Cellular and Mitochondrial Pathways Contribute to SGLT2 Inhibitors-mediated Tissue Protection: Experimental and Clinical Data.

In metabolic syndrome and diabetes, compromised mitochondrial function emerges as a critical driver of cardiovascular disease, fueling its development and persistence, culminating in cardiac remodeling and adverse events. In this context, angiotensin II - the main interlocutor of the renin-angiotensin-aldosterone system - promotes local and systemic oxidative inflammatory processes. To highlight, the low activity/expression of proteins called sirtuins negatively participates in these processes, allowing more significant oxidative imbalance, which impacts cellular and tissue responses, causing tissue damage, inflammation, and cardiac and vascular remodeling. The reduction in energy production of mitochondria has been widely described as a significant element in all types of metabolic disorders. Additionally, high sirtuin levels and AMPK signaling stimulate hypoxia- inducible factor 1 beta and promote ketonemia. Consequently, enhanced autophagy and mitophagy advance through cardiac cells, sweeping away debris and silencing the orchestra of oxidative stress and inflammation, ultimately protecting vulnerable tissue from damage. To highlight and of particular interest, SGLT2 inhibitors (SGLT2i) profoundly influence all these mechanisms. Randomized clinical trials have evidenced a compelling picture of SGLT2i emerging as game-changers, wielding their power to demonstrably improve cardiac function and slash the rates of cardiovascular and renal events. Furthermore, driven by recent evidence, SGLT2i emerge as cellular supermolecules, exerting their beneficial actions to increase mitochondrial efficiency, alleviate oxidative stress, and curb severe inflammation. Its actions strengthen tissues and create a resilient defense against disease. In conclusion, like a treasure chest brimming with untold riches, the influence of SGLT2i on mitochondrial function holds untold potential for cardiovascular health. Unlocking these secrets, like a map guiding adventurers to hidden riches, promises to pave the way for even more potent therapeutic strategies.

Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins.

PURPOSE OF REVIEW: To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes. RECENT FINDINGS: Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1ß (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.

[Renal effects of GLP-1 agonists in type 2 diabetes]. / Efectos renales de los agonistas GLP-1 en la diabetes tipo 2.

The prevalence of type 2 diabetes mellitus (DM2) is increasing, generating a great impact both at individual and public health level. Nearly half of the patients with DM2 develop impaired renal function, so nephron-protection is highly important. The robust body of evidence that shifted the therapeutic focus from glycemic to cardio-renal metabolic therapy in DM2 led to the inclusion of new therapies with cardiovascular and renal benefits in international guidelines. Type 1 glucagon (GLP-1) receptor agonists have showed favorable effects on renal function and their potential protective actions are multifactorial, beyond glycemic control. These benefits have been demonstrated in efficacy and safety clinical studies, as well as in cardiovascular outcomes and real-life studies. This comprehensive review describes the direct and indirect effects of these molecules, as well as evidence obtained from pivotal clinical (LEADER, SUSTAIN 6 and REWIND) and real-life studies demonstrating their beneficial effects on renal function, and also introduces expectations of future results from ongoing studies with renal endpoints.

La prevalencia de diabetes mellitus tipo 2 (DM2) está en aumento, generando un gran impacto tanto a nivel individual como en salud pública. Cerca de la mitad de los pacientes con DM2 sufren un deterioro de la función renal, por esto la nefroprotección resulta de fundamental importancia. El conjunto de evidencia que cambió del enfoque terapéutico glucocéntrico al cardiorrenometabólico en la DM2 motivó la inclusión en las recomendaciones internacionales de nuevas terapias con beneficios cardiovasculares y renales. Los agonistas del receptor del péptido similar al glucagón tipo 1 (GLP-1) tienen efectos favorables sobre la función renal y sus posibles acciones protectoras son multifactoriales, más allá del control glucémico. Estos beneficios han sido demostrados en los estudios clínicos de eficacia y seguridad, así como también en los estudios de resultados cardiovasculares y de vida real. En esta revisión narrativa se describen los efectos directos e indirectos de estas moléculas, así como su evidencia en los principales estudios clínicos (LEADER, SUSTAIN 6 y REWIND) y de vida real que demuestran sus efectos beneficiosos sobre la función renal e introduce la expectativa de los resultados futuros de los estudios en curso con objetivos renales.

