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.

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 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 13^th, 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 11^th, 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).

Aim: To evaluate angiotensin II (Ang II) and Ang-(1-7) levels and the cytokine profile in patients hospitalized with mild coronavirus disease 2019 (COVID-19) and contrast them with patients with identical clinical conditions but treated with high doses of vitamin D (vitD). Methods: From the 218 patients recruited (ClinicalTrials.gov NCT04411446), 16 participated in this sub-study and were randomized to a single oral dose of 500,000 IU vitD (n = 10) or placebo (n = 6). Plasmatic Ang II and Ang-(1-7) levels were determined by radioimmunoassay and interleukins (ILs) 1, 6, 8, and 10 and tumor necrosis factor alpha (TNF-α) by enzyme-linked immunosorbent assay before and after treatment. Parallel, serum 25-hydroxyvitamin D3 (25-OH vitD) concentrations as vitD status was measured by a chemiluminescence immunoassay. Results: A trend towards an increase in Ang-(1-7) and a decrease in Ang II levels were observed in placebo- and vitD-treated COVID-19 patients compared to baseline values. There was no difference in Ang II and Ang-(1-7) levels between placebo- and vitD-treated COVID-19 patients. Similar results were obtained with ILs profile. COVID-19 patients showed an increase in the protective component of the RAS which was not improved by vitD treatment. Conclusions: VitD did not improve RAS disbalance in COVID-19. Notwithstanding, the authors visualize that acute treatment with high doses of vitD may show a trend to a decline in inflammatory ILs and an increase in protective markers. Finally, the authors would like to highlight the limitations of this preliminary study, namely the small number of patients and the use of a large single bolus dose of vitD rather than lower daily doses for extended periods with prolonged follow-up times. All these factors need special consideration in the designs of new vitD supplementation trials. All these factors need special consideration in the designs of new vitD supplementation trials (ClinicalTrials.gov identifier: NCT04411446).

Un nuevo y sorprendente paradigma se ha conformado con la llegada de las “gliflozinas”. Más allá de su acción antihiperglucémica, estos fármacos han impactado centralmente en la terapéutica de las alteraciones cardio-vásculo-reno-metabólicas responsables de las enfermedades más prevalentes que abordamos en la práctica clínica. Los inhibidores del cotransportador sodio glucosa tipo 2 (iSGLT-2) ayudan a controlar y reducir la progresión del daño de órgano blanco. En esta Toma de Posición, cuatro de las Sociedades Médicas vinculadas con estas temáticas acordaron plasmar el conocimiento de este esperanzador fenómeno generado por más de 7500 publicaciones difundidas en los últimos 10 años sobre el beneficio de las “gliflozinas”. Decidimos revisar de manera rigurosa las evidencias experimentales y los múltiples trabajos controlados que muestran sus efectos metabólicos, vasculares, cardíacos, renales y también celulares, incluyendo aspectos no resueltos y advertencias acerca de las precauciones en su uso.

Los inhibidores SGLT-2 han cambiado el horizonte del tratamiento de los pacientes con DM2 y también en aquellos que sin DM padecen enfermedad renal y/o ECV. Revisaremos la evidencia actual de estas drogas denominadas gliflozinas. Durante los estudios realizados para evaluar, primariamente, seguridad CV en poblaciones con DM2, las complicaciones microvasculares, como la enfermedad renal que acompaña a la diabetes (ERD), se evaluaron como objetivos secundarios preespecificados. En el estudio EMPA-REG OUTCOME, centralizado en pacientes con DM2 con ECV establecida se redujo un 39% el riesgo relativo (RR) en el objetivo preespecificado de nefropatía incidente o empeoramiento de la nefropatía, con resultados similares con ambas dosis de empagliflozina, 10 mg y 25 mg2. Un análisis post hoc de dicho estudio en pacientes sin ERC al inicio del tratamiento TFGe ≥60 ml/min/1,73 m2 o RAC ≤30 mg/g), el 47% mostró un RR para incidencia de ERD de 0,67 (0,47-0,94) y del compuesto renal (duplicación de creatinina basal, inicio de diálisis o trasplante o muerte renal) de 0,31 (0,16-0,63).