Low-Chloride Diet Prevents the Development of Arterial Hypertension and Protects Kidney Function in Angiotensin II-Infused Mice.

INTRODUCTION: A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl- while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. METHODS: C56BL/6J mice fed with standard Cl- diet or a low-Cl- diet (equimolar substitution of Cl- by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl- diet. RESULTS: The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl- diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl- diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl- diet and infused with AngII presented a similar contractile response. CONCLUSION: We conclude that the reduction in dietary Cl- as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis.

A Combined Biomarker That Includes Plasma Fibroblast Growth Factor 23, Erythropoietin, and Klotho Predicts Short- and Long-Term Morbimortality and Development of Chronic Kidney Disease in Critical Care Patients with Sepsis: A Prospective Cohort.

Acute Kidney Injury (AKI) is a frequent complication in intensive care unit (ICU) patients that increases mortality and chronic kidney disease (CKD) development. AKI is associated with elevated plasma fibroblast growth factor 23 (FGF23), which can be modulated by erythropoietin (EPO) and Klotho. We aimed to evaluate whether a combined biomarker that includes these molecules predicted short-/long-term outcomes. We performed a prospective cohort of ICU patients with sepsis and previously normal renal function. They were followed during their inpatient stay and for one year after admission. We measured plasma FGF23, EPO, and Klotho levels at admission and calculated a combined biomarker (FEK). A total of 164 patients were recruited. Of these, 50 (30.5%) had AKI at admission, and 55 (33.5%) developed AKI within 48 h. Patients with AKI at admission and those who developed AKI within 48 h had 12- and 5-fold higher FEK values than non-AKI patients, respectively. Additionally, patients with higher FEK values had increased 1-year mortality (41.9% vs. 18.6%, p = 0.003) and CKD progression (26.2% vs. 8.3%, p = 0.023). Our data suggest that the FEK indicator predicts the risk of AKI, short-/long-term mortality, and CKD progression in ICU patients with sepsis. This new indicator can improve clinical outcome prediction and guide early therapeutic strategies.

Nephrologists' perspectives on the impact of COVID-19 on caring for patients undergoing dialysis in Latin America: a qualitative study.

OBJECTIVE: To describe the experiences of nephrologists on caring for patients undergoing in-centre haemodialysis during the COVID-19 pandemic in Latin America. DESIGN: Twenty-five semistructured interviews were conducted by Zoom videoconference in English and Spanish languages during 2020 until data saturation. Using thematic analysis, we conducted line-by-line coding to inductively identify themes. SETTING: 25 centres across nine countries in Latin America. PARTICIPANTS: Nephrologists (17 male and 8 female) were purposively sampled to include diverse demographic characteristics and clinical experience. RESULTS: We identified five themes: shock and immediate mobilisation for preparedness (overwhelmed and distressed, expanding responsibilities to manage COVID-19 infection and united for workforce resilience); personal vulnerability (being infected with COVID-19 and fear of transmitting COVID-19 to family); infrastructural susceptibility of dialysis units (lacking resources and facilities for quarantine, struggling to prevent cross-contamination, and depletion of personal protective equipment and cleaning supplies); helplessness and moral distress (being forced to ration life-sustaining equipment and care, being concerned about delayed and shortened dialysis sessions, patient hesitancy to attend to dialysis sessions, being grieved by socioeconomic disparities, deterioration of patients with COVID-19, harms of isolation and inability to provide kidney replacement therapy); and fostering innovative delivery of care (expanding use of telehealth, increasing uptake of PD and shifting focus on preventing syndemics). CONCLUSION: Nephrologists felt personally and professionally vulnerable and reported feeling helpless and morally distressed because they doubted their capacity to provide safe care for patients undergoing dialysis. Better availability and mobilisation of resources and capacities to adapt models of care, including telehealth and home-based dialysis, are urgently needed.

High Plasma Levels of Fibroblast Growth Factor 23 Are Associated with Increased Risk of COVID-19 in End-Stage Renal Disease Patients on Hemodialysis: Results of a Prospective Cohort.

