Vitamina D, inflamación y sistema FGF23/KLOTHO : implicaciones en el daño vascular

La enfermedad renal crónica (ERC) es reconocida actualmente como un problema de salud pública. Los estudios relizados en población americana muestran que la prevalencia global se sitúa en torno al 12%, mientras que en nuestro país, el estudio EPIRCE (Estudio de Prevalencia de la Insuficiencia Renal Crónica en España) demostró que dicha prevalencia era superior al 9% lo que representa, en términos absolutos, que más de 4 millones de personas presentan ERC en España. La enfermedad cardiovascular (ECV) es la causa más común de muerte en los pacientes con ERC, siendo entre 20 y 30 veces mayor que en la población general. Este exceso de riesgo cardiovascular (CV) es explicado por la elevada prevalencia de factores de riesgo CV tradicionales, así como por la presencia de factores de riesgo específicos relacionados con la ERC. Entre estos últimos destacan las alteraciones del metabolismo mineral y la inflamación. Los trabajos que conforman la presente Tesis pretenden profundizar en el conocimiento de las interrelaciones entre el metabolismo mineral, la inflamación y la ECV en el contexto de la ERC. Algunos de los avances más relevantes en este campo derivan del descubrimiento de nuevas relaciones entre la terapia con análogos de la vitamina D y la inflamación, del estudio del eje constituido por el factor de crecimiento fibroblástico 23 (fibroblast growth factor, FGF-23) y la proteína Klotho, recientemente identificado como el regulador principal de la homeostasis del fósforo, y de la relación de esta última con el mantenimiento de la salud CV. Dentro de las alteraciones del metabolismo mineral, uno de los trastornos más frecuentes que presentan los pacientes con ERC es el hiperparatiroidismo secundario (HPTS), para cuyo tratamiento se han usado ampliamente análogos de la vitamina D. Desde hace pocos años se cuenta con una nueva molécula, el 19-nor-1-25-dihidroxi-vitamina D2 (paricalcitol), un activador selectivo del receptor de la vitamina D (RVD) que, más allá de su efectividad como terapia frente al HPTS, se ha relacionado con una mejoría de la supervivencia. Estudios experimentales han mostrado que el paricalcitol presenta propiedades anti-inflamatorias, lo cual podría contribuir a los beneficios referidos para esta molécula, aunque esta posibilidad no ha sido analizada en estudios clínicos. Para evaluar si la administración de paricalcitol se asocia a efectos moduladores del fenómeno inflamatorio a nivel clínico, desarrollamos un estudio en pacientes en hemodiálisis cuyos resultados se han publicado en la revista Journal of Clinical Pharmacology (revista oficial de la Asociación Americana de Farmacología Clínica). Este trabajo se presenta en esta memoria como el Capítulo 1: Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study. Navarro-González JF, Donate-Correa J, Méndez ML, Muros-de-Fuentes M, García-Pérez J, Mora-Fernández C. Journal of Clinical Pharmacology. 2013;53(4):421-6. Por otra parte, hemos fijado nuestra atención en la posible relación existente entre el sistema FGF-23/Klotho y el daño vascular. Este sistema, más allá de su papel en el contexto del metabolismo mineral, parece tener implicaciones significativas en la ECV. Estudios clínicos en pacientes con ERC han mostrado una asociación independiente entre los elevados niveles de FGF-23 y la presencia de hipertrofia ventricular izquierda, así como con un incremento en el riesgo de mortalidad. Respecto a Klotho, esta proteína ha sido relacionada con el mantenimiento de la salud vascular. Dado que los estudios previos que presentaban datos sobre los elementos del sistema FGF-23/Klotho a nivel de la pared vascular habían sido realizados en animales de experimentación, nuestro objetivo fue caracterizar en la pared vascular humana la expresión de FGF-23, de sus receptores y de Klotho. Los resultados se han publicado en la revista International Journal of Cardiology y dicho trabajo se incluye en esta memoria bajo el epígrafe Capítulo 2: Expression of FGF23/KLOTHO system in human vascular tissue. International Journal oF Cardiology. Donate-Correa J, Mora-Fernández C, Martínez-Sanz R, Muros-de-Fuentes M, Pérez H, Meneses-Pérez B, Cazaña-Pérez V, Navarro-González JF. International Journal of Cardiology. 2013;165:179-83. Finalmente, como paso siguiente en el estudio del vínculo potencial existente entre el sistema FGF-23/Klotho y el daño vascular, nos hemos centrado en la relación entre Klotho y la enfermedad arterial coronaria (EAC). Descensos en los niveles de esta proteína se relacionan con un síndrome de envejecimiento prematuro que incluye disfunción endotelial y aterosclerosis, además de un descenso en la esperanza de vida. Dado que se ha propuesto que la proteína Klotho está involucrada en el mantenimiento de la salud vascular por distintos mecanismos, se ha sugerido que podría constituir un nuevo regulador de la ECV, con un papel potencial en la patogénesis de la aterosclerosis. La EAC es la principal causa de muerte en el mundo, y aunque el riesgo de ECV puede ser cuantificado mediante asociaciones con factores de riesgo CV tradicionales, la susceptibilidad, severidad y progresión de la EAC no se ajusta completamente a estos factores. Por tanto, la aparición en este escenario de un nuevo sistema biológico relacionado con la salud CV, podría aportar nueva información que mejore nuestra comprensión de la biología de la enfermedad aterosclerótica y la determinación del riesgo CV. Bajo estas consideraciones hemos llevado a cabo un estudio transversal para testar la hipótesis que relaciona una reducción en la concentración de la proteína Klotho soluble y un descenso en los niveles de su expresión vascular con la presencia y severidad de la EAC. Los resultados se recogen en el artículo publicado en la revista Heart y conforman el Capítulo 3: Reduced Klotho is associated with the presence and severity of coronary artery disease. Navarro-González JF, Donate-Correa J, Muros-de-Fuentes M, Pérez-Hernández H, Martínez-Sanz R, Mora-Fernández C. Heart. 2014;100:34-40

