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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.


Sanchez-Nino M.D.,IDIPAZ | Ruiz-Ortega M.,Autonomous University of Madrid | Egido J.,Autonomous University of Madrid | Ortiz A.,Autonomous University of Madrid
International Urology and Nephrology | Year: 2014

Unilateral ureteral obstruction is a popular experimental model of renal injury. However, the study of the kidney response to urinary tract obstruction is only one of several advantages of this model. Unilateral ureteral obstruction causes subacute renal injury characterized by tubular cell injury, interstitial inflammation and fibrosis. For this reason, it serves as a model both of irreversible acute kidney injury and of events taking place during human chronic kidney disease. Being a unilateral disease, it is not useful to study changes in global kidney function, but has the advantage of a low mortality and the availability of an internal control (the non-obstructed kidney). Experimental unilateral ureteral obstruction has illustrated the molecular mechanisms of apoptosis, inflammation and fibrosis, all three key processes in kidney injury of any cause, thus providing information beyond obstruction. Recently this model has supported key concepts on the role in kidney fibrosis of epithelial-mesenchymal transition, tubular epithelial cell G2/M arrest, the anti-Aging hormone Klotho and renal innervation. We now review the experimental model and its contribution to identifying novel therapeutic targets in kidney injury and fibrosis, independently of the noxa. © 2013 Springer Science+Business Media Dordrecht.


Sanchez-Nino M.D.,IdiPAZ | Poveda J.,Autonomous University of Madrid | Sanz A.B.,Autonomous University of Madrid | Carrasco S.,Autonomous University of Madrid | And 4 more authors.
Archives of Toxicology | Year: 2014

Hyperglycemia is the key driver of diabetic complications and increased concentrations of glucose degradation products. The study of peritoneal dialysis solution biocompatibility has highlighted the adverse biological effects of glucose degradation products. Recently, 3,4-dideoxyglucosone-3-ene (3,4-DGE) was identified as the most toxic glucose degradation product in peritoneal dialysis fluids. In addition, 3,4-DGE is present in high-fructose corn syrup, and its precursor 3-deoxyglucosone is increased in diabetes. The role of 3,4-DGE in glomerular injury had not been addressed. We studied the effects of 3,4-DGE on cultured human podocytes and in vivo in mice. 3,4-DGE induced apoptosis in podocytes in a dose- and time-dependent manner. 3,4-DGE promoted the release of cytochrome c from mitochondria and activation of caspase-3. While high glucose concentrations increased the levels of the podocyte intracellular antiapoptotic protein HSP27/HSPB1, 3,4-DGE decreased the expression of podocyte HSP27/HSPB1. Apoptosis induced by 3,4-DGE was caspase-dependent and could be prevented by the broad-spectrum caspase inhibitor zVAD-fmk. Antagonism of Bax by a Ku-70-derived peptide also prevented apoptosis. Intravenous administration of 3,4-DGE to healthy mice resulted in a decreased expression of HSP27/HSPB1 and caspase-3 activation in whole kidney and in podocytes in vivo. In conclusion, 3,4-DGE induces apoptotic cell death in cultured human podocytes, suggesting a potential role in glomerular injury resulting from metabolic disorders. © 2013 Springer-Verlag Berlin Heidelberg.


Sanchez-Nino M.D.,IDIPaz | Sanz A.B.,IDIPaz | Ruiz-Andres O.,IIS Fundacion Jimenez Diaz | Poveda J.,IIS Fundacion Jimenez Diaz | And 6 more authors.
Cytokine and Growth Factor Reviews | Year: 2013

Macrophage migration inhibitory factor (MIF) is increased in kidney and urine during kidney disease. MIF binds to and activates CD74 and chemokine receptors CXCR2 and CXCR4. CD74 is a protein trafficking regulator and a cell membrane receptor for MIF, D-dopachrome tautomerase (D-DT/MIF-2) and bacterial proteins. MIF signaling through CD74 requires CD44. CD74, CD44 and CXCR4 are upregulated in renal cells in diseased kidneys and MIF activation of CD74 in kidney cells promotes an inflammatory response. MIF or CXCR2 targeting protects from experimental kidney injury, CD44 deficiency modulates kidney injury and CXCR4 activation promotes glomerular injury. However, the contribution of MIF or MIF-2 to these actions of MIF receptors has not been explored. The safety and efficacy of strategies targeting MIF, CD74, CD44 and CXCR4 are under study in humans. © 2012 Elsevier Ltd.