End-stage renal disease (ESRD) patients are a population with high rates of COVID-19 and mortality. These patients present a low response to anti-SARS-CoV-2 immunization, which is associated with immune dysfunction. ESRD patients also present high plasma titers of Fibroblast Growth Factor 23 (FGF23), a protein hormone that reduces immune response in vivo and in vitro. Increased FGF23 levels associate with higher infection-related hospitalizations and adverse infectious outcomes. Thus, we evaluated whether ESRD patients with high FGF23 titers have an increased rate of SARS-CoV-2 infection. METHODS: We performed a prospective cohort of ESRD patients in hemodialysis who had measurements of plasma intact FGF23 in 2019. We determined COVID-19 infections, hospitalizations, and mortality between January 2020 and December 2021. RESULTS: We evaluated 243 patients. Age: 60.4 ± 10.8 years. Female: 120 (49.3%), diabetes: 110 (45.2%). During follow-up, 45 patients developed COVID-19 (18.5%), 35 patients were hospitalized, and 12 patients died (mortality rate: 26.6%). We found that patients with higher FGF23 levels (defined as equal or above median) had a higher rate of SARS-CoV-2 infection versus those with lower levels (18.8% versus 9.9%; Hazard ratio: 1.92 [1.03-3.56], p = 0.039). Multivariate analysis showed that increased plasma FGF23 was independently associated with SARS-CoV-2 infection and severe COVID-19. DISCUSSION: Our results suggest that high plasma FGF23 levels are a risk factor for developing COVID-19 in ESRD patients. These data support the potential immunosuppressive effects of high circulating FGF23 as a factor implicated in the association with worse clinical outcomes. Further data are needed to confirm this hypothesis.

[Efficacy of a standardized and simplified strategy for the treatment of high blood pressure in Chile: the HEARTS Initiative in the AmericasEficácia de uma estratégia padronizada e simplificada para o tratamento da hipertensão arterial no Chile: a iniciativa HEARTS nas Américas]. / Eficacia de una estrategia estandarizada y simplificada para tratamiento de la hipertensión arterial en Chile: la Iniciativa HEARTS en las Américas.

Objective: To evaluate the effectiveness of a standardized and simplified protocol based on the technical pillars of the HEARTS Initiative for the control of hypertensive patients in the Cardiovascular Health Program at the first level of care in Chile. Methods: Longitudinal observational study (historical cohort) in two family health centers at the first level of care in Santiago. The control of blood pressure in hypertensive adults using a standardized and simplified protocol was compared to the usual protocol based on national guidelines. Innovations in the standardized protocol included changes in how the health team is coordinated, initiation of pharmacological treatment immediately after confirmed diagnosis, standardized pharmacological treatment with a combination of at least two or three antihypertensive drugs taken daily in a single tablet. Follow-up was conducted after one year to assess the percentage of adherence to treatment and achievement of blood pressure control targets (< 140/90 mmHg). Results: A total of 1490 patients were evaluated: 562 who followed the standardized and simplified protocol, and 928 who were treated with the usual protocol (family health centers: 650; family health centers: 278). After one year, patients in the standardized and simplified protocol group had a higher proportion of adherence to blood pressure control targets (65% versus 37% and 41%, p<0.001) and higher adherence to treatment compared to those following the usual protocol (71% versus 18% and 23%, p<0.001). Conclusions: The results show that the standardized and simplified protocol is more effective than the usual protocol in controlling arterial hypertension in patients undergoing treatment at the first level of care in Chile. Its implementation at the national level could contribute to a decrease in major cardiovascular events.

Objetivo: Avaliar a eficácia de um protocolo padronizado e simplificado, com base nos pilares técnicos da iniciativa HEARTS, para o controle de pacientes com hipertensão arterial do Programa de Saúde Cardiovascular na atenção primária à saúde do Chile. Métodos: Estudo observacional longitudinal (coorte histórica) em 2 centros de atenção primária de saúde da família em Santiago, que comparou o controle da pressão arterial em adultos com hipertensão, atingido com o protocolo padronizado e simplificado, versus o protocolo habitual, de acordo com as diretrizes nacionais. As inovações do protocolo padronizado incluíram mudanças na coordenação da equipe de saúde, início do tratamento farmacológico imediatamente após a confirmação do diagnóstico e tratamento farmacológico padronizado com associação de pelo menos 2 ou 3 anti-hipertensivos em um único comprimido, tomados uma vez ao dia. O acompanhamento foi realizado por 1 ano para avaliar o percentual de adesão ao tratamento e o cumprimento das metas de controle da pressão arterial (menor que 140/90 mmHg). Resultados: Foram avaliados 1.490 pacientes: 562 que utilizaram o protocolo padronizado e simplificado e 928 que foram tratados com o protocolo habitual (unidade de saúde da família 1: 650, unidade de saúde da família 2: 278). Em 1 ano de seguimento, os pacientes do grupo do protocolo padronizado e simplificado apresentaram maior proporção de cumprimento das metas de controle da pressão arterial (65% versus 37% e 41%, p<0,001) e maior percentual de adesão ao tratamento, em comparação com aqueles que utilizaram o protocolo habitual (71% versus 18% e 23%, p<0,001). Conclusões: Os resultados mostram que o protocolo padronizado e simplificado é mais eficaz que o protocolo habitual no controle da hipertensão arterial em pacientes que estão em tratamento na atenção primária do Chile. Sua implementação no nível nacional poderia contribuir para a redução de eventos cardiovasculares maiores.