High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial.

BACKGROUND: The role of oral vitamin D3 supplementation for hospitalized patients with COVID-19 remains to be determined. The study was aimed to evaluate whether vitamin D3 supplementation could prevent respiratory worsening among hospitalized patients with COVID-19. METHODS AND FINDINGS: We designed a multicentre, randomized, double-blind, sequential, placebo-controlled clinical trial. The study was conducted in 17 second and third level hospitals, located in four provinces of Argentina, from 14 August 2020 to 22 June 2021. We enrolled 218 adult patients, hospitalized in general wards with SARS-CoV-2 confirmed infection, mild-to-moderate COVID-19 and risk factors for disease progression. Participants were randomized to a single oral dose of 500 000 IU of vitamin D3 or matching placebo. Randomization ratio was 1:1, with permuted blocks and stratified for study site, diabetes and age (≤60 vs >60 years). The primary outcome was the change in the respiratory Sepsis related Organ Failure Assessment score between baseline and the highest value recorded up to day 7. Secondary outcomes included the length of hospital stay; intensive care unit admission; and in-hospital mortality. Overall, 115 participants were assigned to vitamin D3 and 105 to placebo (mean [SD] age, 59.1 [10.7] years; 103 [47.2%] women). There were no significant differences in the primary outcome between groups (median [IQR] 0.0 [0.0-1.0] vs 0.0 [0.0-1.0], for vitamin D3 and placebo, respectively; p = 0.925). Median [IQR] length of hospital stay was not significantly different between vitamin D3 group (6.0 [4.0-9.0] days) and placebo group (6.0 [4.0-10.0] days; p = 0.632). There were no significant differences for intensive care unit admissions (7.8% vs 10.7%; RR 0.73; 95% CI 0.32 to 1.70; p = 0.622), or in-hospital mortality (4.3% vs 1.9%; RR 2.24; 95% CI 0.44 to 11.29; p = 0.451). There were no significant differences in serious adverse events (vitamin D3 = 14.8%, placebo = 11.7%). CONCLUSIONS: Among hospitalized patients with mild-to-moderate COVID-19 and risk factors, a single high oral dose of vitamin D3 as compared with placebo, did not prevent the respiratory worsening. TRIAL REGISTRATION: ClincicalTrials.gov Identifier: NCT04411446.

Efectos renales de los agonistas GLP-1 en la diabetes tipo 2 / Renal effects of GLP-1 agonists in type 2 diabetes

Resumen La prevalencia de diabetes mellitus tipo 2 (DM2) está en aumento, generando un gran impacto tanto a nivel individual como en salud pública. Cerca de la mitad de los pacientes con DM2 sufren un deterioro de la función renal, por esto la nefroprotección resulta de fundamental importancia. El conjunto de evidencia que cambió del enfoque terapéutico glucocéntrico al cardiorrenometabólico en la DM2 motivó la inclu sión en las recomendaciones internacionales de nuevas terapias con beneficios cardiovasculares y renales. Los agonistas del receptor del péptido similar al glucagón tipo 1 (GLP-1) tienen efectos favorables sobre la función renal y sus posibles acciones protectoras son multifactoriales, más allá del control glucémico. Estos beneficios han sido demostrados en los estudios clínicos de eficacia y seguridad, así como también en los estudios de re sultados cardiovasculares y de vida real. En esta revisión narrativa se describen los efectos directos e indirectos de estas moléculas, así como su evidencia en los principales estudios clínicos (LEADER, SUSTAIN 6 y REWIND) y de vida real que demuestran sus efectos beneficiosos sobre la función renal e introduce la expectativa de los resultados futuros de los estudios en curso con objetivos renales.

Abstract The prevalence of type 2 diabetes mellitus (DM2) is increasing, generating a great impact both at individual and public health level. Nearly half of the patients with DM2 develop impaired renal function, so nephron-protection is highly important. The robust body of evidence that shifted the therapeutic focus from glycemic to cardio-renal metabolic therapy in DM2 led to the inclusion of new therapies with cardiovascular and renal benefits in international guidelines. Type 1 glucagon (GLP-1) receptor agonists have showed favorable effects on renal function and their potential protective actions are multifactorial, beyond glycemic control. These benefits have been demonstrated in efficacy and safety clini cal studies, as well as in cardiovascular outcomes and real-life studies. This comprehensive review describes the direct and indirect effects of these molecules, as well as evidence obtained from pivotal clinical (LEADER, SUSTAIN 6 and REWIND) and real-life studies demonstrating their beneficial effects on renal function, and also introduces expectations of future results from ongoing studies with renal endpoints.