New Staphylococcus aureus genetic cluster associated with infectious osteomyelitis

Diverse genotyping methods, including multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA), pulsed field gel electrophoresis (PFGE), and multilocus sequence typing (MLST), were used for genotyping Staphylococcus aureus in samples recovered from a clinical case of osteomyelitis. An unexpected genetic diversity of strains was determined, including four new sequence types (ST 1521, 1522, 1628 and 1629) belonging to the same genetic lineage, implying the appearance of a new subgroup derived from clonal complex CC121 isolated from that hospital. A close phylogenetic relationship among the STs was demonstrated, reflecting a possible diversifying evolution process. To our knowledge, there have no been previous reports of staphylococcal genetic variability observed within a single individual with such a high degree of variation. These findings emphasize the need for infection control measures to monitor the high genetic variability continuously occurring in this often dangerous infectious agent. [Int Microbiol 2011; 14(1):33-39

Effect of hesperidin treatment on α-Klotho/FGF-23 pathway in rats with experimentally-induced diabetes

Objective Non-alcoholic fatty liver disease, steatohepatitis and nephropathy are considered among the mostimportant complications of diabetes mellitus (DM), which recently increased due to increased frequency of DMand the prolonged life span of diabetic patients The aim of the present study was to reveal the possible effect ofhesperidin (HP) on alpha-klotho (α-KL)/fibroblast growth factor-23 (FGF-23) pathway in rats with diabetesinduced by streptozotocin (STZ).Materials and methods Thirty six male Sprague-Dawley rats were randomly divided into three groups. Therats of the control, diabetes, and treatment groups were fed with standard feed and water throughout the 2-weekstudy. In order to induce diabetes mellitus in rats, those in the diabetes group were administered a single dose of50 mg/kg STZ. For the DM + HP group, a single dose of 50 mg/kg STZ, when diabetes was induced, hesperidinwas administered orally at a dose of 100 mg/kg by gavage.Results Theα-KL levels of our study groups, both the liver and kidneyα-KL levels and serumα-KL of the STZ-induced diabetic group were statistically significantly lower than the control group (respectively, p < 0.05,p < 0.001, p < 0.05). It was observed that hesperidin administration statistically significantly increasedα-KLlevels in serum, liver and renal tissue (p < 0.001). Liver, kidney and serum FGF-23 levels of the diabetic groupincreased significantly in comparison to the control group (respectively, p < 0.05, p < 0.01, p < 0.001). FGF-23 levels that increased in kidney tissue and serum samples of the diabetic group decreased statistically sig-nificantly with hesperidin administration (respectively, p < 0.01, p < 0.001).Conclusion Theα-KL/FGF-23 pathway is a promising bio-indicator in various cases of systemic toxicity andpathology. In addition, the strong positive effects of hesperidin administration on diabetic toxicity in the liverand kidneys suggest that it may be included in the alternative treatment methods in the future.This work was supported by Coordinator of Scientific Research Projects ( 2017.M83.02.01 ) at University of Artvin Coruh

Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: a clinical and experimental study

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r − 0.45, P < 0.001) and urinary TNFa (r − 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5.2 %) and urinary Klotho (38.9 %). Changes in urinary TNFa (β − 0.53, P = 0.001) and albuminuria (β − 0.31, P < 0.05) were independently associated with changes in urinary Klotho (adjusted R2 = 0.54, P < 0.001). Studies in renal tubular cells demonstrated that high glucose, albumin and TWEAK decreased Klotho mRNA expression and protein levels, an effect similarly prevented by SGLT2i. SGLT2i increase Klotho availability in type 2 diabetic patients with poorly controlled diabetes and early DKD, as well as in stressed tubular cells. This effect on Klotho may contribute to the kidney and heart protection afforded by SGLT2iThe authors thank all the study participants, without whom this study would not have been possible. The authors acknowledge the support from Instituto de Salud Carlos III (ISCIII) FIS/Fondos FEDER (PI18/01366, PI19/00815, PI19/00035, PI20/00744, PI21/00251, DTS18/00032), ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064, ISCIII-RETIC REDinREN RD16/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM, Fundacion ´ Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), PIFUN05/18. Instituto de Salud Carlos III (ISCIII) RICORS program to RICORS2040 (RD21/0005/0001 and RD21/0005/0013) and SPACKDc PMP21/00109, FEDER funds, Cátedra Mundipharma-UAM of Diabetic Kidney Disease and Cátedra Astrazeneca-UAM of Chronic Kidney Disease and Electrolytes. J.D.C is recipient of a contract from Miguel Servet Programme (CP20/00122), ISCII

Repurposing drugs for highly prevalent diseases: pentoxifylline, an old drug and a new opportunity for diabetic kidney disease

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney diseaseThis work was supported by Instituto de Salud Carlos III (ISCIII): PI07/0870, PI15/00298, PI16/02057, PI16/00024, PI19/00035, PI20/00744, PI21/00251, PI21/01037, PI19/00815, DTS18/00032 ISCIII-RETIC REDinREN RD16/0009, and RICORS2040. We acknowledge cofunding by Fondo Europeo de Desarrollo Regional [FEDER], Unión Europea [‘Una forma de hacer Europa’]. J.D.-C. is the recipient of a contract from Miguel Servet Program (CP20/00122) of the ISCIII. A.G.-L. and C.F. are recipients of contracts from Agencia Canaria de Investigación Innovación y Sociedad de la Información del Gobierno de Canarias (ACIISI) (TESIS2021010045 and TESIS2018010110). E.M.-N. is funded by a research contract from REDinREN-ISCIII (RD16/0009/0022). V.G.- T. is supported by Cabildo de Tenerife, TF Innova, Fondo de Desarrollo de Canarias (FDCAN) and Marco Estratégico de Desarrollo Insular (MEDI), in the Agustín de Betancourt programm

Role of Klotho and AGE/RAGE-Wnt/β-catenin signalling pathway on the development of cardiac and renal fibrosis in diabetes

Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/β-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-β1, and Wnt/β-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats

COVID-19 testing, infection, and vaccination among deported Mexican migrants: Results from a survey on the Mexico-U.S. border

