Enfermedad renal crónica: la carga sanitaria invisible para los organismos

The uptake of the current concept of chronic kidney disease (CKD) by the public, physicians and health authorities is low. Physicians still mix up CKD with chronic kidney insufficiency or failure. In a recent manuscript, only 23% of participants in a cohort of persons with CKD had been diagnosed by their physicians as having CKD while 29% has a diagnosis of cancer and 82% had a diagnosis of hypertension. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. A prevalent view is that for those in whom kidneys fail, the problem is “solved” by dialysis or kidney transplantation. However, the main burden of CKD is accelerated aging and allcause and cardiovascular premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Moreover, men and women undergoing KRT still have an annual mortality which is 10–100- fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true. However, only the highest level of research funding through the CIBER will allow to adequately address the issue before it is too lateEl impacto del concepto actual de enfermedad renal crónica (ERC) en la población, médicos y autoridades sanitarias ha sido bajo. Los médicos aún confunden la ERC con la insuficiencia renal crónica. En un manuscrito reciente, en una cohorte de personas con ERC, solo el 23% de los participantes fueron diagnosticados de ERC por sus médicos mientras que el 29% estaban diagnosticados de cáncer y el 82% de hipertensión. Para el público en general y las autoridades sanitarias, la ERC evoca la terapia de reemplazo renal (TRR). En España, la prevalencia de TRR es del 0,13%. La opinión predominante es que para aquellos en los que fallan los riñones el problema se “resuelve” mediante diálisis o trasplante de riñón. Sin embargo, la principal carga sanitaria de la ERC es el envejecimiento acelerado y la muerte prematura de causa cardiovascular o de cualquier causa. La ERC es el factor mas prevalente de riesgo de mortalidad por COVID-19 después de la edad avanzada. Además, los hombres y mujeres que se someten a TRR todavía tienen una mortalidad anual que es de 10 a 100 veces superior a sus pares de edades similares, y la esperanza de vida se reduce en alrededor de 40 años para jóvenes en diálisis y en 15 años para jóvenes con un injerto renal funcionante. Se espera que la ERC se convierta en la quinta causa mundial de muerte para 2040 y la segunda causa de muerte en España antes de fin de siglo, época en la que 1 de cada 4 españoles tendrá ERC. Sin embargo, para 2022, la ERC se convertirá en la única causa de muerte entre las 15 principales a nivel mundial que no cuenta con el respaldo de una estructura de investigación CIBER en España. Los Principales grupos de investigación renal en España agrupados en la red de investigación colaborativa renal REDINREN han solicitado la convocatoria RICORS de investigación colaborativa en España con el apoyo de la Sociedad Española de Nefrología, ALCER y ONT: RICORS 040 tiene como objetivo evitar que se hagan realidad las terribles predicciones sobre la carga mundial de ERC para 2040. Sin embargo, solo el más alto nivel de financiación de la investigación a través del CIBER permitirá abordar adecuadamente el problema antes de que sea demasiado tard

Inflammatory and fibrotic mediators in renal diseases

This work was supported by the Instituto de Salud Carlos III and Fondos FEDER European Union (PI014/00041, PI17/00119), Red de Investigación Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), and Sociedad Española de Nefrología. The “Juan de la Cierva de Formacion” training program of the Ministerio de Economía, Industria y Competitividad, Gobierno de España, supported the salary of SR-M (FJCI-2016-2905

Prohibició de l'eutanàsia en les gosseres

Treball presentat a la Facultat de Veterinària de la Universitat Autònoma de Barcelona.Treball presentat a l'assignatura de Deontologia i Veterinària Legal (21223

Paricalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production

Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice.This study was supported by RETICS 06/0016 (VFM, RS) and FIS PI 09/0064 (RS) from the Fondo de Investigaciones Sanitarias (Health Research Fund). MLC was funded by SAF 2013-47611-R, SAF 2010-21249, and SAF 2007-61201 from the Ministerio de Economía y competitividad. MRO was supported by RETICS 12/0021,S2012DMD2321 from the Comunidad Autónoma de Madrid, PI 11/01854 from Fondo Investigaciones Sanitarias. GTGM was supported by Renal Foundation Íñigo Álvarez de Toledo, FIBHULP, and by Severo Ochoa FoundationPeer Reviewe

Rapid Climate Changes in the Westernmost Mediterranean (Alboran Sea) Over the Last 35 kyr: New Insights From Four Lipid Paleothermometers (UK' 37, TEXH 86, RI-OH', and LDI)