Evaluación de la función renal para la detección y seguimiento de la enfermedad renal crónica. Documento multidisciplinario de consenso 2021. Especial atención sobre situaciones clínicas específicas / Evaluation of renal function for the detection and follow-up of chronic kidney disease. Multidisciplinaryconsensus document 2021. Special attention to specific clinical situations

Resumen El filtrado glomerular (FG) se considera el mejor índice para evaluar la función renal en la práctica clínica. Recientemente, ha ganado popularidad la utilización de ecuaciones que estiman el FG, en distintas poblaciones, a partir de los niveles séricos de algunos biomarcadores. Sin embargo, no todas las fórmulas han sido validadas en los diversos escenarios clínicos probables. Las sociedades participantes: Sociedad Argentina de Nefrología, Asociación Bioquímica Argentina, Fundación Bioquímica Argentina y Confederación Unificada Bioquímica de la República Argentina, integradas por nefrólogos y bioquímicos, realizaron un consenso actualizado sobre la utilización del FG como herramienta de detección de la enfermedad renal crónica (ERC) en la Argentina. Se analizó la bibliografía existente y, teniendo en cuenta aspectos de nuestra realidad sanitaria, se establecieron sugerencias para su utilización. Se actualizaron las indicaciones del uso del FG medido. En sucesivos capítulos se puso foco en distintos estados del FG en diversas poblaciones y situaciones. En los estados de reducción del FG, se mencionaron tanto los fisiológicos propios del envejecimiento, como los determinados por situaciones patológicas, por ejemplo, el observado en la ERC avanzada o el determinado en aquellos pacientes que recibieron un trasplante renal. Se revisaron, por otro lado, las situaciones de incremento del FG, como las observadas en el embarazo o en la obesidad. Se refirieron, asimismo, las limitaciones de la estimación del FG, se reconoció su valor en situaciones de la práctica clínica habitual, o en contextos epidemiológicos definidos y se sugirieron las ecuaciones más adecuadas para su utilización en cada caso.

Abstract The glomerular filtration rate (GFR) is considered the best index to assess the renal function in clinical practice. Recently, the use of equations to estimate GFR in different populations, based on the serum levels of some biomarkers, has gained popularity. However, not all the equations have been validated in the various likely clinical scenarios. Thus, the participating societies, i.e. the Argentine Society of Nephrology, the Argentine Association of Biochemistry, the Argentine Foundation of Biochemistry, and the Unified Confederation of Biochemistry of Argentina, composed of nephrologists and biochemists, have established an updated consensus on the use of the GFR as a tool for the detection of chronic kidney disease (CKD) in Argentina. The consensus was established on the basis of the analysis of the existing literature and taking into account aspects of the health situation in Argentina. Suggestions for the use of the GFR were made, and the indications for its use were updated. The successive chapters of the consensus consider different values of the GFR in different populations and situations. The different situations considered and reviewed include cases of a decrease in the GFR, such as the physiological one related to aging and that related to pathological situations, as observed in advanced CKD or in patients who have received a kidney transplant, as well as cases of an increase in the GRF, such as that observed in pregnancy or obesity. The consensus also mentions the advantages and limitations of the estimation of the GFR in situations of usual clinical practice or in specific epidemiological contexts, and the most appropriate equations for its use in each case is suggested.