Eficacia de una estrategia estandarizada y simplificada para tratamiento de la hipertensión arterial en Chile: la Iniciativa HEARTS en las Américas

[RESUMEN]. Objetivo. Evaluar la eficacia de un protocolo estandarizado y simplificado basado en los pilares técnicos de la Iniciativa HEARTS para el control de pacientes hipertensos del Programa de Salud Cardiovascular en el primer nivel de atención de salud en Chile. Métodos. Estudio observacional longitudinal (cohorte histórica), en 2 centros de salud familiar del primer nivel de atención en Santiago, que comparó el control de presión arterial en adultos hipertensos logrado con el protocolo estandarizado y simplificado, frente al protocolo habitual, según las guías nacionales. Las inno- vaciones del protocolo estandarizado incluyeron cambios en la coordinación del equipo de salud, inicio de tratamiento farmacológico inmediatamente después de confirmación diagnóstica, tratamiento farmacológico estandarizado con combinación de al menos 2 o 3 fármacos antihipertensivos en un sólo comprimido, en una toma diaria. Se realizó seguimiento por 1 año para evaluar el porcentaje de adherencia al tratamiento y cumplimiento de metas de control de presión arterial (menor a 140/90 mmHg). Resultados. Se evaluaron 1 490 pacientes: 562 que utilizaron el protocolo estandarizado y simplificado y 928 tratados con el protocolo habitual (centros de salud familiar-1: 650, centros de salud familiar -2: 278). A 1 año de seguimiento, los pacientes del grupo del protocolo estandarizado y simplificado tuvieron mayor proporción de cumplimiento de metas de control de presión arterial (65% versus 37% y 41%, p<0,001) y mayor porcen- taje de adherencia al tratamiento en comparación con aquellos con el protocolo habitual (71% versus 18% y 23%, p<0,001). Conclusiones. Los resultados muestran que el protocolo estandarizado y simplificado es más efectivo que el protocolo habitual en el control de hipertensión arterial en pacientes en tratamiento en el primer nivel de atención en Chile. Su implementación a nivel nacional podría contribuir a la disminución de eventos cardio- vasculares mayores.

[ABSTRACT]. Objective. To evaluate the effectiveness of a standardized and simplified protocol based on the technical pillars of the HEARTS Initiative for the control of hypertensive patients in the Cardiovascular Health Program at the first level of care in Chile. Methods. Longitudinal observational study (historical cohort) in two family health centers at the first level of care in Santiago. The control of blood pressure in hypertensive adults using a standardized and simplified protocol was compared to the usual protocol based on national guidelines. Innovations in the standardized protocol included changes in how the health team is coordinated, initiation of pharmacological treatment immediately after confirmed diagnosis, standardized pharmacological treatment with a combination of at least two or three antihypertensive drugs taken daily in a single tablet. Follow-up was conducted after one year to assess the percentage of adherence to treatment and achievement of blood pressure control targets (< 140/90 mmHg). Results. A total of 1490 patients were evaluated: 562 who followed the standardized and simplified protocol, and 928 who were treated with the usual protocol (family health centers: 650; family health centers: 278). After one year, patients in the standardized and simplified protocol group had a higher proportion of adherence to blood pressure control targets (65% versus 37% and 41%, p<0.001) and higher adherence to treatment com- pared to those following the usual protocol (71% versus 18% and 23%, p<0.001). Conclusions. The results show that the standardized and simplified protocol is more effective than the usual protocol in controlling arterial hypertension in patients undergoing treatment at the first level of care in Chile. Its implementation at the national level could contribute to a decrease in major cardiovascular events.