PubMed | Hospital Universitario La Paz, Oh no sequences! Research group, CSIC - National Center for Biotechnology, Charles III University of Madrid and 5 more.
Type: Case Reports | Journal: Mucosal immunology | Year: 2015

Methicillin-resistant Staphylococcus aureus (MRSA) causes chronic pulmonary infections in patients with cystic fibrosis (CF). This study tracks the 13-year evolution (1996-2009) of a single MRSA clone in a male patient with CF, evaluating both the host immunogenic response and the microbial variations. Whole-genome sequencing was performed for the initial (CF-96) and evolved (CF-09) isolates. The immunogenicity of CF-96 and CF-09 was evaluated by incubation with innate immune cells from healthy volunteers. We also studied the patients innate immune response profile, cytokine production, expression of triggering receptor expressed on myeloid cells-1 (TREM-1), and phagocytosis. A total of 30 MRSA ST247-SCCmecI-pvl(-) isolates were collected, which evidenced a genome size reduction from the CF-96 ancestor to the evolved CF-09 strain. Up to six changes in the spa-type were observed over the course of the 13-year evolution. Cytokine production, TREM-1 expression, and phagocytosis were significantly lower for the healthy volunteer monocytes exposed to CF-09, compared with those exposed to CF-96. Patient monocytes exhibited a reduced inflammatory response when challenged with CF-09. Genetic changes in MRSA, leading to reduced immunogenicity and entry into the refractory state, may contribute to the attenuation of virulence and efficient persistence of the bacteria in the CF lung.


PubMed | Autonomous University of Madrid and IDIPAZ
Type: Journal Article | Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | Year: 2015

Systemic lupus erythematosus (SLE) is characterized by autoantibodies that mediate tissue injury. However, the pathogenesis of SLE remains poorly understood and available therapeutic approaches are not fully satisfactory. Belimumab, a monoclonal antibody that neutralizes B-cell activating factor (BAFF), was the first drug approved to treat SLE in more than 50 years. However, it is not labelled for use in severe lupus nephritis. Recently, a novel high-throughput multiplex protein microarray platform to profile circulating immunoglobulin G (IgG) autoantibodies in SLE patients identified IgG autoantibodies against several cytokines and growth factors at higher titres in SLE patients than in controls. The presence of autoantibodies to BAFF was validated in a subset of SLE patients by enzyme-linked immunosorbent assay. Low levels of anti-BAFF autoantibodies were also present in healthy controls. The association of anti-BAFF reactivity to clinical features and response to therapy was not addressed. However, preliminary data suggested an association to an interferon--responsive mRNA signature, itself associated with severity. Functional studies disclosed a neutralizing activity of autoantibodies against BAFF. These findings raise new questions regarding the role of BAFF in SLE and the functional and therapeutic significance of anti-BAFF and anti-cytokine autoantibodies.


