Renin–angiotensin–aldosterone system blockers effect in chronic kidney disease progression in hypertensive elderly patients without proteinuria: PROERCAN trial / Efecto de los bloqueantes del sistema renina-angiotensina-aldosterona en la progresión de enfermedad renal crónica en pacientes hipertensos añosos sin proteinuria: ensayo clínico Progresión de Enfermedad Renal Crónica en Ancianos

Introduction: Evidence about nefroprotective effect with RAAS blockers in elderly patients with chronic kidney disease (CKD) without proteinuria is lacking. The primary outcome of our study is to evaluate the impact of RAAS blockers in CKD progression in elderly patients without proteinuria. Materials and methods: Multicenter open-label, randomized controlled clinical trial including patients over 65 year-old with hypertension and CKD stages 3–4 without proteinuria. Patients were randomized in a 1:1 ratio to either receive RAAS blockers or other antihypertensive drugs and were followed up for three years. Primary outcome is estimated glomerular filtration rate (eGFR) decline at 3 years. Secondary outcome measures include BP control, renal and cardiovascular events and mortality. Results: 88 patients were included with a mean age of 77.9±6.1 years and a follow up period of 3 years: 40 were randomized to RAAS group and 48 to standard treatment. Ethiology of CKD was: 53 vascular, 16 interstitial and 19 of unknown ethiology. In the RAAS group eGFR slope during follow up was −4.3±1.1ml/min, whereas in the standard treatment group an increase on eGFR was observed after 3 years (+4.6±0.4ml/min), p=0.024. We found no differences in blood pressure control, number of antihypertensive drugs, albuminuria, potassium serum levels, incidence of cardiovascular events nor mortality during the follow up period. Conclusions: In elderly patients without diabetes nor cardiopathy and with non proteinuric CKD the use of RAAS blockers does not show a reduction in CKD progression. The PROERCAN (PROgresión de Enfermedad Renal Crónica en ANcianos) trial (trial registration: NCT03195023). (AU)

Introducción: Actualmente no existe suficiente evidencia sobre el efecto nefroprotector de los bloqueantes del sistema renina-angiotensina-aldosterona (BSRAA) en pacientes añosos con enfermedad renal crónica (ERC) sin proteinuria y sin cardiopatía. El objetivo es evaluar el efecto de los BSRAA en la progresión de la ERC en este grupo poblacional. Métodos: Se trata de un estudio prospectivo, aleatorizado, que compara la eficacia de los BSRAA vs. otros tratamientos antihipertensivos en la progresión renal en personas mayores de 65 años con ERC estadios 3 y 4 e índice albúmina/creatinina<30mg/g. Aleatorización 1:1 BSRAA o tratamiento antihipertensivo estándar. Se recogieron cifras tensionales y parámetros analíticos de un año previo a la aleatorización y durante el seguimiento. Resultados: Se incluyeron 88 pacientes seguidos durante tres años con edad media de 77,9±6,1 años. De estos, se aleatorizaron 40 al grupo BSRAA y 48 al estándar. La etiología de ERC fue: 53 vascular, 16 intersticial y 19 no filiada. En el primer grupo se observó una progresión de la ERC con una caída del filtrado glomerular estimado (FGe) de -4,3±1,1mL/min, mientras que en el grupo estándar un aumento del FGe durante el seguimiento de 4,6±0,4mL/min, p=0,024. No se apreciaron diferencias entre ambos en el control tensional, el número de antihipertensivos, la albuminuria, los niveles de potasio, la incidencia de eventos cardiovasculares ni la mortalidad durante el seguimiento. Conclusiones: En pacientes añosos no diabéticos con ERC no proteinúrica y sin cardiopatía el uso de BSRAA no añade beneficio en la progresión de la ERC. Ensayo clínico Progresión de Enfermedad Renal Crónica en Ancianos (PROERCAN) (NCT03195023). (AU)

Renin-angiotensin-aldosterone system blockers effect in chronic kidney disease progression in hypertensive elderly patients without proteinuria: PROERCAN trial.

INTRODUCTION: Evidence about nefroprotective effect with RAAS blockers in elderly patients with chronic kidney disease (CKD) without proteinuria is lacking. The primary outcome of our study is to evaluate the impact of RAAS blockers in CKD progression in elderly patients without proteinuria. MATERIALS AND METHODS: Multicenter open-label, randomized controlled clinical trial including patients over 65 year-old with hypertension and CKD stages 3-4 without proteinuria. Patients were randomized in a 1:1 ratio to either receive RAAS blockers or other antihypertensive drugs and were followed up for three years. Primary outcome is estimated glomerular filtration rate (eGFR) decline at 3 years. Secondary outcome measures include BP control, renal and cardiovascular events and mortality. RESULTS: 88 patients were included with a mean age of 77.9±6.1 years and a follow up period of 3 years: 40 were randomized to RAAS group and 48 to standard treatment. Ethiology of CKD was: 53 vascular, 16 interstitial and 19 of unknown ethiology. In the RAAS group eGFR slope during follow up was -4.3±1.1ml/min, whereas in the standard treatment group an increase on eGFR was observed after 3 years (+4.6±0.4ml/min), p=0.024. We found no differences in blood pressure control, number of antihypertensive drugs, albuminuria, potassium serum levels, incidence of cardiovascular events nor mortality during the follow up period. CONCLUSIONS: In elderly patients without diabetes nor cardiopathy and with non proteinuric CKD the use of RAAS blockers does not show a reduction in CKD progression. The PROERCAN (PROgresión de Enfermedad Renal Crónica en ANcianos) trial (trial registration: NCT03195023).

