IIS Fundacion Jimenez Diaz. UAM

Madrid, Spain

IIS Fundacion Jimenez Diaz. UAM

Madrid, Spain
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Diaz-Garcia J.D.,National Polytechnic Institute of Mexico | Gallegos-Villalobos A.,IIS Fundacion Jimenez Diaz UAM | Gonzalez-Espinoza L.,IIS Fundacion Jimenez Diaz UAM | Sanchez-Nino M.D.,IDIPAZ | Villarrubia J.,Hospital Ramon y Cajal
Nature Reviews Nephrology | Year: 2014

In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients. © 2014 Macmillan Publishers Limited. All rights reserved.

Weidemann F.,University of Würzburg | Sanchez-Nino M.D.,IDIPAZ REDINREN | Politei J.,Trinity Dupuytren Clinic | Oliveira J.-P.,Centro Hospitalar Of Sao Joao | And 3 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease. © 2013 Weidemann et al.; licensee BioMed Central Ltd.

PubMed | University Utrecht, Karolinska Institutet, University of Sheffield, Jagiellonian University and 11 more.
Type: Journal Article | Journal: European heart journal | Year: 2015

Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction.

PubMed | University of Padua, Albert Ludwigs University of Freiburg, Leiden University, University of Groningen and 12 more.
Type: | Journal: Head & neck | Year: 2016

Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking.Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients.Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST.Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. 2015 Wiley Periodicals, Inc. Head Neck 38: 673-679, 2016.

Martin-Lorenzo M.,IIS Fundacion Jimenez Diaz UAM | Gonzalez-Calero L.,IIS Fundacion Jimenez Diaz UAM | Zubiri I.,IIS Fundacion Jimenez Diaz UAM | Diaz-Payno P.J.,IIS Fundacion Jimenez Diaz UAM | And 6 more authors.
Electrophoresis | Year: 2014

Urine is a source of potential markers of disease. In the context of renal disease, urine is particularly important as it may directly reflect kidney injury. Current markers of renal dysfunction lack both optimal specificity and sensitivity, and improved technologies and approaches are needed. There is no clear consensus about the best sample pretreatment procedure for 2DE analysis of the urine proteome. Sample pretreatment conditions spots resolution and detection sensitivity, critically. As a first goal, we exhaustively compared eight different sample cleaning and protein purification methodologies for 2DE analysis of urine from healthy individuals. Oasis® HLB cartridges allowed the detection of the highest number of low molecular weight proteins; while PD10 desalting columns resulted in the highest number of detected spots in the high molecular weight area. Sample pretreatment strategies were also explored in the context of proteinuria, a clinical condition often associated to renal damage. Testing of urine samples from 13 patients with hypertension or kidney disease and different levels of proteinuria identified Oasis® HLB cartridge purification in combination with albumin depletion by ProteoPrep kit as the best option for urine proteome profiling from patients with proteinuric (> 30 mg/L albumin in urine) renal disease. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PubMed | Autonomous University of Barcelona, Molecular Biology Laboratory and IIS Fundacion Jimenez Diaz UAM
Type: | Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | Year: 2016

Kidney transplants from living donors (LDs) have a better outcome than those from deceased donors (DDs). Different factors have been suggested to justify the different outcome. In this study, we analyzed the infiltration and phenotype of monocytes/macrophages and the expression of inflammatory and fibrotic markers in renal biopsy specimens from 94 kidney recipients (60 DDs and 34 LDs) at baseline and 4 months after transplantation. We evaluated their association with medium- and long-term renal function. At baseline, inflammatory gene expression was higher in DDs than in LDs. These results were confirmed by the high number of CD68-positive cells in DD kidneys, which correlated negatively with long-term renal function. Expression of the fibrotic markers vimentin, fibronectin, and -smooth muscle actin was more elevated in biopsy specimens from DDs at 4 months than in those from LDs. Gene expression of inflammatory and fibrotic markers at 4 months and difference between 4 months and baseline correlated negatively with medium- and long-term renal function in DDs. Multivariate analysis point to transforming growth factor-1 as the best predictor of long-term renal function in DDs. We conclude that early macrophage infiltration, sustained inflammation, and transforming growth factor-1 expression, at least for the first 4 months, contribute significantly to the difference in DD and LD transplant outcome.