SEATTLE--(BUSINESS WIRE)--Gilead Sciences, Inc. (NASDAQ: GILD) today announced 144-week data from two Phase 3 studies (Studies 104 and 111) evaluating the safety and efficacy of Genvoya® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg) for the treatment of HIV-1 infection in treatment-naïve adults. Through Week 144, Genvoya demonstrated significantly higher rates of virologic suppression compared to Gilead’s Stribild® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg), based on the percentage of patients with HIV-1 RNA levels less than 50 copies/mL. Patients receiving Genvoya also demonstrated favorable renal and bone laboratory parameters compared to those treated with Stribild. The data were presented in a poster session (Poster 0393) at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. Genvoya is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA levels less than 50 copies/mL) on a stable antiretroviral regimen for at least six months with no history of treatment failure and no known resistance to the components of Genvoya. Genvoya has a boxed warning in its product label regarding the risks of lactic acidosis/severe hepatomegaly with steatosis, and post treatment acute exacerbation of hepatitis B. See below for important safety information. “As people grow older with HIV, physicians are increasingly looking for highly effective medications that may help address the evolving needs of their patients who face a lifetime of antiretroviral therapy,” said Jose Arribas, MD, Associated Professor of Medicine, Hospital La Paz, IdiPAZ, Madrid, Spain and the lead study investigator. “These study results further demonstrate that Genvoya provides durable viral suppression and has a demonstrated safety profile for long-term use by a range of appropriate HIV patients.” In the combined analysis of Studies 104 and 111, a total of 1,733 treatment-naïve adults with HIV were randomized to receive either Genvoya or Stribild. At Week 144, 84.2 percent (n=729/866) of patients taking Genvoya and 80 percent (n=694/867; 95 percent CI: 0.6 percent to 7.8 percent, p=.021) of patients taking Stribild achieved HIV-1 RNA levels less than 50 copies/mL. Additionally, at Week 144, 81.1 percent (n=702/866) of patients taking Genvoya and 75.8 percent (n=657/867; 95 percent CI: 1.5 to 9.2 percent, p=.006) of patients taking Stribild achieved HIV-1 RNA levels less than 20 copies/mL, a secondary endpoint. At Week 144, virologic failure was similar between groups (Genvoya, 4.6 percent; Stribild, 3.9 percent); the difference in overall results was driven by fewer discontinuations on Genvoya due to adverse events or other reasons not related to efficacy (Genvoya, 11.2 percent; Stribild, 16.0 percent). There were statistically significant fewer adverse events leading to discontinuation in the Genvoya arm compared to the Stribild arm (Genvoya, 1.3 percent; Stribild, 3.3 percent, p=0.01). The most common drug-related adverse events in both groups were nausea, diarrhea and headache. A separate analysis investigated the effect of the two regimens on laboratory parameters of kidney, bone and plasma lipid levels. To examine kidney function, specific protein markers of glomerular and tubular function were examined, all of which favored Genvoya. This included a statistically significant difference in the median change in estimated glomerular filtration rate (eGFR) from baseline to Week 144 (Genvoya, -1.6 mL/min; Stribild, -7.7 mL/min, p<0.001). There were no cases of renal tubulopathy in the Genvoya arm and four cases in the Stribild arm. No participants on Genvoya had renal-related discontinuations compared to 12 participants in the Stribild arm (p˂0.001). The analysis also found that decreases in bone mineral density (BMD) were significantly less in the Genvoya group versus the Stribild group for both lumbar spine and total hip (spine: Genvoya, -0.92 percent; Stribild, -2.95 percent, p<0.001; hip: Genvoya, -0.75 percent; Stribild, -3.36 percent, p<0.001). The long-term clinical significance of changes in eGFR and BMD is not known. Finally, patients on Genvoya had statistically higher increases in total, LDL and HDL cholesterol from baseline to Week 144 compared to patients on Stribild. There was no significant difference in the total cholesterol-to-HDL ratio at Week 144, nor any difference in the rate of initiation of lipid-modifying agents. Studies 104 and 111, originally planned for 96 weeks and extended to 144 weeks, were randomized, double-blind, controlled Phase 3 trials conducted among 1,733 treatment-naïve adults living with HIV. The primary endpoint of the study was at Week 48, in which Genvoya was non-inferior to Stribild. Genvoya was also non-inferior at the secondary endpoint of efficacy at Week 96. At study enrollment, 15 percent of subjects were women, 25 percent identified themselves as Black or of African descent and 23 percent had viral loads ≥100,000 copies/mL. Patients were randomized 1:1 to receive a single tablet regimen of Genvoya or Stribild; randomization included stratification for CD4 count (< 50 cells/µL, 50 to 199 cells/µL, or ≥ 200 cells/µL) and region (United States or ex-United States) at screening. Additional information about the studies can be found at www.clinicaltrials.gov. BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Renal monitoring: In all patients, monitor serum creatinine, serum phosphorus, CrCl, urine glucose, and urine protein prior to initiating and during therapy as clinically appropriate. If serum creatinine increases >0.4 mg/dL from baseline, closely monitor for renal safety. Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California. This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that physicians may not see the benefits of prescribing Genvoya for the treatment of HIV. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements. U.S. full prescribing information for Genvoya and Stribild, including BOXED WARNINGS, is available at www.gilead.com. GENVOYA and STRIBILD are trademarks of Gilead Sciences, Inc., or its related companies. For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.