Resumo A filtração glomerular (FG) é considerada o melhor índice para avaliar a função renal na prática clínica. Recentemente, a utilização de equações que calculam a FG, em diferentes populações, ganhou popularidade a partir dos níveis séricos de alguns biomarcadores. Entretanto, nem todas as fórmulas têm sido validadas nos diversos cenários clínicos prováveis. As sociedades participantes: Sociedade Argentina de Nefrologia, Associação Bioquímica Argentina, Fundação Bioquímica Argentina e Confederação Unificada Bioquímica da República Argentina, integradas por nefrologistas e bioquímicos, realizaram um consenso atualizado sobre a utilização da FG, como ferramenta de detecção da doença renal crônica (DRC) na Argentina. Foi analisada a bibliografia existente e, considerando aspectos da nossa realidade sanitária, foram estabelecidas sugestões para sua utilização. Foram atualizadas as indicações do uso da FG medida. Em sucessivos capítulos se colocou o foco em diferentes estados da FG em populações e situações diversas. Nos estados de redução da FG, foram mencionados tanto os fisiológicos próprios do envelhecimento, quanto os determinados por situações patológicas, por exemplo, aquele observado na DRC avançada ou o determinado naqueles pacientes que receberam um transplante renal. Por outra parte, foram revistas as situações de aumento da FG como as observadas na gravidez ou na obesidade. Foram referidas, também, as limitações da estimativa da FG, foi reconhecido o seu valor em situações da prática clínica habitual, ou em contextos epidemiológicos definidos e se sugeriram equações mais adequadas para sua utilização em cada caso.

Chronic Kidney Disease and Arterial Stiffness: A Two-Way Path.

The kidney-heart relationship has raised interest for the medical population since its vast and complex interaction significantly impacts health. Chronic kidney disease (CKD) generates vascular structure and function changes, with significant hemodynamic effects. The early arterial stiffening in CKD patients is a consequence of the interaction between oxidative stress and chronic vascular inflammation, leading to an accelerated deterioration of left ventricular function and alteration in tissue perfusion. CKD amplifies the inflammatory cascade's activation and is responsible for altering the endothelium function, increasing the vascular tone, wall thickening, and favors calcium deposits in the arterial wall. Simultaneously, the autonomic imbalance, and alteration in other hormonal systems, also favor the overactivation of inflammatory and fibrotic mediators. Thus, hormonal disarrangement also contributes to structural and functional lesions throughout the arterial wall. On the other hand, a rise in arterial stiffening and volume overload generates high left ventricular afterload. It increases the left ventricular burden with consequent myocardial remodeling, development of left ventricular hypertrophy and, in turn, heart failure. It is noteworthy that reduction in glomerular mass of renal diseases generates a compensatory glomerular filtration overdriven associated with large-arteries stiffness and high cardiovascular events. Furthermore, we consider that the consequent alterations of the arterial system's mechanical properties are crucial for altering tissue perfusion, mainly in low resistance. Thus, increasing the knowledge of these processes may help the reader to integrate them from a pathophysiological perspective, providing a comprehensive idea of this two-way path between arterial stiffness and renal dysfunction and their impact at the cardiovascular level.

High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial (CARED-TRIAL).