Impacto económico del uso de patiromer en enfermedad renal crónica o insuficiencia cardíaca para el tratamiento de la hiperpotasemia crónica en España / Economic impact of the use of patiromer in chronic kidney disease or heart failure for the treatment of chronic hyperkalemia in Spain

Introducción La hiperpotasemia crónica tiene consecuencias negativas a medio y largo plazo, condicionando generalmente la suspensión de fármacos nefro y cardioprotectores, en pacientes con enfermedad renal crónica (ERC) e insuficiencia cardíaca (IC), como son los inhibidores del sistema renina-angiotensina-aldosterona. Existe una alternativa a la suspensión o reducción de dosis de estos tratamientos y es la administración de quelantes del potasio. El objetivo de este estudio es estimar el impacto económico que supondría el uso de patiromer en pacientes con ERC o IC e hiperpotasemia en España. Material y métodos Se ha estimado el impacto económico anual del uso de patiromer desde la perspectiva de la sociedad española, comparando 2 escenarios: pacientes con ERC o IC e hiperpotasemia tratada con patiromer y sin patiromer. Los costes se han actualizado a euros de 2020, utilizando el índice de precios de consumo de Sanidad. Se han considerado los costes directos sanitarios relacionados con el uso de recursos (el tratamiento con inhibidores del sistema renina-angiotensina-aldosterona, la progresión de la ERC, los eventos cardiovasculares y la hospitalización por hiperpotasemia), los costes directos no sanitarios (cuidados informales: costes derivados del tiempo de dedicación por parte de los familiares del paciente), los costes indirectos (pérdidas de productividad laboral), así como un coste intangible (por mortalidad prematura). Se realizó un análisis de sensibilidad determinístico para validar la consistencia de los resultados del estudio. Resultados El coste medio anual por paciente en el escenario sin patiromer es de 9.834,09 € y 10.739,37 € en ERC e IC, respectivamente. El uso de patiromer supondría un ahorro de costes superior al 30% en ambas enfermedades. En el caso de la ERC, el mayor ahorro procede del retraso de la progresión de la ERC (AU)

Introduction Chronic hyperkalemia has negative consequences in the medium and long term, and determines the suspension of nephro and cardioprotective drugs, such as renin–angiotensin–aldosterone system inhibitors (RAASi). There is an alternative to the suspension or dose reduction of these treatments: the administration of potassium chelators. The aim of this study is to estimate the economic impact of the use of patiromer in patients with chronic kidney disease (CKD) or heart failure (HF) and hyperkalemia in Spain. Materials and method The annual economic impact of the use of patiromer has been estimated from the perspective of the Spanish society. Two scenarios were compared: patients with CKD or HF and hyperkalemia treated with and without patiromer. The costs have been updated to 2020 euros, using the Health Consumer Price Index. Direct healthcare costs related to the use of resources (treatment with RAASi, CKD progression, cardiovascular events and hospitalization due to hyperkalemia), direct non-healthcare costs (informal care: costs derived from time dedicated by patient's relatives), the indirect costs (productivity loss), as well as an intangible cost (due to premature mortality) were considered. A deterministic sensitivity analysis was performed to validate the robustness of the study results. Results The mean annual cost per patient in the scenario without patiromer is €9834.09 and €10,739.37 in CKD and HF, respectively. The use of patiromer would lead to cost savings of over 30% in both diseases. The greatest savings in CKD come from the delay in the progression of CKD. While in the case of HF, 80.1% of these savings come from premature mortality reduction. The sensitivity analyses carried out show the robustness of the results, obtaining savings in all cases (AU)

[Classical nephroprotection: Renin angiotensin aldosterone system inhibitors]. / Nefroprotección clásica: inhibidores del sistema renina angiotensina aldosterona.

The role of the renin angiotensin aldosterone system (RAAS) in the pathophysiology of hypertension, cardiovascular disease and kidney disease has been known for years. RAAS inhibitors have been the mainstay of chronic kidney disease (CKD) treatment. Studies have shown that therapy with angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensinII receptor blockers (ARBs) reduce the excretion of albuminuria and slow the progression of kidney disease in patients with and without diabetes. In clinical practice, RAAS inhibitors are recommended as the antihypertensive of choice in patients with CKD and albuminuria with or without diabetes. In addition, they have demonstrated cardiovascular benefits beyond blood pressure control. The use of RAAS inhibitors in non-proteinuric nephropathy and advanced CKD is not without controversy. Double blockade of the RAAS is contraindicated. On the other hand, it is essential to know how to titrate doses and avoid side effects, mainly hyperkalaemia.

Economic impact of the use of patiromer in chronic kidney disease or heart failure for the treatment of chronic hyperkalemia in Spain.