PubMed | Hospital Universitario La Paz, Institute Investigacion Hospital 12 Of Octubre I12, IdiPaz, g Policlinica Valdemoro Plaza and European University at Madrid
Type: Journal Article | Journal: AIDS care | Year: 2016

Depression is a common but frequently undiagnosed feature in individuals with HIV infection. To find a strategy to detect depression in a non-specialized clinical setting, the overall performance of the Hospital Anxiety and Depression Scale (HADS) and the depression identification questions proposed by the European AIDS Clinical Society (EACS) guidelines were assessed in a descriptive cross-sectional study of 113 patients with HIV infection. The clinician asked the two screening questions that were proposed under the EACS guidelines and requested patients to complete the HADS. A psychiatrist or psychologist administered semi-structured clinical interviews to yield psychiatric diagnoses of depression (gold standard). A receiver operating characteristic (ROC) analysis for the HADS-Depression (HADS-D) subscale indicated that the best sensitivity and specificity were obtained between the cut-off points of 5 and 8, and the ROC curve for the HADS-Total (HADS-T) indicated that the best cut-off points were between 12 and 14. There were no statistically significant differences in the correlations of the EACS (considering positive responses to one [A] or both questions [B]), the HADS-D8 or the HADS-T12 with the gold standard. The study concludes that both approaches (the two EACS questions and the HADS-D subscale) are appropriate depression-screening methods in HIV population. We believe that using the EACS-B and the HADS-D subscale in a two-step approach allows for rapid, assumable and accurate clinical diagnosis in non-psychiatric hospital settings.


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.


Elewa U.,IIS Fundacion Jimenez Diaz UAM FRIAT | Sanchez-Nino M.D.,IDIPAZ | Martin-Cleary C.,IIS Fundacion Jimenez Diaz UAM FRIAT | Fernandez-Fernandez B.,IIS Fundacion Jimenez Diaz UAM FRIAT | And 2 more authors.
International Urology and Nephrology | Year: 2012

End-stage renal disease patients suffer a syndrome of accelerated aging characterized by a 10- to 100-fold increase in cardiovascular and all-cause mortality when compared to age-matched controls. No specific therapeutic interventions have been shown to improve this dismal outcome. Inflammation, chronic kidney disease-mineral and bone disorder (CKD-MBD) and other biomarkers predict outcome in observational studies. However, we lack clinical trials that address the role of these biomarkers in risk stratification and therapeutic decision making. Biomarkers may also provide insights into the pathophysiology of disease and identify novel therapeutic targets. Inflammation emerges as a prime potential target for intervention. Thus, CKD-MBD biomarkers, asymmetrical dimethyl arginine and tri-iodothyronine have a link to inflammation. Interleukin-6 (IL-6) is one of the inflammation biomarkers with highest predictive value for outcome in ESRD. Biologicals targeting IL-6 are approved for the treatment of chronic inflammatory conditions such as rheumatoid arthritis. Furthermore, trials are underway to test IL-6 targeting potential to decrease cardiovascular injury in non-CKD patients. In this regard, targeting IL-1 was recently shown to decrease systemic inflammation in hemodialysis patients. The success of these trials will likely influence future studies on biomarker targeting in CKD. © 2012 Springer Science+Business Media, B.V.

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