[RESUMO]. Objetivo. Avaliar a eficácia de um protocolo padronizado e simplificado, com base nos pilares técnicos da iniciativa HEARTS, para o controle de pacientes com hipertensão arterial do Programa de Saúde Cardiovas- cular na atenção primária à saúde do Chile. Métodos. Estudo observacional longitudinal (coorte histórica) em 2 centros de atenção primária de saúde da família em Santiago, que comparou o controle da pressão arterial em adultos com hipertensão, atingido com o protocolo padronizado e simplificado, versus o protocolo habitual, de acordo com as diretrizes nacionais. As inovações do protocolo padronizado incluíram mudanças na coordenação da equipe de saúde, início do tratamento farmacológico imediatamente após a confirmação do diagnóstico e tratamento farmacológico padronizado com associação de pelo menos 2 ou 3 anti-hipertensivos em um único comprimido, tomados uma vez ao dia. O acompanhamento foi realizado por 1 ano para avaliar o percentual de adesão ao trata- mento e o cumprimento das metas de controle da pressão arterial (menor que 140/90 mmHg). Resultados. Foram avaliados 1.490 pacientes: 562 que utilizaram o protocolo padronizado e simplificado e 928 que foram tratados com o protocolo habitual (unidade de saúde da família 1: 650, unidade de saúde da família 2: 278). Em 1 ano de seguimento, os pacientes do grupo do protocolo padronizado e simplificado apresentaram maior proporção de cumprimento das metas de controle da pressão arterial (65% versus 37% e 41%, p<0,001) e maior percentual de adesão ao tratamento, em comparação com aqueles que utilizaram o protocolo habitual (71% versus 18% e 23%, p<0,001). Conclusões. Os resultados mostram que o protocolo padronizado e simplificado é mais eficaz que o proto- colo habitual no controle da hipertensão arterial em pacientes que estão em tratamento na atenção primária do Chile. Sua implementação no nível nacional poderia contribuir para a redução de eventos cardiovasculares maiores.

Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy.

Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7-9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients.

Eficacia de una estrategia estandarizada y simplificada para tratamiento de la hipertensión arterial en Chile: la Iniciativa HEARTS en las Américas / Efficacy of a standardized and simplified strategy for the treatment of high blood pressure in Chile: the HEARTS Initiative in the Americas / Eficácia de uma estratégia padronizada e simplificada para o tratamento da hipertensão arterial no Chile: a iniciativa HEARTS nas Américas

RESUMEN Objetivo. Evaluar la eficacia de un protocolo estandarizado y simplificado basado en los pilares técnicos de la Iniciativa HEARTS para el control de pacientes hipertensos del Programa de Salud Cardiovascular en el primer nivel de atención de salud en Chile. Métodos. Estudio observacional longitudinal (cohorte histórica), en 2 centros de salud familiar del primer nivel de atención en Santiago, que comparó el control de presión arterial en adultos hipertensos logrado con el protocolo estandarizado y simplificado, frente al protocolo habitual, según las guías nacionales. Las innovaciones del protocolo estandarizado incluyeron cambios en la coordinación del equipo de salud, inicio de tratamiento farmacológico inmediatamente después de confirmación diagnóstica, tratamiento farmacológico estandarizado con combinación de al menos 2 o 3 fármacos antihipertensivos en un sólo comprimido, en una toma diaria. Se realizó seguimiento por 1 año para evaluar el porcentaje de adherencia al tratamiento y cumplimiento de metas de control de presión arterial (menor a 140/90 mmHg). Resultados. Se evaluaron 1 490 pacientes: 562 que utilizaron el protocolo estandarizado y simplificado y 928 tratados con el protocolo habitual (centros de salud familiar-1: 650, centros de salud familiar -2: 278). A 1 año de seguimiento, los pacientes del grupo del protocolo estandarizado y simplificado tuvieron mayor proporción de cumplimiento de metas de control de presión arterial (65% versus 37% y 41%, p<0,001) y mayor porcentaje de adherencia al tratamiento en comparación con aquellos con el protocolo habitual (71% versus 18% y 23%, p<0,001). Conclusiones. Los resultados muestran que el protocolo estandarizado y simplificado es más efectivo que el protocolo habitual en el control de hipertensión arterial en pacientes en tratamiento en el primer nivel de atención en Chile. Su implementación a nivel nacional podría contribuir a la disminución de eventos cardiovasculares mayores.