INTRODUCTION: Chronic hyperkalemia has negative consequences in the medium and long term, and determines the suspension of nephro and cardioprotective drugs, such as renin-angiotensin-aldosterone system inhibitors (RAASi). There is an alternative to the suspension or dose reduction of these treatments: the administration of potassium chelators. The aim of this study is to estimate the economic impact of the use of patiromer in patients with chronic kidney disease (CKD) or heart failure (HF) and hyperkalemia in Spain. MATERIALS AND METHOD: The annual economic impact of the use of patiromer has been estimated from the perspective of the Spanish society. Two scenarios were compared: patients with CKD or HF and hyperkalemia treated with and without patiromer. The costs have been updated to 2020 euros, using the Health Consumer Price Index. Direct healthcare costs related to the use of resources (treatment with RAASi, CKD progression, cardiovascular events and hospitalization due to hyperkalemia), direct non-healthcare costs (informal care: costs derived from time dedicated by patient's relatives), the indirect costs (productivity loss), as well as an intangible cost (due to premature mortality) were considered. A deterministic sensitivity analysis was performed to validate the robustness of the study results. RESULTS: The mean annual cost per patient in the scenario without patiromer is €9,834.09 and €10,739.37 in CKD and HF, respectively. The use of patiromer would lead to cost savings of over 30% in both diseases. The greatest savings in CKD come from the delay in the progression of CKD. While in the case of HF, 80.1% of these savings come from premature mortality reduction. The sensitivity analyses carried out show the robustness of the results, obtaining savings in all cases. CONCLUSIONS: The incorporation of patiromer allows better control of hyperkalemia and, as a consequence, maintain treatment with RAASi in patients with CKD or HF. This would generate a 32% of annual savings in Spain (€3,127 in CKD; €3,466 in HF). The results support the positive contribution of patiromer to health cost in patients with only CKD or in patients with only HF.

Consenso sobre el manejo de la hiperpotasemia en pacientes con insuficiencia cardíaca: recomendaciones de la SEC-SEMI / Consensus on the management of hyperkalemia in patients with heart failure: recommendations from the SEC-SEMI

n los pacientes con insuficiencia cardíaca (IC) y fracción de eyección reducida, el uso de los inhibidores del sistema renina-angiotensina-aldosterona (iSRAA) se asocia con una mejoría funcional, incremento de la calidad de vida percibida, reducción de la probabilidad de muerte cardiovascular y disminución del número de hospitalizaciones. Algunos de esos fármacos también resultan eficaces en pacientes con enfermedad renal crónica y albuminuria, así como en pacientes con hipertensión arterial resistente. A pesar de sus numerosos beneficios, los iSRAA se asocian a un incremento de la incidencia de hiperpotasemia, sobre todo en pacientes con insuficiencia renal crónica concomitante. La hiperpotasemia es un trastorno iónico frecuente que se define como la elevación de las concentraciones plasmáticas de potasio por encima de 5 mEq/L, y se ha relacionado con la presencia de rehospitalizaciones, arritmias cardíacas malignas y aumento de la mortalidad. Por otro lado, un tratamiento optimizado con iSRAA requiere de incrementos progresivos de las dosis que pueden suponer a su vez una mayor probabilidad de hiperpotasemia. Por todo ello, es necesario establecer unas directrices para el manejo y tratamiento de estos pacientes. Con este objetivo surge este documento de consenso, cuyas recomendaciones han sido elaboradas por un grupo de 10 expertos y revisado por un panel de otros 10 especialistas en el tratamiento de pacientes con IC (en total 10 cardiólogos y 10 internistas). El documento ha sido avalado por la Sociedad Española de Cardiología (SEC) y la Sociedad Española de Medicina Interna (SEMI) (AU)

Use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with heart failure (HF) and reduced ejection fraction is associated with functional improvement, an increase in perceived quality of life, a reduction in the probability of cardiovascular death, and a decrease in the number of hospitalizations. Some of these drugs are also efficacious in patients with chronic kidney disease and albuminuria as well as in patients with resistant hypertension. Despite their numerous benefits, RAASi are associated with an increase in incidence of hyperkalemia, especially in patients with concomitant chronic kidney disease. Hyperkalemia is a common electrolyte disorder that is defined as an elevation in plasma concentrations of potassium above 5 mEq/L. It has been related to rehospitalizations, malignant arrhythmias, and an increase in mortality. On the other hand, optimized treatment with RAASi requires progressive dose increases which can in turn entail a greater probability of hyperkalemia. For all of these reasons, it is necessary to establish management and treatment guidelines for these patients. This consensus document arises from this objective. Its recommendations have been developed by a group of ten experts and reviewed by a panel of another ten specialists in the treatment of patients with HF (ten cardiologists and ten internists in total). This document has been endorsed by the Spanish Society of Cardiology (SEC, for its initials in Spanish) and the Spanish Society of Internal Medicine (SEMI, for its initials in Spanish) (AU)

Consensus on the management of hyperkalemia in patients with heart failure: Recommendations from the SEC-SEMI.

Use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with heart failure (HF) and reduced ejection fraction is associated with functional improvement, an increase in perceived quality of life, a reduction in the probability of cardiovascular death, and a decrease in the number of hospitalizations. Some of these drugs are also efficacious in patients with chronic kidney disease and albuminuria as well as in patients with resistant hypertension. Despite their numerous benefits, RAASi are associated with an increase in incidence of hyperkalemia, especially in patients with concomitant chronic kidney disease. Hyperkalemia is a common electrolyte disorder that is defined as an elevation in plasma concentrations of potassium above 5 mEq/L. It has been related to rehospitalizations, malignant arrhythmias, and an increase in mortality. On the other hand, optimized treatment with RAASi requires progressive dose increases which can in turn entail a greater probability of hyperkalemia. For all of these reasons, it is necessary to establish management and treatment guidelines for these patients. This consensus document arises from this objective. Its recommendations have been developed by a group of ten experts and reviewed by a panel of another ten specialists in the treatment of patients with HF (ten cardiologists and ten internists in total). This document has been endorsed by the Spanish Society of Cardiology (SEC, for its initials in Spanish) and the Spanish Society of Internal Medicine (SEMI, for its initials in Spanish).