This study was supported by Grant PID2019-104624RB-I00 funded by MCIN/AEI/ 10.13039/501100011033, Grants FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento P18-RT-3804 and P18-RT- 4074, and Research Group RNM-179 (Junta de Andalucia). The authors also thank the Unidad Cientifica de Excelencia UCE-PP2016-05 (University of Granada). This study also received funding from the Netherlands Earth System Science Center (NESSC) through a gravitation grant (024.002.001) to J. S. Sinninghe Damste and S. Schouten from the Dutch Ministry for Education, Culture and Science. M. Rodrigo-Gamiz acknowledges funding from the Andalucia Talent Hub Program co-funded by the European Union's Seventh Framework Program (COFUND-Grant Agreement No 291780) and the Junta de Andalucia and from the Juan de la Cierva-Incorporacion program in the University of Granada (IJCI-2017-33,755) from Secretaria de Estado de I + D + i, Spain. We thank the captain, crew, and participants of the Gasalb cruise onboard R/V Pelagia for assistance during sampling. We are also grateful to the Poznan Radiocarbon Laboratory (Poland), the Leibniz Laboratory for Radiometric Dating and Stable Isotope Research (Germany), and the Centre for Scientific Instrumentation (CIC, Spain) for analyses. The authors thank Jort Ossebaar, Anchelique Mets, Marianne Baas and Karsten Dekker (all at NIOZ) for laboratory assistance. Thanks to Prof. Giuseppe Siani (Universite Paris-Sud Orsay) and Jose Manuel Mesa Fernandez for their help and comments on the age model. We thank the Associate Editor, Dr. Yige Zhang, two anonymous reviewers, and Dr. Felix J. Elling for their helpful comments that improved the manuscript substantially. Funding for open access charge from Universidad de Granada/CBUA.The westernmost Mediterranean is one of the most sensitive areas to global climate change and high sedimentation rates allow recording high frequency variability. We present a high-resolution paleotemperature reconstruction over the last 35 kyr using, for the first time, four independent organic sea surface temperature (SST) proxies (UK' 37, TEXH 86, RI-OH' and LDI) based on alkenones, (hydroxy) isoprenoid GDGTs, and long-chain diols. We also generated a δ18O of planktonic foraminifera G. bulloides record together with records of bulk parameters (total organic carbon content, δ13Corg) and the accumulation rates of different biomarkers to provide insights into terrestrial input and primary producers. All derived-SST records showed similar trends over the last 35 kyr, revealing abrupt temperature variations during the last seven Dansgaard- Oeschger (D/O) cycles, the three Heinrich (H) events, the Last Glacial Maximum, and the Younger Dryas. H3 is recognized as the coldest event, while H1 was recorded by all SST proxies as the most abrupt one. In general, TEXH 86-, RI-OH'- and LDI-SST estimates were lower than those obtained from UK' 37. The LDI paleothermometer recorded the largest range of absolute SSTs over the whole period (ca. 20°C) followed by RI-OH' (ca. 16°C). TEXH 86, RI-OH' and LDI proxies reflected sudden SST changes during the D/O 6 and 5 particularly well. Low BIT values and the abundance of C32 1,15-diol in range with typical marine values indicated only minor input of continental organic matter. Accumulation rates of different lipid biomarkers were generally modulated by D/O cycles, suggesting enhanced productivity during D/O interstadials and the Bölling- Alleröd period.Grants FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento PID2019-104624RB-I00 MCIN/AEI/ 10.13039/501100011033 P18-RT-3804 P18-RT- 4074Research Group RNM-179Unidad Cientifica de Excelencia UCE-PP2016-05Netherlands Earth System Science Center (NESSC) through a gravitation grant 024.002.001Andalucia Talent Hub Program - European Union's Seventh Framework Program (COFUND-Grant) 291780 Junta de AndaluciaJuan de la Cierva-Incorporacion program in the University of Granada from Secretaria de Estado de I + D + i, Spain IJCI-2017-33,755Universidad de Granada/CBU

Statins Inhibit Angiotensin II/Smad Pathway and Related Vascular Fibrosis, by a TGF-β-Independent Process

We have recently described that in an experimental model of atherosclerosis and in vascular smooth muscle cells (VSMCs) statins increased the activation of the Smad pathway by transforming growth factor-β (TGF-β), leading to an increase in TGF-β-dependent matrix accumulation and plaque stabilization. Angiotensin II (AngII) activates the Smad pathway and contributes to vascular fibrosis, although the in vivo contribution of TGF-β has not been completely elucidated. Our aim was to further investigate the mechanisms involved in AngII-induced Smad activation in the vasculature, and to clarify the beneficial effects of statins on AngII-induced vascular fibrosis. Infusion of AngII into rats for 3 days activates the Smad pathway and increases fibrotic-related factors, independently of TGF-β, in rat aorta. Treatment with atorvastatin or simvastatin inhibited AngII-induced Smad activation and related-fibrosis. In cultured rat VSMCs, direct AngII/Smad pathway activation was mediated by p38 MAPK and ROCK activation. Preincubation of VSMCs with statins inhibited AngII-induced Smad activation at all time points studied (from 20 minutes to 24 hours). All these data show that statins inhibited several AngII-activated intracellular signaling systems, including p38-MAPK and ROCK, which regulates the AngII/Smad pathway and related profibrotic factors and matrix proteins, independently of TGF-β responses. The inhibitory effect of statins on the AngII/Smad pathway could explain, at least in part, their beneficial effects on hypertension-induced vascular damage