OBJECTIVES: To evaluate whether a single high dose of oral cholecalciferol improves the respiratory outcomes as compared with placebo among adults COVID-19 patients at moderate risk of clinical complications. TRIAL DESIGN: The CARED trial is an investigator-initiated, multicentre, randomized, parallel, two-arm, sequential, double-blind and placebo-controlled clinical trial. It was planned as a pragmatic trial since the inclusion criteria are broad and the study procedures are as simple as possible, in order to be implemented in the routine clinical practice in general wards in the pandemic setting and a middle-income country context. The sequential design involves two stages. The first stage will assess the effects of vitamin D supplementation on blood oxygenation (physiological effects). The second stage will assess the effects on clinical outcomes. PARTICIPANTS: Participants of either gender admitted to general adult wards in 21 hospital sites located in four provinces of Argentina are invited to participate in the study if they meet the following inclusion criteria and none of the exclusion criteria: Inclusion criteria SARS-CoV-2 confirmed infection by RT-PCR; Hospital admission at least 24 hours before; Expected hospitalization in the same site ≥24 hours; Oxygen saturation ≥90% (measured by pulse oximetry) breathing ambient air; Age ≥45 years or at least one of the following conditions: ○ Hypertension; ○ Diabetes; ○ At least moderate COPD or asthma; ○ Cardiovascular disease (history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting or valve replacement surgery); ○ Body mass index ≥30; Willingness to sign informed consent (online supplementary material 1 and 2). EXCLUSION CRITERIA: Age <18 years; Women in childbearing age; >= 72 hs since current admission; Requirement for a high dose of oxygen (>5 litres/minute) or mechanical ventilation (non-invasive or invasive); History of chronic kidney disease requiring haemodialysis or chronic liver failure; Inability for oral intake. Chronic supplementation with pharmacological vitamin D; Current treatment with anticonvulsants; History of: ○ Sarcoidosis; ○ Malabsorption syndrome; ○ Known hypercalcemia or serum calcium >10.5 mg/dL; Life expectancy <6 months; Known allergy to study medication; Any condition at discretion of investigator impeding to understand the study and give informed consent. INTERVENTION AND COMPARATOR: The intervention consists in a single oral dose of 500.000 IU of commercially available cholecalciferol soft gel capsules (5 capsules of 100.000 IU) or matching placebo MAIN OUTCOMES: The primary outcome for the first stage is the change in the respiratory Sepsis-related Organ Failure Assessment (SOFAr) score between pre-treatment value and the worst value recorded during the first 7 seven days of hospitalization, the death or discharge, whichever occurs first. The SOFAr score measured as the ratio between the pulse oximetry saturation (SpO2) and FiO2 (27, 28) is used instead of the arterial partial pressure of oxygen (PaO2). SOFAr score is a 4-points scale, with higher values indicating deeper respiratory derangement as follows: 1 PaO2 <400; 2 PaO2 <300; 3 PaO2 <200; 4 PaO2 <100. The primary outcome for the second stage is the combined occurrence of requirement ≥40% of FiO2, invasive or non-invasive ventilation, up to 30 days or hospital discharge. RANDOMISATION: A computer-generated random sequence and the treatment assignment is performed through the web-based randomization module available in the electronic data capture system (Castor®). A randomization ratio 1:1, stratified and with permuted blocks was used. Stratification variables were diabetes (yes/no), age (≤60/>60 years) and the site. BLINDING (MASKING): Double-blind was achieved by using placebo soft gel capsules with the same organoleptic properties as the active medication. Central management of the medication is carried out by a pharmacist in charge of packaging the study drug in unblinded fashion, who have no contact with on-site investigators. Medication is packaged in opaque white bottles, each containing five soft gel capsules of the active drug or matching placebo, corresponding to complete individual treatment. Treatment codes are kept under the pharmacist responsibility, and all researchers are unaware of them. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first stage is planned to include 200 patients (100 per group), the second stage is planned to include 1064 additional patients. The total sample size is 1264 patients. TRIAL STATUS: Currently the protocol version is the number 1.4 (from October 13th, 2020). The recruitment is ongoing since August 11th, 2020, and the first subject was enrolled on August 14th. Since then, 21 sites located in four provinces of Argentina were initiated, and 167 patients were recruited by January 11th, 2021. We anticipate to finish the recruitment for the first stage in mid-February, 2021, and in August, 2021 for the second stage. TRIAL REGISTRATION: The study protocol is registered in ClinicalTrials.gov (identifier number NCT04411446 ) on June 2, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Differences in RAAS/vitamin D linked to genetics and socioeconomic factors could explain the higher mortality rate in African Americans with COVID-19.

COVID-19 is said to be a pandemic that does not distinguish between skin color or ethnic origin. However, data in many parts of the world, especially in the United States, begin to show that there is a sector of society suffering a more significant impact from this pandemic. The Black population is more vulnerable than the White population to infection and death by COVID-19, with hypertension and diabetes mellitus as probable predisposing factors. Over time, multiple disparities have been observed between the health of Black and White populations, associated mainly with socioeconomic inequalities. However, some mechanisms and pathophysiological susceptibilities begin to be elucidated that are related directly to the higher prevalence of multiple diseases in the Black population, including infection and death by COVID-19. Plasma vitamin D levels and evolutionary adaptations of the renin-angiotensin-aldosterone system (RAAS) in Black people differ considerably from those of other races. The role of these factors in the development and progression of hypertension and multiple lung diseases, among them SARS-CoV-2 infection, is well established. In this sense, the present review attempts to elucidate the link between vitamin D and RAAS ethnic disparities and susceptibility to infection and death by COVID-19 in Black people, and suggests possible mechanisms for this susceptibility.