Enfermedad cardiovascular, oncológica y reumatológica, su comportamiento en pacientes COVID-19: Factores pronósticos, complicaciones y tratamiento

La infección por SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) puede presentar manifestaciones propias, pero también, puede exacerbar las de enfermedades preexistentes o provocar manifestaciones que simulen dichas patologías. Las enfermedades cardiovasculares, neoplásicas o reumatológicas son ejemplos de ello. Este tipo de patologías comparten factores de riesgo de mal pronóstico y de muerte por la infección, la posibilidad de desarrollar complicaciones a largo plazo, e implican un desafío al momento de instaurar medidas de seguimiento y tratamiento con requerimiento de valoración multidisciplinaria. Por ello, nuestro objetivo fue plantear las dificultades en el seguimiento a corto y largo plazo de este tipo de pacientes y evaluar cómo la pandemia afecta su tratamiento. La pandemia ha cambiado la práctica médica habitual, promoviendo nuevas formas de seguimiento de los pacientes, como la telemedicina, imponiendo jerarquizar la necesidad de atención y procedimientos presenciales, obligando a reasignar las partidas presupuestarias para poder hacer frente a la misma, con consecuencias que probablemente habrá que analizar a largo plazo.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection clinical course can present its own manifestations, but it can also exacerbate those of pre-existing diseases or cause manifestations that simulate said pathologies. Cardiovascular, cancer or rheumatological diseases are examples of this. These types of pathologies share risk factors for poor prognosis and death due to infection, the possibility of developing long-term complications, and they imply a challenge when establishing follow-up and treatment measures requiring multidisciplinary assessment. Therefore, our objective was to raise the difficulties in the short and long-term follow-up of this type of patients and to evaluate how the pandemic affects their treatment. The pandemic has changed the usual medical practice, promoting new forms of patient follow-up, such as telemedicine, imposing a hierarchy of the need for face-to-face care and procedures, forcing budget items to be reallocated to be able to deal with it, with consequences that are likely to it will have to be analyzed in the long term.

A infecção por SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pode apresentar manifestações próprias, mas também pode exacerbar aquelas de doenças pré-existentes ou causar manifestações que simulam essas patologias. Doenças cardiovasculares, neoplásicas ou reumatológicas são exemplos disso. Esses tipos de patologias compartilham fatores de risco para mau prognóstico e óbito por infecção, possibilidade de desenvolvimento de complicações em longo prazo, e representam um desafio no estabelecimento de medidas de acompanhamento e tratamento que requerem avaliação multidisciplinar. Portanto, nosso objetivo foi levantar as dificuldades no acompanhamento a curto e longo prazo desse tipo de paciente e avaliar como a pandemia afeta seu tratamento. A pandemia alterou a prática médica usual, promovendo novas formas de acompanhamento do paciente, como a telemedicina, impondo uma hierarquia da necessidade de atendimento e procedimentos presenciais, obrigando a realocação de itens orçamentários para poderem lidar com ela, com consequências que provavelmente terá que ser analisado a longo prazo.

Vitamina d, sus acciones "no clásicas" y su utilidad en la pandemia del covid-19 / Vitamin d, its "non-classic" actions and it utility in the covid-19 pandemic

RESUMEN El descubrimiento de que la síntesis de 1,25 vitamina D no fue solo renal, la enzima 1 alfa hidroxilasa se encuentra en numerosos tejidos del organismo, además de la evidencia de que la asociación entre el déficit de vitamina D y la presencia de enfermedades no óseas (cáncer, esclerosis múltiple, enfermedades autoinmunes, etc.) nos ofrece la posibilidad de intentar prevenir estas afecciones. Los estudios de suplementación contra placebo no han dado resultados positivos para algunas afecciones, aunque algunos de esos trials se realizaron en población "suficiente" y no "deficiente" de vitamina D. Sin embargo, otros metaanálisis han demostrado prevención en los grupos suplementados con déficit para algunas patologías (infecciones respiratorias, prediabetes). Además, existe evidencia de efecto antiviral de la misma. La acción antiinfecciosa e inmunomoduladora que ejerce y su efecto sobre el sistema renina angiotensina, estimulando la enzima convertidora de angiotensina 2 (que es el receptor virus del SARS-CoV), permiten sospechar, actualmente, que con niveles elevados podría ser más difícil, o menos grave, la infección por COVID-19. La suplementación con vitamina D es conveniente para prevenir enfermedades en sujetos con déficit, pero en medio de la grave pandemia 2020 administrarla, aún sin tener un dosaje previo en las poblaciones de mayor riesgo, podría disminuir la chance de esta enfermedad.

ABSTRACT The discovery that the synthesis of 1-25-vitamin D is not only renal and that the enzyme 1 alpha hydroxylase is found in numerous tissues of the body, together with the evidence of the association between vitamin D deficiency and the presence of non-bone diseases (cancer, multiple sclerosis, autoimmune diseases, etc.), gives us the possibility of trying to prevent these conditions. Placebo-controlled supplementation studies have not provided positive results for certain conditions, but some of these trials have been carried out on populations with "sufficient" and not "deficient" vitamin D levels. However, other meta-analyses have shown prevention of some conditions (respiratory infections, prediabetes) in groups of patients with deficiencies who were given supplements. There is also evidence of antiviral effect of vitamin D. Its anti-infective and immunomodulatory action and its effect upon the renin-angiotensin system, stimulating the angiotensin-converting enzyme 2 (the SARS-CoV virus receptor), nowadays allow us to think that, in high levels, COVID-19 infection could be less likely or serious. Vitamin D supplementation is adequate for preventing diseases in patients with deficiencies; administering vitamin D within the 2020 pandemic, even without having tested it in high-risk populations, could diminish the incidence of this disease.