Special issue “Diabetic nephropathy: Diagnosis, prevention and treatment”

Diabetic nephropathy (DN) is the main cause of end-stage renal disease. DN is a complex disease mediated by genetic and environmental factors, and many cellular and molecular mechanisms are involved in renal damage in diabetes. There are no biomarkers that reflect the severity of the underlying renal histopathological changes and can e ectively predict the progression of renal damage and stratify the risk of DN among individuals with diabetes mellitus. Current therapeutic strategies are based on the strict control of glucose and blood pressure levels and, although there are new anti-diabetic drugs, these treatments only retard renal damage progression, being necessary novel therapies. In this Special Issue, there are several comprehensive reviews and interesting original papers covering all these topics, which would be of interest to the growing number of readers of the Journal of Clinical MedicineEditors are funding by Grants from the Instituto de Salud Carlos III(ISCIII) and Fondos FEDER European Union (PI17/00119 and Red de Investigación Renal (REDINREN): RD16/0009, to M.R-O), Comunidad de Madrid (“NOVELREN” B2017/BMD-3751 to M.R-O); the José Castillejo grant (CAS19/00133 to R.R.R-D); the “Juan de la Cierva Formacion” training program of the Ministerio de Economia, Industria y Competitividad (MINECO) supported the salary of SR-M (FJCI-2016-29050); Sociedad Española de Nefrologia (S.E.N. to M.R-O). Grants PAI 82140017 to C.L. of Chile; IMPROVE-PD project (“Identification and Management of Patients atRisk–Outcome and Vascular Events in Peritoneal Dialysis”) funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 812699 to M.R.O

Dependence From The Perspective Of Primary Caregivers Of People With Disabilities

The paper is focused on informal caregivers of people with disabilities, particularly in mentally handicapped persons. Informal caregiver refers to those relatives, friends or any person who make this task without any formal economic remuneration. Only in few cases, caregivers are able to receive some economic aid by the administration. We develop a questionnaire to analyze personal, familiar, economic and social situation of primary caregivers. The empirical results are based on a sample of 128 caregivers of a spanish association created for people with disabilities

TWEAK Activates the Non-Canonical NFκB Pathway in Murine Renal Tubular Cells: Modulation of CCL21

TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-lasting NFκB activation suggestive of engagement of the non-canonical NFκB pathway. We now explore TWEAK-induced activation of NFκB2 and RelB, as well as expression of CCL21, a T-cell chemotactic factor, in cultured murine tubular epithelial cells and in healthy kidneys in vivo. In cultured tubular cells, TWEAK and TNFα activated different DNA-binding NFκB complexes. TWEAK-induced sustained NFκB activation was associated with NFκB2 p100 processing to p52 via proteasome and nuclear translocation and DNA-binding of p52 and RelB. TWEAK, but not TNFα used as control), induced a delayed increase in CCL21a mRNA (3.5±1.22-fold over control) and CCL21 protein (2.5±0.8-fold over control), which was prevented by inhibition of the proteasome, or siRNA targeting of NIK or RelB, but not by RelA inhibition with parthenolide. A second NFκB2-dependent chemokine, CCL19, was upregulates by TWEAK, but not by TNFα. However, both cytokines promoted chemokine RANTES expression (3-fold mRNA at 24 h). In vivo, TWEAK induced nuclear NFκB2 and RelB translocation and CCL21a mRNA (1.5±0.3-fold over control) and CCL21 protein (1.6±0.5-fold over control) expression in normal kidney. Increased tubular nuclear RelB and tubular CCL21 expression in acute kidney injury were decreased by neutralization (2±0.9 vs 1.3±0.6-fold over healthy control) or deficiency of TWEAK (2±0.9 vs 0.8±0.6-fold over healthy control). Moreover, anti-TWEAK treatment prevented the recruitment of T cells to the kidney in this model (4.1±1.4 vs 1.8±1-fold over healthy control). Our results thus identify TWEAK as a regulator of non-canonical NFκB activation and CCL21 expression in tubular cells thus promoting lymphocyte recruitment to the kidney during acute injury