Poveda J.,IIS Fundacion Jimenez Diaz UAM | Sanchez-Nino M.D.,IDIPAZ | Glorieux G.,Ghent University | Sanz A.B.,IIS Fundacion Jimenez Diaz UAM | And 3 more authors.
Nephrology Dialysis Transplantation | Year: 2014

Backgroundp-Cresyl sulphate (p-CS) and p-cresyl glucuronide (p-CG) are uraemic toxins that exhibit pro-inflammatory features in leukocytes and are associated with the progression of chronic kidney disease (CKD). Tubular cells are key targets of nephrotoxic agents and tubular cell death and activation contribute to the progression of CKD. However, the potential toxicity of these compounds on tubular cells is not fully understood. More specifically, apoptosis has never been studied.MethodsHK-2 human proximal tubular epithelial cells were studied. Cell death was evaluated by flow cytometry of DNA content and by morphology. Gene expression was studied by real-time (RT)-PCR. Protein expression was studied by western blot and flow cytometry.ResultsLong-term (7 days) exposure to p-CS induced apoptosis in HK-2 cells in a concentration- dependent manner. In addition, short-term (3 h) exposure to p-CS promoted the expression of the TWEAK receptor Fn14, cooperated with TWEAK in promoting cell death and increased inflammatory gene expression. Albumin was cytotoxic and increased the inflammatory response to p-CS concentrations found in the circulation of non-dialysis CKD patients. In contrast, no biological actions of p-CG were observed on HK-2 cells, either alone or in combination with p-CS.ConclusionsThis study demonstrates for the first time that p-CS has pro-apoptotic and pro-inflammatory effects on tubular cells. These results identify mechanisms by which uraemic toxicity may contribute to CKD progression. © 2013 The Author.

PubMed | Fundacion Jimenez Diaz IIS and IIS Fundacion Jimenez Diaz UAM
Type: Journal Article | Journal: PloS one | Year: 2016

To date, non-invasive prenatal diagnosis (NIPD) of monogenic disorders has been limited to cases with a paternal origin. This work shows a validation study of the Droplet Digital PCR (ddPCR) technology for analysis of both paternally and maternally inherited fetal alleles. For the purpose, single nucleotide polymorphisms (SNPs) were studied with the only intention to mimic monogenic disorders.NIPD SNP genotyping was performed by ddPCR in 55 maternal plasma samples. In 19 out of 55 cases, inheritance of the paternal allele was determined by presence/absence criteria. In the remaining 36, determination of the maternally inherited fetal allele was performed by relative mutation dosage (RMD) analysis.ddPCR exhibited 100% accuracy for detection of paternal alleles. For diagnosis of fetal alleles with maternal origin by RMD analysis, the technology showed an accuracy of 96%. Twenty-nine out of 36 were correctly diagnosed. There was one FP and six maternal plasma samples that could not be diagnosed.In this study, ddPCR has shown to be capable to detect both paternal and maternal fetal alleles in maternal plasma. This represents a step forward towards the introduction of NIPD for all pregnancies independently of the parental origin of the disease.

PubMed | Institute for Rare Disease Research and IIS Fundacion Jimenez Diaz UAM
Type: Journal Article | Journal: Journal of investigative medicine : the official publication of the American Federation for Clinical Research | Year: 2016

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impairments in verbal and non-verbal communication, impaired social interactions and repetitive behaviors. There is evidence of a link between ASD symptoms and immune dysfunction, but few studies have been performed in adult patients to confirm this. In this work, we used flow cytometry to study immunological differences in peripheral blood mononuclear cells from 59 adult patients and 26 healthy control subjects to identify possible immune cell profiles related with this group of disorders. We analyzed six immune cell subpopulations (ie, B-cells, CD4(+) and CD8(+) T-cells, NK, NKT cells, and monocytes) and their corresponding stages of apoptosis and activation. The most noteworthy results showed that, compared to healthy controls, patients had increased percentages of CD8(+) T-cells and B-cells, and a decrease in the percentage of NKT cells. Regarding CD25 expression, we found overall CD25(+) overexpression, primarily in NK and NKT cells. Apoptosis percentage showed an increasing trend only in monocytes of patients. These data support a link between ASD and immune dysfunction, suggesting that specific cellular phenotypes and/or activation status of immune cells may be relevant in adult ASD.

PubMed | University of Cantabria, Metropolitan Autonomous University and IIS Fundacion Jimenez Diaz UAM
Type: | Journal: Scientific reports | Year: 2016

Implementation of therapy for acute kidney injury (AKI) depends on successful prediction of individual patient prognosis. Clinical markers as serum creatinine (sCr) have limitations in sensitivity and early response. The aim of the study was to identify novel molecules in urine which show altered levels in response to AKI and investigate their value as predictors of recovery. Changes in the urinary proteome were here investigated in a cohort of 88 subjects (55 AKI patients and 33 healthy donors) grouped in discovery and validation independent cohorts. Patients urine was collected at three time points: within the first 48h after diagnosis(T1), at 7 days of follow-up(T2) and at discharge of Nephrology(T3). Differential gel electrophoresis was performed and data were confirmed by Western blot (WB), liquid chromatography/mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA). Retinol binding protein 4 (RBP4) and kininogen-1 (KNG1) were found significantly altered following AKI. RBP4 increased at T1, and progressively decreased towards normalization. Maintained decrease was observed for KNG1 from T1. Individual patient response along time revealed RBP4 responds to recovery earlier than sCr. In conclusion, KNG1 and RBP4 respond to AKI. By monitoring RBP4, patients recovery can be anticipated pointing to a role of RBP4 in prognosis evaluation.

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