BackgroundMigrants detained and held in immigration and other detention settings in the U.S. have faced increased risk of COVID-19 infection, but data on this population is scarce. This study sought to estimate rates of COVID-19 testing, infection, care seeking, and vaccination among Mexican migrants detained by U.S. immigration authorities and forcibly returned to Mexico.MethodsWe conducted a cross-sectional probability survey of Mexican migrants deported from the U.S. to three Mexican border cities: Tijuana, Ciudad Juárez, and Matamoros (N = 306). Deported migrants were recruited at Mexican migration facilities after being processed and cleared for departure. A two-stage sampling strategy was used. Within each city, a selection of days and shifts were selected during the operating hours of these deportation facilities. The probability of selection was proportional to the volume of migrants deported on each day of the month and during each time period. During the selected survey shifts, migrants were consecutively approached, screened for eligibility, and invited to participate in the survey. Survey measures included self-reported history of COVID-19 testing, infection, care seeking, vaccination, intentions to vaccinate, and other prevention and risk factors. Weighted data were used to estimate population-level prevalence rates. Bivariate tests and adjusted logistic regression models were estimated to identify associations between these COVID-19 outcomes and demographic, migration, and contextual factors.ResultsAbout 84.1% of migrants were tested for COVID-19, close to a third were estimated to have been infected, and, among them, 63% had sought care for COVID-19. An estimated 70.1% had been vaccinated against COVID-19 and, among those not yet vaccinated, 32.5% intended to get vaccinated. Close to half (44.3%) of respondents had experienced crowdedness while in detention in the U.S. Socio-demographic (e.g. age, education, English fluency) and migration-related (e.g. type of detention facility and time in detention) variables were significantly associated with COVID-19 testing, infection, care seeking, and vaccination history. Age, English fluency, and length of detention were positively associated with testing and vaccination history, whereas detention in an immigration center and length of time living in the U.S. were negatively related to testing, infection, and vaccination history. Survey city and survey quarter also showed adjusted associations with testing, infection, and vaccination history, reflecting potential variations in access to services across geographic regions and over time as the pandemic unfolded.ConclusionThese findings are evidence of increased risk of COVID-19 infection, insufficient access to testing and treatment, and missed opportunities for vaccination among Mexican migrants detained in and deported from the U.S. Deportee receiving stations can be leveraged to reduce disparities in testing and vaccination for deported migrants. In addition, decarceration of migrants and other measures informed by public health principles must be implemented to reduce COVID-19 risk and increase access to prevention, diagnostic, and treatment services among this underserved population

The next phases of the Migrante Project: Study protocol to expand an observatory of migrant health on the Mexico—U.S. border

BackgroundMexican migrants traveling across the Mexico-United States (U.S.) border region represent a large, highly mobile, and socially vulnerable subset of Mexican nationals. Population-level health data for this group is hard to obtain given their geographic dispersion, mobility, and largely unauthorized status in the U.S. Over the last 14 years, the Migrante Project has implemented a unique migration framework and novel methodological approach to generate population-level estimates of disease burden and healthcare access for migrants traversing the Mexico-U.S. border. This paper describes the rationale and history of the Migrante Project and the protocol for the next phases of the project.Methods/designIn the next phases, two probability, face-to-face surveys of Mexican migrant flows will be conducted at key crossing points in Tijuana, Ciudad Juarez, and Matamoros (N = 1,200 each). Both survey waves will obtain data on demographics, migration history, health status, health care access, COVID-19 history, and from biometric tests. In addition, the first survey will focus on non-communicable disease (NCD), while the second will dive deeper into mental health and substance use. The project will also pilot test the feasibility of a longitudinal dimension with 90 survey respondents that will be re-interviewed by phone 6 months after completing the face-to-face baseline survey.DiscussionInterview and biometric data from the Migrante project will help to characterize health care access and health status and identify variations in NCD-related outcomes, mental health, and substance use across migration phases. The results will also set the basis for a future longitudinal extension of this migrant health observatory. Analyses of previous Migrante data, paired with data from these upcoming phases, can shed light on the impact of health care and immigration policies on migrants’ health and inform policy and programmatic responses to improve migrant health in sending, transit, and receiving communities