from the knowledge gained in the self-regenerative properties of the kidney, new concepts in regenerative medicine such as organ engineering and the use of mesenchymal stem cell-based therapies are currently the focus of attention in the field. SUMMARY: Overall, kidney regeneration is a reality and the knowledge on how to control it will be one of the main scopes in the present and future

ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

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

Datasets for the validation of the "in vivo" siRNA-silencing of CD40 and for the detection of new markers of atherosclerosis progression in ApoE-deficient mice

AbstractData 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

Chronic Kidney Allograft Disease: New Concepts and Opportunities

Chronic kidney disease (CKD) is increasing in most countries and kidney transplantation is the best option for those patients requiring renal replacement therapy. Therefore, there is a significant number of patients living with a functioning kidney allograft. However, progressive kidney allograft functional deterioration remains unchanged despite of major advances in the field. After the first post-transplant year, it has been estimated that this chronic allograft damage may cause a 5% graft loss per year. Most studies focused on mechanisms of kidney graft damage, especially on ischemia-reperfusion injury, alloimmunity, nephrotoxicity, infection and disease recurrence. Thus, therapeutic interventions focus on those modifiable factors associated with chronic kidney allograft disease (CKaD). There are strategies to reduce ischemia-reperfusion injury, to improve the immunologic risk stratification and monitoring, to reduce calcineurin-inhibitor exposure and to identify recurrence of primary renal disease early. On the other hand, control of risk factors for chronic disease progression are particularly relevant as kidney transplantation is inherently associated with renal mass reduction. However, despite progress in pathophysiology and interventions, clinical advances in terms of long-term kidney allograft survival have been subtle. New approaches are needed and probably a holistic view can help. Chronic kidney allograft deterioration is probably the consequence of damage from various etiologies but can be attenuated by kidney repair mechanisms. Thus, besides immunological and other mechanisms of damage, the intrinsic repair kidney graft capacity should be considered to generate new hypothesis and potential therapeutic targets. In this review, the critical risk factors that define CKaD will be discussed but also how the renal mechanisms of regeneration could contribute to a change chronic kidney allograft disease paradigm

Unveiling ncRNA regulatory axes in atherosclerosis progression

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