COVID-19 e hipertensión arterial: ¿existe evidencia para suspender antagonistas del sistema renina-angiotensina-aldosterona? / COVID-19 and arterial hypertension: is there evidence to suspend renin-angiotensin-aldosteronesystem blockade?

Resumen El nuevo coronavirus SARS-CoV-2, causante de la enfermedad COVID-19, presenta una alta mortalidad en pacientes con enfermedades cardiovasculares, diabetes e hipertensión, trastornos que comparten la fisiopatología subyacente relacionada con el sistema renina-angiotensina (RAS). El SARS-CoV-2 utiliza la proteína de la membrana angiotensina I y convierte a la enzima convertidora de angiotensina tipo 2 (ACE2) en un receptor de entrada celular; por tanto, el RAS, regulado por ACE y ACE2, puede verse alterado en pacientes con COVID-19. Sin embargo, aún no es claro si el uso de fármacos antihipertensivos inhibidores de la ACE2 y bloqueadores del receptor de angiotensina II podría potencializar el daño ocasionado por el virus o contrarrestar su efecto, sobre todo a nivel pulmonar. El desafío se ve agravado por la información exagerada publicada en diferentes revistas científicas, la cual podría llevar a acciones inapropiadas, por lo que es importante diferenciar rápidamente la verdadera epidemia de hipótesis falsas, que podría llevar a conductas medicas potencialmente dañinas.

Abstract The new coronavirus SARS-CoV-2, which causes the disease COVID-19, has a high mortality in patients with cardiovascular diseases, diabetes and hypertension, disorders that share the underlying pathophysiology related to the renin-angiotensin system (RAS). SARS-CoV-2 uses the membrane protein angiotensin I and converts angiotensin converting enzyme type 2 (ACE2) into a cellular entry receptor, therefore, RAS, regulated by ACE and ACE2, can be altered in COVID-19 patients. However, it is not yet clear whether the use of antihypertensive drugs ACE2 inhibitors and angiotensin II receptor blockers could potentiate the damage caused by the virus or counteract its effect, especially in the lungs. The challenge is compounded by the exaggerated information published in different scientific journals, which could lead to inappropriate actions, so it is important to quickly differentiate the true epidemic from false hypotheses, which could lead to potentially harmful medical behaviors.

Hyperkalemia and management of renin-angiotensin-aldosterone system inhibitors in chronic heart failure with reduced ejection fraction: A systematic review.

INTRODUCTION AND OBJECTIVES: Renin-angiotensin-aldosterone system inhibitors (RAASi) are the cornerstone of treatment of heart failure with reduced ejection fraction (HFrEF). RAASi optimization in real-life care is challenged by hyperkalemia, a potentially fatal adverse event, which can necessitate downtitration or discontinuation of RAASi and negatively impact survival in HFrEF. The literature on this problem is sparse. We performed a systematic review of studies on HFrEF to investigate the prevalence, incidence, and risk factors of hyperkalemia, RAASi prescription rates, frequency of RAASi downtitration or discontinuation due to hyperkalemia, and the potential negative effect of the latter on prognosis. METHODS: We conducted a MEDLINE (PubMed) search including observational and interventional studies published between January 1987 and May 2018. RESULTS: A total of 30 observational and 18 interventional studies were included in the review. The incidence of hyperkalemia reported was between 0% and 63% in observational studies and was between 0% and 30% in clinical trials. Risk factors for hyperkalemia included RAASi prescription, older age, diabetes, and chronic kidney disease. In real-life studies, RAASi were downtitrated or discontinued in 3-22% of HFrEF patients; hyperkalemia was the reported cause in 5% of cases. No reports were found on the impact on prognosis of RAASi downtitration or discontinuation due to hyperkalemia. CONCLUSIONS: Hyperkalemia and RAASi downtitration or discontinuation are frequent, particularly in real-life HFrEF studies. Further research is needed to clarify the role of RAASi downtitration or discontinuation due to hyperkalemia and to assess its long-term prognostic impact in HFrEF patients.

IECA E BRA: EXISTEM DIFERENÇAS? / ACE AND ARBS: ARE THERE DIFFERENCES?

O bloqueio do sistema renina angiotensina aldosterona é uma estratégia fundamental no tratamento e prevenção da doença cardiovascular. No contexto da hipertensão arterial (HAS), os inibidores da enzima conversora de angiotensina e os bloqueadores dos receptores de angiotensina compõem, juntamente com os diuréticos tiazídicos e os antagonistas dos canais de cálcio; o tripé fundamental no tratamento farmacológico da HAS. Adicionalmente, estas classes de fármacos são comumente usadas em pacientes com insuficiência cardíaca, doença arterial coronariana, diabetes e doença renal crônica. Neste ponto de vista os autores discutem as semelhanças e diferenças entre inibidores da enzima conversora de angiotensina e os bloqueadores dos receptores de angiotensina, demonstrando que, à luz dos conhecimentos disponíveis atualmente na literatura, é possível reconhecer que essas duas classes de fármacos são diferentes e têm efeitos clínicos distintos

Blockade of the renin angiotensin aldosterone system is a fundamental strategy in the treatment and prevention of cardiovascular disease. In the context of arterial hypertension, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers make up, along with thiazide diuretics and calcium channel antagonists; the fundamental tripod in the pharmacological treatment of SAH. In addition, these classes of drugs are commonly used in patients with heart failure, coronary artery disease, diabetes and chronic kidney disease. From this point of view, the authors discuss the similarities and differences between angiotensinconverting enzyme inhibitors and angiotensin receptor blockers, demonstrating that in light of the knowledge currently available in the literature, it is possible to recognize that these two classes of drugs are different and have distinct clinical effects

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.