ABSTRACT Objective. To evaluate the effectiveness of a standardized and simplified protocol based on the technical pillars of the HEARTS Initiative for the control of hypertensive patients in the Cardiovascular Health Program at the first level of care in Chile. Methods. Longitudinal observational study (historical cohort) in two family health centers at the first level of care in Santiago. The control of blood pressure in hypertensive adults using a standardized and simplified protocol was compared to the usual protocol based on national guidelines. Innovations in the standardized protocol included changes in how the health team is coordinated, initiation of pharmacological treatment immediately after confirmed diagnosis, standardized pharmacological treatment with a combination of at least two or three antihypertensive drugs taken daily in a single tablet. Follow-up was conducted after one year to assess the percentage of adherence to treatment and achievement of blood pressure control targets (< 140/90 mmHg). Results. A total of 1490 patients were evaluated: 562 who followed the standardized and simplified protocol, and 928 who were treated with the usual protocol (family health centers: 650; family health centers: 278). After one year, patients in the standardized and simplified protocol group had a higher proportion of adherence to blood pressure control targets (65% versus 37% and 41%, p<0.001) and higher adherence to treatment compared to those following the usual protocol (71% versus 18% and 23%, p<0.001). Conclusions. The results show that the standardized and simplified protocol is more effective than the usual protocol in controlling arterial hypertension in patients undergoing treatment at the first level of care in Chile. Its implementation at the national level could contribute to a decrease in major cardiovascular events.

RESUMO Objetivo. Avaliar a eficácia de um protocolo padronizado e simplificado, com base nos pilares técnicos da iniciativa HEARTS, para o controle de pacientes com hipertensão arterial do Programa de Saúde Cardiovascular na atenção primária à saúde do Chile. Métodos. Estudo observacional longitudinal (coorte histórica) em 2 centros de atenção primária de saúde da família em Santiago, que comparou o controle da pressão arterial em adultos com hipertensão, atingido com o protocolo padronizado e simplificado, versus o protocolo habitual, de acordo com as diretrizes nacionais. As inovações do protocolo padronizado incluíram mudanças na coordenação da equipe de saúde, início do tratamento farmacológico imediatamente após a confirmação do diagnóstico e tratamento farmacológico padronizado com associação de pelo menos 2 ou 3 anti-hipertensivos em um único comprimido, tomados uma vez ao dia. O acompanhamento foi realizado por 1 ano para avaliar o percentual de adesão ao tratamento e o cumprimento das metas de controle da pressão arterial (menor que 140/90 mmHg). Resultados. Foram avaliados 1.490 pacientes: 562 que utilizaram o protocolo padronizado e simplificado e 928 que foram tratados com o protocolo habitual (unidade de saúde da família 1: 650, unidade de saúde da família 2: 278). Em 1 ano de seguimento, os pacientes do grupo do protocolo padronizado e simplificado apresentaram maior proporção de cumprimento das metas de controle da pressão arterial (65% versus 37% e 41%, p<0,001) e maior percentual de adesão ao tratamento, em comparação com aqueles que utilizaram o protocolo habitual (71% versus 18% e 23%, p<0,001). Conclusões. Os resultados mostram que o protocolo padronizado e simplificado é mais eficaz que o protocolo habitual no controle da hipertensão arterial em pacientes que estão em tratamento na atenção primária do Chile. Sua implementação no nível nacional poderia contribuir para a redução de eventos cardiovasculares maiores.

Aminoguanidine Prevents the Oxidative Stress, Inhibiting Elements of Inflammation, Endothelial Activation, Mesenchymal Markers, and Confers a Renoprotective Effect in Renal Ischemia and Reperfusion Injury.

Oxidative stress produces macromolecules dysfunction and cellular damage. Renal ischemia-reperfusion injury (IRI) induces oxidative stress, inflammation, epithelium and endothelium damage, and cessation of renal function. The IRI is an inevitable process during kidney transplantation. Preliminary studies suggest that aminoguanidine (AG) is an antioxidant compound. In this study, we investigated the antioxidant effects of AG (50 mg/kg, intraperitoneal) and its association with molecular pathways activated by IRI (30 min/48 h) in the kidney. The antioxidant effect of AG was studied measuring GSSH/GSSG ratio, GST activity, lipoperoxidation, iNOS, and Hsp27 levels. In addition, we examined the effect of AG on elements associated with cell survival, inflammation, endothelium, and mesenchymal transition during IRI. AG prevented lipid peroxidation, increased GSH levels, and recovered the GST activity impaired by IRI. AG was associated with inhibition of iNOS, Hsp27, endothelial activation (VE-cadherin, PECAM), mesenchymal markers (vimentin, fascin, and HSP47), and inflammation (IL-1ß, IL-6, Foxp3, and IL-10) upregulation. In addition, AG reduced kidney injury (NGAL, clusterin, Arg-2, and TFG-ß1) and improved kidney function (glomerular filtration rate) during IRI. In conclusion, we found new evidence of the antioxidant properties of AG as a renoprotective compound during IRI. Therefore, AG is a promising compound to treat the deleterious effect of renal IRI.