El suplemento con altas dosis de vitaminaD podría representar una alternativa promisoria para prevenir o tratar la infección por COVID-19 / Vitamin D high doses supplementation could represent a promising alternative to prevent or treat COVID-19 infection

Si bien carecemos de suficiente evidencia que justifique suplementar con vitaminaD en la prevención y/o tratamiento de la infección por COVID-19, a la fecha resulta cada vez más factible que esta hipótesis sea válida. Dos mecanismos básicos generales deberían ser considerados. Uno sería la acción antiinfecciosa e inmunomoduladora que ejerce mejorando las barreras intercelulares por estímulo de la inmunidad innata, así también por modulación de la inmunidad adaptativa. También, la vitaminaD reduce la producción de citoquinas inflamatorias como IL-2 e interferón gamma (INF-γ). Más recientemente se han demostrado múltiples efectos pleiotrópicos sobre las acciones de la vitaminaD a nivel antiinflamatorio e inmunomodulador. Esto explica resultados positivos en estudios con influenza, coronavirus y otras infecciones respiratorias. Se ha descrito relación inversa entre niveles séricos de vitaminaD y prevalencia de patología infecciosa respiratoria. De interés, otro abordaje mecanístico responde a considerar la inhibición del sistema renina-angiotensina-aldosterona, que se exacerba en la infección por COVID-19 debido a que el virus se une a la enzima ECA2, quedando disponible más angiotensinaII para causar daño. La vitaminaD inhibe mediadores del SRAA -presente en todas las células del organismo-, y al inhibir la actividad ECA y aumentar la ECA2, disminuye los niveles de angiotensinaII. Presentamos estudios con propuestas de dosis recomendadas de vitaminaD, y aunque no quede concretada una única guía, los posibles beneficios son promisorios. Finalmente, el propósito de la presente revisión es compartir esta idea con profesionales de la salud para encender el debate y llamar a la reflexión crítica, de modo tal que se pueda contribuir con el emprendimiento de diseños clínicos adecuados para validar los beneficios de utilizar altas dosis de vitaminaD en beneficio de la salud pública, sobre todo en tiempos de esta emergencia por COVID-19

Although we lack enough evidence to justify supplementing with vitaminD in the prevention and treatment of COVID-19 infection, it is increasingly feasible that this hypothesis is valid. Two general underlying mechanisms should be considered. One would be the anti-infectious and immunomodulatory action that it exerts by improving intercellular barriers by stimulating innate immunity, as well as by modulating adaptive immunity. Also, vitaminD reduces the production of inflammatory cytokines, such as IL-2 and interferon-gamma (INF-γ). More recently, multiple pleiotropic effects have been demonstrated on the actions of vitaminD at the anti-inflammatory and immunomodulatory level with positive results in studies with influenza, coronavirus, and other respiratory infections. An inverse relationship between serum vitaminD levels and the prevalence of the respiratory infectious disease has been described. Of interest, another mechanistic approach responds to considering the inhibition of the renin-angiotensin-aldosterone system (RAAS), which is exacerbated in COVID-19 infection because the virus binds to the enzyme ACE2, making more angiotensinII available to cause damage. VitaminD inhibits mediators of RAAS - present in all cells of the body - and by inhibiting ACE activity and increasing ACE2, it lowers angiotensinII levels. We present studies with proposals for recommended doses of vitaminD, and although a single guideline is not specified, the possible benefits are promising. Finally, the purpose of this review is to share this idea with health professionals to ignite the debate and call for critical reflection, so that it can contribute to the undertaking of more and better clinical designs to validate the benefits of using high doses of vitaminD for the benefit of public health and especially in times of crisis for COVID-19

Vitamin D supplementation as a rational pharmacological approach in the COVID-19 pandemic.

The COVID-19 pandemic has reached most of the countries worldwide causing death, which often results from an inflammatory storm associated with severe acute respiratory syndrome (SARS). This has prompted researchers to seek specific novel and definitive treatments urgently. In this context, it is interesting to evaluate the preventive and therapeutic effects of existing pharmacological agents that could be useful. In this regard, vitamin D supplementation, particularly in individuals likely to be deficient, may be a promising option. Vitamin D is a hormone that modulates many of the same inflammatory and oxidative signaling pathways triggered during COVID-19. For example, vitamin D suppresses the actions of the renin-angiotensin system, which has a determining role in the pathophysiology of the inflammatory response related to COVID-19. This paper analyzes the evidence that vitamin D supplementation might be a valuable preventive/therapeutic measure in groups at risk for or infected with COVID-19. It also discusses how clinical studies could be best designed to evaluate the possible advantages of vitamin D supplementation for the benefit of public health during the pandemic.