[The RAAS and SARS-CoV-2: A riddle to solve]. / El SRAA y el SARS-CoV-2: el acertijo a resolver.

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.

COVID-19 and the renin, angiotensin, aldosterone system. A complex relationship.

The COVID-19 pandemic has had major negative health, psychological, social and economic repercussions for individuals, families, communities, countries and for humanity in general. The interrelation with age and the presence of chronic non-communicable diseases (hypertension, diabetes, obesity, smoking) seems to go further than what would be explained by the prevalence and distribution of both. The drugs that act on the renin-angiotensin-aldosterone system are in many cases the backbone for the management of these diseases, it has been known for a long time that these drugs significantly increase the expression of receptors for angiotensin conversion enzyme type 2 in the lung tissue. This fact, together with the knowledge that the route of entry of the virus into the cell is precisely the ACE-2 receptor, initiated a hypothesis, based on very low-quality evidence, which quickly became generalized in the media, that the use of these drugs could be negative and that they should be interrupted immediately. The response of practically all Scientific Societies was almost immediate, with the precise indication that treatment with these drugs should not be discontinued, since the evidence of their usefulness is based on very solid and high-quality evidence. Simultaneously, a different hypothesis also appeared, also based on very preliminary evidence, that these drugs are not only harmful but also beneficial, however these medicaments are not yet accepted as agents for the prevention or treatment of this disease or its complications. This review reports current knowledge on the relationship between COVID-19 and SRAA.

La pandemia por COVID-19 ha tenido muy importantes repercusiones negativas, sanitarias, psicológicas, sociales y económicas para las personas, las familias, las comunidades, los países y para las para la humanidad en general. La interrelación con la edad y la presencia de enfermedades crónicas no trasmisibles (hipertensión, diabetes, obesidad, tabaquismo) parece ir mas lejos que lo que explicaría la prevalencia y distribución de ambas. Los medicamentos que actúan sobre el sistema renina-angiotensina-aldosterona, son pilares básicos en el manejo de estas enfermedades. Se sabe de tiempo atrás que estos fármacos aumentan en forma significativa la expresión en el tejido pulmonar de receptores para la enzima de conversión de angiotensina de tipo 2. Este hecho junto con el conocimiento de que la vía de entrada del virus a la célula es precisamente el receptor de ECA-2, inició una hipótesis, basada en evidencia de muy baja calidad, que rápidamente se generalizó en los medios de comunicación, de que el empleo de estos medicamentos podría ser negativo y que deberían suspenderse. La respuesta de prácticamente todas las sociedades científicas fue casi inmediata, con la indicación precisa de que no debería suspenderse el tratamiento con estos fármacos, puesto que la evidencia de su utilidad está basada en una evidencia muy sólida y de gran calidad. Casi simultáneamente también apareció la hipótesis, también basada en evidencia muy preliminar, de que estos medicamentos no solo resultan dañinos sino que son benéficos, tampoco se aceptan todavía como agentes para la prevención o tratamiento de esta enfermedad o sus complicaciones. La presente revisión relata los conocimientos actuales sobre la relación entre COVID-19 y SRAA.

COVID-19: relación entre enzima convertidora de angiotensina 2, sistema cardiovascular y respuesta inmune del huésped

La enfermedad por coronavirus 2019 (COVID-19) provoca el síndrome respiratorio agudo severo por coronavirus 2 (SARS-CoV-2), pudiendo ser particularmente perjudicial para los pacientes con enfermedad cardiovascular (ECV) subyacente, y siendo una causa de morbilidad y mortalidad significativas en todo el mundo. El virus infecta las células huésped a través de los receptores de la enzima convertidora de la angiotensina 2 (ECA2) y su internalización del complejo en dicha célula. ACE2 es un componente enzimático clave del sistema renina-angiotensina-aldosterona (SRAA), degradando angiotensina (Ang) II, un péptido con múltiples acciones que promueven ECV, y generando Ang-(1-7), que antagoniza los efectos de Ang II. Además, la evidencia experimental sugiere que el bloqueo de SRAA por los inhibidores de la ECA y los antagonistas de los receptores de tipo 1 de Ang II, aumentan la ECA2 que, en parte, contribuye al beneficio de estos pacientes. Este virus lleva a una neumopatía, al tiempo que causa lesiones agudas de miocardio y daño crónico al sistema cardiovascular. Esta lesión miocárdica se presenta en la fase más severa de COVID-19; pero aún, el mecanismo fisiopatológico de la lesión no fue esclarecido. Por lo tanto, se debe prestar especial atención a la protección cardiovascular durante el tratamiento para COVID-19. El síndrome de dificultad respiratoria aguda (SDRA) es una enfermedad clínica de alta mortalidad, y ACE2 tiene un efecto protector sobre este tipo de lesión pulmonar aguda. La investigación actual muestra que el mal pronóstico de los pacientes con COVID-19 está relacionado con factores como género masculino, la edad >60 años, las enfermedades subyacentes: hipertensión, diabetes, ECV, SDRA secundario y otros factores relevantes. Si bien los datos son limitados, los posibles mecanismos de lesión miocárdica incluyen la entrada viral directa a través del receptor de membrana de la ECA2 y la toxicidad en las células huésped, la lesión de miocitos relacionada con la hipoxia y el síndrome de liberación de citoquinas mediado por el sistema inmune, necesitándose más estudios para esclarecer el mecanismo de cardiotoxicidad y su prevención. En este artículo se actualiza el conocimiento actual de la biología del SARS-CoV-2 y los posibles mecanismos de lesión miocárdica debido a toxicidades virales y respuestas inmunes del huésped.

