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

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

The Iberian pig fed with high-fat diet: a model of renal disease in obesity and metabolic syndrome

The pathogenesis of renal disease in the context of overweight/obesity, metabolic syndrome, and insulin resistance is not completely understood. This may be due to the lack of a definitive animal model of disease, which limits our understanding of obesity-induced renal damage. We evaluated the changes in renal histology and lipid deposits induced by obesity in a model of insulin resistance: the Iberian swine fed with fat-enriched food.The IMBRAIN (CIBICAN) project (FP7-RE6-POT-2012-CT2012-31637-IMBRAIN) 329 funded under the 7th Framework Program (capacities); the Instituto de Salud Carlos 330 III (ISCIII) for the following grants: PI13/00342, PI, PI16/01814, the REDINREN RD16/0009 and PI10/02428; funding from the IRSIN (Instituto Reina Sofia de Investigacion), FEDER funds, SLL is a research fellow supported by the Instituto de Salud Carlos III (Grants for Río Hortega specialized healthcare post training contracts), ISCIII CM15/00214, Spain; EP is a Researcher of the Ramón y Cajal Program of the ISCIII.Peer reviewe

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~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 greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four 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 Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Inflammatory Targets in Diabetic Nephropathy

One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation

Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease

Reducing oxidative stress stands at the center of a prevention and control strategy for mitigating cellular senescence and aging. Kidney disease is characterized by a premature aging syndrome, and to find a modulator targeting against oxidative stress, mitochondrial dysfunction, and cellular senescence in kidney cells could be of great significance to prevent and control the progression of this disease. This review focuses on the pathogenic mechanisms related to the appearance of oxidative stress damage and mitochondrial dysfunction in kidney disease. In this scenario, the anti-aging Klotho protein plays a crucial role by modulating signaling pathways involving the manganese-containing superoxide dismutase (Mn-SOD) and the transcription factors FoxO and Nrf2, known antioxidant systems, and other known mitochondrial function regulators, such as mitochondrial uncoupling protein 1 (UCP1), B-cell lymphoma-2 (BCL-2), Wnt/β-catenin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), transcription factor EB, (TFEB), and peroxisome proliferator-activated receptor gamma (PPAR-gamma). Therefore, Klotho is postulated as a very promising new target for future therapeutic strategies against oxidative stress, mitochondria abnormalities, and cellular senescence in kidney disease patients

Inflammatory Cytokines in Diabetic Nephropathy

Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy

Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease

Reducing oxidative stress stands at the center of a prevention and control strategy for mitigating cellular senescence and aging. Kidney disease is characterized by a premature aging syndrome, and to find a modulator targeting against oxidative stress, mitochondrial dysfunction, and cellular senescence in kidney cells could be of great significance to prevent and control the progression of this disease. This review focuses on the pathogenic mechanisms related to the appearance of oxidative stress damage and mitochondrial dysfunction in kidney disease. In this scenario, the anti-aging Klotho protein plays a crucial role by modulating signaling pathways involving the manganese-containing superoxide dismutase (Mn-SOD) and the transcription factors FoxO and Nrf2, known antioxidant systems, and other known mitochondrial function regulators, such as mitochondrial uncoupling protein 1 (UCP1), B-cell lymphoma-2 (BCL-2), Wnt/β-catenin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), transcription factor EB, (TFEB), and peroxisome proliferator-activated receptor gamma (PPAR-gamma). Therefore, Klotho is postulated as a very promising new target for future therapeutic strategies against oxidative stress, mitochondria abnormalities, and cellular senescence in kidney disease patients