La Vasculatura Sistémica En La Enfermedad Renal Crónica. Tercera Parte / Systemic Vasculature In Chronic Kidney Disease. Third Part

Resumen En esta revisión de la literatura presentamos diversos mecanismos terapéuticos para tratar la rigidez vascular en pacientes con enfermedad renal crónica. En el ámbito de la terapéutica no farmacológica la restricción de sodio y la indicación de dieta mediterránea han demostrado efectos benéficos, mientras que acerca de la indicación de actividad física aún no hay evidencia clara sobre su utilidad para disminuir la rigidez vascular en este grupo específico de pacientes. Es con el tratamiento farmacológico donde se evidencian los mayores beneficios, tanto en la rigidez vascular como en los eventos cardiovasculares asociados. Está ampliamente demostrada la efectividad de los inhibidores del sistema renina-angiotensina-aldosterona y de los fármacos antialdosterónicos para disminuir la presión y la rigidez arterial. Otras drogas, como los bloqueadores del receptor de endotelina, han demostrado sus efectos protectores sobre la pared arterial, aunque no están carentes de potenciales efectos adversos. También repasamos los resultados obtenidos con el uso de las nuevas drogas antidiabéticas, en particular los iSLGT2 y los aGLP-1, y su efecto sobre la presión arterial y la rigidez vascular, en particular en pacientes con enfermedad renal crónica. Se revisan además la utilidad de aquellas drogas con efecto sobre la cascada inflamatoria y sobre las calcificaciones vasculares, muy propensas durante los tratamientos sustitutivos de la función renal. Este trabajo se enfoca, en síntesis, en las diversas intervenciones terapéuticas sobre la rigidez arterial, con énfasis en la disminución de eventos cardiovasculares y de la mortalidad en pacientes con enfermedad renal crónica.

Abstract In this literature review we present various therapeutic alternatives for vascular stiffness in patients with chronic kidney disease. Here we discussed the role of non-pharmacological treatments with evidence of the benefit of sodium restriction on vascular stiffness, the positive effects in that sense shown by the Mediterranean diet, and the small benefits of physical activity on vascular stiffness in this group of patients. Is in the pharmacological treatment where the best benefits are evidenced; both, on vascular stiffness and on the associated cardiovascular events. The effectiveness of renin-angiotensin-aldosterone system inhibitors and antialdosteronic drugs to decrease blood pressure and stiffness has been widely demonstrated. Other drugs, such as endothelin receptor blockers, showed their protective effects on the arterial wall, but with potential adverse effects. This article also reviews the effects of new anti-diabetic drugs, iSLGT2 and aGLP-1 in particular, and their effect on blood pressure and vascular stiffness, particularly in patients with chronic kidney disease. The utility of drugs with effects on the inflammatory cascade and drugs with a potential effect on vascular calcification, complication occurring frequently during renal function replacement treatment, are also reviewed. In short, this work focuses in the therapeutic interventions on arterial stiffness, with emphasis on the reduction of cardiovascular events and mortality in patients with chronic kidney disease.

Blood pressure control is not enough to normalize endothelial repair by progenitor cells.