Coronavirus disease 2019 (COVID-19) causes severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2), and can be particularly detrimental to patients with underlying cardiovascular disease (CVD), and is a cause of morbidity and mortality. significant worldwide. The virus infects host cells through angiotensin-converting enzyme 2 (ACE2) receptors and their internalization of the complex into that cell. ACE2 is a key enzyme component of the renin-angiotensin-aldosterone (RAAS) system, degrading angiotensin (Ang) II, a peptide with multiple actions that promote CVD, and generating Ang- (1-7), which antagonizes the effects of Ang II . Furthermore, experimental evidence suggests that blocking SRAA by ACE inhibitors and Ang II type 1 receptor antagonists increases ACE2, which in part contributes to the benefit of these patients. This virus leads to lung disease, while causing acute myocardial injury and chronic damage to the cardiovascular system. This myocardial injury occurs in the most severe phase of COVID-19; but still, the pathophysiological mechanism of the injury was not clarified. Therefore, special attention should be paid to cardiovascular protection during treatment for COVID-19. Acute respiratory distress syndrome (ARDS) is a highmortality clinical disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of COVID-19 patients is related to factors such as male gender, age> 60 years, underlying diseases: hypertension, diabetes and CVD, secondary ARDS, and other relevant factors. Although the data is limited, possible mechanisms of myocardial injury include direct viral entry through the ACE2 membrane receptor and host cell toxicity, hypoxia-related myocyte injury, and cytokine release syndrome. mediated by the immune system, further studies are needed to clarify the mechanism of cardiotoxicity and its prevention. This article updates current knowledge of the biology of SARS-CoV-2 and the possible mechanisms of myocardial injury due to viral toxicities and host immune responses.

A doença de coronavírus 2019 (COVID-19) causa síndrome respiratória aguda grave devido ao coronavírus 2 (SARSCoV-2) e pode ser particularmente prejudicial para pacientes com doença cardiovascular subjacente (DCV) e é uma causa de morbidade e mortalidade significativo em todo o mundo. O vírus infecta as células hospedeiras através dos receptores da enzima conversora de angiotensina 2 (ECA2) e sua internalização do complexo nessa célula. O ACE2 é um componente enzimático chave do sistema renina-angiotensina-aldosterona (SRAA), degradando a angiotensina (Ang) II, um peptídeo com múltiplas ações que promovem DCV e gerando Ang- (1-7), que antagoniza os efeitos da Ang II . Além disso, evidências experimentais sugerem que o bloqueio do SRAA por inibidores da ECA e antagonistas dos receptores Ang II tipo 1 aumenta a ECA2, o que em parte contribui para o benefício desses pacientes. Este vírus leva a doenças pulmonares, causando lesão miocárdica aguda e danos crônicos ao sistema cardiovascular. Essa lesão do miocárdio ocorre na fase mais grave do COVID-19; mas ainda assim, o mecanismo fisiopatológico da lesão não foi esclarecido. Portanto, atenção especial deve ser dada à proteção cardiovascular durante o tratamento para COVID-19. A síndrome do desconforto respiratório agudo (SDRA) é uma doença clínica de alta mortalidade e a ECA2 tem um efeito protetor sobre esse tipo de lesão pulmonar aguda. Pesquisas atuais mostram que o mau prognóstico dos pacientes com COVID-19 está relacionado a fatores como sexo masculino, idade> 60 anos, doenças subjacentes: hipertensão, diabetes e DCV, SDRA secundária e outros fatores relevantes. Embora os dados sejam limitados, os possíveis mecanismos de lesão do miocárdio incluem entrada viral direta através do receptor da membrana ACE2 e toxicidade das células hospedeiras, lesão de miócitos relacionados à hipóxia e síndrome de liberação de citocinas.mediados pelo sistema imunológico, são necessários mais estudos para esclarecer o mecanismo da cardiotoxicidade e sua prevenção. Este artigo atualiza o conhecimento atual da biologia da SARS-CoV-2 e os possíveis mecanismos de lesão do miocárdio devido a toxicidades virais e respostas imunes do hospedeiro.

Vitamin D-mitochondria cross-talk could modulate the signaling pathway involved in hypertension development: a translational integrative overview. / La interacción vitamina D-mitocondria podría modular el camino de señalización involucrado en el desarrollo de la hipertensión: una visión integrativa translacional.

Vitamin D deficiency is a worldwide pandemic and results in osteoporosis, hypertension, and other cardiovascular diseases. At the cellular level, it produces significant oxidative stress, inflammatory markers, and mitochondrial damage. There is increasing evidence about the role of vitamin D in the regulation of the renin-angiotensin-aldosterone system (RAAS). Moreover, there is evidence of involvement in cardiovascular complications, as well as in the immune system disorders. Vitamin D values below 25ng/mL are related to an increase in vascular tone mediated by smooth muscle contraction. Furthermore, it can produce direct effects on vascular smooth muscle cells, RAAS over-regulation, modulation of calcium metabolism, and secondary hyperparathyroidism. All this predisposes patients to develop hypertrophy of the left ventricle and vascular wall, causing hypertension. In this work, a review is presented of the main mechanisms involved in the development of hypertension due to vitamin D deficiency. Among them are the link established between the levels of extra-mitochondrial inorganic phosphate, its main regulatory hormones -such as vitamin D-, the cardiovascular system, reactive oxygen species, and mitochondrial metabolism. The role of the mitochondrial vitamin D receptor and the regulation of the respiratory chain could influence arterial remodelling since its activation would reduce oxidative damage and preserve cell life. However, there are aspects not yet understood about the intricate signalling network that appeared simple in experimental trials, but complex in clinical studies. In this way, the completion of new studies as VITAL, could clarify, and thus support or refute the possible benefits of vitamin D in hypertensive cardiovascular disease.