Glutathione S-Transferase and Clusterin, New Players in the Ischemic Preconditioning Renal Protection in a Murine Model of Ischemia and Reperfusion.

BACKGROUND/AIMS: Renal ischemia and reperfusion injury (IRI) involves oxidative stress, disruption of microvasculature due to endothelial cell damage, loss of epithelial cell polarity secondary to cytoskeletal alterations, inflammation, and the subsequent transition into a mesenchymal phenotype. Ischemic preconditioning (IPC) has been proposed as a therapeutic strategy to avoid/ameliorate the IRI. Since previous results showed that IPC could have differential effects in kidney cortex vs. kidney medulla, in the present study we analyzed the effectiveness and molecular mechanisms implicated in IPC in both kidney regions. METHODS: We evaluated 3 experimental groups of BALB/c male mice: control (sham surgery); renal ischemia (30 min) by bilateral occlusion of the renal pedicle and reperfusion (48 hours) (I/R); and renal IPC (two cycles of 5 min of ischemia and 5 min of reperfusion) applied just before I/R. Acute kidney injury was evaluated by glomerular filtration rate (GFR), Neutrophil Gelatinase-Associated Lipocalin (NGAL) blood level, and histologic analysis. Oxidative stress was studied measurement the Glutathione S-Transferase (GST) activity, GSH/GSSG ratio, and lipoperoxidation levels. Inflammatory mediators (IL-1ß, IL-6, Foxp3, and IL-10) were quantified by qRT-PCR. The endothelial (PECAM-1), epithelial (AQP-1), mesenchymal (Vimentin, Fascin, and Hsp47), iNOS, clusterin, and Hsp27 expression were evaluated (qRT-PCR and/or Western blot). RESULTS: The IPC protocol prevented the decrease of GFR, reduced the plasma NGAL, and ameliorated morphological damage in the kidney cortex after I/R. The IPC also prevented the downregulation of GST activity, lipoperoxidation and ameliorated the oxidized glutathione. In addition, IPC prevented the upregulation of vimentin, fascin, and Hsp47, which was associated with the prevention of the downregulation of AQP1 after I/R. The protective effect of IPC was associated with the upregulation of Hsp27, Foxp3, and IL-10 expression in the renal cortex. However, the upregulation of iNOS, IL-1ß, IL-6, and clusterin by I/R were not modified by IPC. CONCLUSION: IPC conferred better protection in the kidney cortex as compared to the kidney medulla. The protective effect of IPC was associated with amelioration of oxidative stress, tubular damage, and the induction of markers of Treg lymphocytes activity in the cortical region. Further studies are needed to evaluate if lower tubular cell stress/damage after I/R may explain the preferential induction of Treg response in the kidney cortex induced by IPC.

[Role of inflammation in hypertension]. / La inflamación en la hipertensión arterial, mecanismos de producción e implicancias terapéuticas.

Even though the mechanisms that mediate essential hypertension (HT) are not fully understood, an immunological-inflammatory mechanism could be the common pathway for diverse pathophysiological mechanisms. We analyze in a simplified way the participation of the immune system in HT. T lymphocytes (TL) and antigen presenting cells (APCs) are components of the immune system capable of generating proinflammatory cytokines. They cause endothelial damage, vasoconstriction, and decreased urinary sodium excretion. CD4+ and CD8+ TL are effector cells, causally implicated in the development of HT, whereas type γδ TL play their pathogenic role in HT enhancing endothelial dysfunction. Additionally, a immunomodulation decrease by regulatory TL, worsens endothelial dysfunction and reduces vasodilation in experimental HT. Results of recent studies indicate that lymphocyte activation would be mediated by antigens captured by antigen APCs for subsequent presentation to "naive" TL. On the other hand, proinflammatory states such as obesity, the change of the intestinal microbiota and the increase in salt intake favors TL and APC activation, contributing to HT development.