Patients presenting with classical cardiovascular risk factors within acceptable or average value ranges often develop cardiovascular disease, suggesting that other risk factors need to be considered. Considering that endothelial progenitor cells (EPCs) contribute to endothelial repair, we investigated whether EPCs might be such a factor. We compared the ability of peripheral blood EPCs to attach to extracellular matrix proteins and to grow and function in culture, between controlled hypertensive patients exhibiting a Framingham score (FS) of <10% while showing severe vascular impairment (intima-media thickness/diameter, carotid-femoral pulse wave velocity, brachial artery flow-mediated dilation, carotid and femoral atherosclerotic plaque presence; vulnerable group, N = 30) and those with an FS of ≥10% and scarce vascular changes (protected group, N = 30). When compared with vulnerable patients, protected patients had significantly higher early and late-EPC and early and late-tunneling nanotube (TNT) numbers. Significant negative associations were found between vascular damage severity and early EPC, late-EPC, or late-TNT numbers, whereas EPC or TNT numbers and patient characteristics or cardiovascular risk factors were not associated. Except for protected patients, in all controlled hypertensive patients, early and late-EPC and early and late-TNT counts were significantly lower than those in the normotensive subjects studied (N = 30). We found that the disparity in vascular status between patients presenting with both an FS of ≥10% and scarce vascular changes and those presenting with both an FS of <10% and severe vascular impairment is related to differences in peripheral blood EPC and TNT numbers. These observations support the role of EPCs as contributors to vascular injury repair and suggest that EPC numbers may be a potential cardiovascular risk factor to be included in the FS calculation.NEW & NOTEWORTHY As individuals who present with risk factors within acceptable or average value ranges often develop cardiovascular (CV) disease, it has been suggested that other CV risk factors need to be considered in addition to those that are commonly combined in the Framingham score (FS) to estimate the risk of general CV disease. We investigated whether peripheral endothelial progenitor cells (EPCs) and tunneling nanotubes (TNTs) deserve to be considered. Here we report that EPCs and TNTs are significantly lower in controlled hypertensive patients versus normotensive subjects and that the disparity in vascular status between patients presenting with an FS of ≥10% with scarce vascular changes and those presenting with an FS of <10% with severe vascular impairment is related to differences in EPC and TNT numbers. These data point to EPC and TNT numbers as potential CV risk factors to be included in the FS calculation.

Vitamin D high doses supplementation could represent a promising alternative to prevent or treat COVID-19 infection. / El suplemento con altas dosis de vitaminaD podría representar una alternativa promisoria para prevenir o tratar la infección por COVID-19.

Although we lack enough evidence to justify supplementing with vitaminD in the prevention and treatment of COVID-19 infection, it is increasingly feasible that this hypothesis is valid. Two general underlying mechanisms should be considered. One would be the anti-infectious and immunomodulatory action that it exerts by improving intercellular barriers by stimulating innate immunity, as well as by modulating adaptive immunity. Also, vitaminD reduces the production of inflammatory cytokines, such as IL-2 and interferon-gamma (INF-γ). More recently, multiple pleiotropic effects have been demonstrated on the actions of vitaminD at the anti-inflammatory and immunomodulatory level with positive results in studies with influenza, coronavirus, and other respiratory infections. An inverse relationship between serum vitaminD levels and the prevalence of the respiratory infectious disease has been described. Of interest, another mechanistic approach responds to considering the inhibition of the renin-angiotensin-aldosterone system (RAAS), which is exacerbated in COVID-19 infection because the virus binds to the enzyme ACE2, making more angiotensinII available to cause damage. VitaminD inhibits mediators of RAAS - present in all cells of the body - and by inhibiting ACE activity and increasing ACE2, it lowers angiotensinII levels. We present studies with proposals for recommended doses of vitaminD, and although a single guideline is not specified, the possible benefits are promising. Finally, the purpose of this review is to share this idea with health professionals to ignite the debate and call for critical reflection, so that it can contribute to the undertaking of more and better clinical designs to validate the benefits of using high doses of vitaminD for the benefit of public health and especially in times of crisis for COVID-19.

Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment.

COVID-19 pandemic has a high mortality rate and is affecting practically the entire world population. The leading cause of death is severe acute respiratory syndrome as a consequence of exacerbated inflammatory response accompanied by uncontrolled oxidative stress as well as the inflammatory reaction at the lung level. Until now, there is not a specific and definitive treatment for this pathology that worries the world population, especially the older adults who constitute the main risk group. In this context, it results in a particular interest in the evaluation of the efficacy of existing pharmacological agents that may be used for overcoming or attenuating the severity of this pulmonary complication that has ended the lives of many people worldwide. Vitamin D and melatonin could be good options for achieving this aim, taking into account that they have many shared underlying mechanisms that are able to modulate and control the immune adequately and oxidative response against COVID-19 infection, possibly even through a synergistic interaction. The renin-angiotensin system exaltation with consequent inflammatory response has a leading role in the physiopathology of COVID-19 infection; and it may be down-regulated by vitamin D and melatonin in many organs. Therefore, it is also essential to analyze this potential therapeutic association and their relation with RAS as part of this new approach.