COVID-19 y el sistema renina, angiotensina, aldosterona. Una relación compleja / COVID-19 and the renin, angiotensin, aldosterone system. A complex relationship

Resumen La pandemia por COVID-19 ha tenido muy importantes repercusiones negativas, sanitarias, psicológicas, sociales y económicas para las personas, las familias, las comunidades, los países y para las para la humanidad en general. La interrelación con la edad y la presencia de enfermedades crónicas no trasmisibles (hipertensión, diabetes, obesidad, tabaquismo) parece ir mas lejos que lo que explicaría la prevalencia y distribución de ambas. Los medicamentos que actúan sobre el sistema renina-angiotensina-aldosterona, son pilares básicos en el manejo de estas enfermedades. Se sabe de tiempo atrás que estos fármacos aumentan en forma significativa la expresión en el tejido pulmonar de receptores para la enzima de conversión de angiotensina de tipo 2. Este hecho junto con el conocimiento de que la vía de entrada del virus a la célula es precisamente el receptor de ECA-2, inició una hipótesis, basada en evidencia de muy baja calidad, que rápidamente se generalizó en los medios de comunicación, de que el empleo de estos medicamentos podría ser negativo y que deberían suspenderse. La respuesta de prácticamente todas las sociedades científicas fue casi inmediata, con la indicación precisa de que no debería suspenderse el tratamiento con estos fármacos, puesto que la evidencia de su utilidad está basada en una evidencia muy sólida y de gran calidad. Casi simultáneamente también apareció la hipótesis, también basada en evidencia muy preliminar, de que estos medicamentos no solo resultan dañinos sino que son benéficos, tampoco se aceptan todavía como agentes para la prevención o tratamiento de esta enfermedad o sus complicaciones. La presente revisión relata los conocimientos actuales sobre la relación entre COVID-19 y SRAA.

Abstract The COVID-19 pandemic has had major negative health, psychological, social and economic repercussions for individuals, families, communities, countries and for humanity in general. The interrelation with age and the presence of chronic non-communicable diseases (hypertension, diabetes, obesity, smoking) seems to go further than what would be explained by the prevalence and distribution of both. The drugs that act on the renin-angiotensin-aldosterone system are in many cases the backbone for the management of these diseases, it has been known for a long time that these drugs significantly increase the expression of receptors for angiotensin conversion enzyme type 2 in the lung tissue. This fact, together with the knowledge that the route of entry of the virus into the cell is precisely the ACE-2 receptor, initiated a hypothesis, based on very low-quality evidence, which quickly became generalized in the media, that the use of these drugs could be negative and that they should be interrupted immediately. The response of practically all Scientific Societies was almost immediate, with the precise indication that treatment with these drugs should not be discontinued, since the evidence of their usefulness is based on very solid and high-quality evidence. Simultaneously, a different hypothesis also appeared, also based on very preliminary evidence, that these drugs are not only harmful but also beneficial, however these medicaments are not yet accepted as agents for the prevention or treatment of this disease or its complications. This review reports current knowledge on the relationship between COVID-19 and SRAA.

Hyperkalemia in chronic kidney disease

SUMMARY Hyperkalemia is a frequent finding in patients with chronic kidney disease (CKD). This increase in serum potassium levels is associated with decreased renal ion excretion, as well as the use of medications to reduce the progression of CKD or to control associated diseases such as diabetes mellitus and heart failure. Hyperkalemia increases the risk of cardiac arrhythmia episodes and sudden death. Thus, the control of potassium elevation is essential for reducing the mortality rate in this population. Initially, the management of hyperkalemia includes orientation of low potassium diets and monitoring of patients' adherence to this procedure. It is also important to know the medications in use and the presence of comorbidities to guide dose reduction or even temporary withdrawal of any of the potassium retention-related drugs. And finally, the use of potassium binders is indicated in both acute episodes and chronic hyperkalemia.

RESUMO A hiperpotassemia é um achado frequente em pacientes com doença renal crônica (DRC). Esta elevação do nível sérico de potássio está associada à diminuição da excreção renal do íon, assim como ao uso de medicações para retardar a progressão da DRC ou para controlar doenças associadas, como diabetes mellitus e insuficiência cardíaca. A hiperpotassemia aumenta o risco de episódios de arritmia cardíaca e morte súbita. Assim, o controle da elevação de potássio é essencial para a diminuição da taxa de mortalidade nessa população. O manejo da hiperpotassemia inclui, inicialmente, orientação de dietas com baixo teor de potássio e acompanhamento da aderência dos pacientes a esse procedimento. Também é importante conhecer as medicações em uso e a presença de comorbidades, a fim de orientar a redução de doses ou até mesmo a suspensão temporária de alguma das drogas relacionadas à retenção de potássio. E, finalmente, o uso de quelantes de potássio é indicado tanto em episódios agudos como nos casos de hiperpotassemia crônica.