Attended Automated Office Blood Pressure Measurement Versus Ambulatory Blood Pressure Monitoring in a Primary Healthcare Setting in Chile.

OBJECTIVES: As part of the HEARTS in the Americas initiative, Chilean primary healthcare centers have implemented novel hypertension management strategies, including new diagnostic approaches. This study evaluated the concordance between attended automated office blood pressure (AOBP) measurements with an oscillometric device and ambulatory blood pressure monitoring (ABPM). METHODS: This was an observational cohort study to evaluate and compare attended AOBP and ABPM for the diagnosis of hypertension in adults in a primary healthcare setting. RESULTS: The study evaluated 309 participants (54.2 ± 15.7 years; 50.5% male) from four primary healthcare centers in Santiago, Chile. Attended AOBP measurements were obtained at the clinic on two separate days, followed by ABPM. AOBP values indicated that 69.6% of patients had a systolic blood pressure (SBP) of ≥140 mm Hg and 34.6% had a diastolic blood pressure (DBP) of ≥90 mm Hg. A total of 83.5% had hypertension, 45.3% had high SBP, and 56.0% had high DBP. ABPM values indicated that 65.0% of patients had hypertension. The combined AOBP and ABPM analysis showed that 57.0% of patients had sustained hypertension, 26.5% had white coat hypertension, 8.1% had masked hypertension, and 8.4% were normotensive. The concordance between AOBP and ABPM (κ coefficient) was low (κ = 0.133; 95% confidence interval 0.028-0.237). The comparison of AOBP and ABPM measurements (Bland-Altman plots and bias calculations) showed an important bias in BP as measured using the AOBP method, especially for SBP (13.7 ± 11.6, 95% confidence interval -9.1 to 36.5). CONCLUSIONS: Attended AOBP alone may not be sufficient for adequate classification, diagnosis, and management of hypertension in Chile or other countries with similar demographics.

La inflamación en la hipertensión arterial, mecanismos de producción e implicancias terapéuticas / Role of inflammation in hypertension

Even though the mechanisms that mediate essential hypertension (HT) are not fully understood, an immunological-inflammatory mechanism could be the common pathway for diverse pathophysiological mechanisms. We analyze in a simplified way the participation of the immune system in HT. T lymphocytes (TL) and antigen presenting cells (APCs) are components of the immune system capable of generating proinflammatory cytokines. They cause endothelial damage, vasoconstriction, and decreased urinary sodium excretion. CD4+ and CD8+ TL are effector cells, causally implicated in the development of HT, whereas type γδ TL play their pathogenic role in HT enhancing endothelial dysfunction. Additionally, a immunomodulation decrease by regulatory TL, worsens endothelial dysfunction and reduces vasodilation in experimental HT. Results of recent studies indicate that lymphocyte activation would be mediated by antigens captured by antigen APCs for subsequent presentation to "naive" TL. On the other hand, proinflammatory states such as obesity, the change of the intestinal microbiota and the increase in salt intake favors TL and APC activation, contributing to HT development.

Sensibilidad aumentada a lidocaína: estudio genético de un caso / Increased sensitivity to lidocaine: Genetic study of a case

Systemic toxicity by local anesthetics (LAs) is a severe and feared complication in anesthetic practice that generally results from the administration of an inappropriately high dose of LAs or an injection at an inappropriate place, either intravascular or a site with high absorption[1]. However, it is known that the susceptibility to these drugs may vary within the population, which may occur due to genetic changes in the LA binding site, located in the potential-dependent Na+ channels (Nav), thus increasing or decreasing its affinity and, therefore, its clinical consequences. We present a case of a 61 years-old female patient with a medical history of increased sensitivity to LAs. In this scenario, a genetic study was performed to exclude a Nav channel dysfunction.

La toxicidad sistémica por anestésicos locales (ALs) es una grave y temida complicación en la práctica anestésica que generalmente resulta de la administración de una dosis inapropiadamente alta de ALs o a una inyección en un lugar inadecuado, llámese intravascular o un sitio al alta absorción[1]. A pesar de lo anterior, es conocido que la susceptibilidad al efecto de estos fármacos puede variar dentro de la población, lo cual puede ocurrir debido a cambios genéticos en el sitio de unión de los AL, localizado en los canales de Na+ dependientes de potencial (Nav), incrementando o disminuyendo así su afinidad y, por ende, sus consecuencias clínicas. Presentamos el caso de una paciente de 61 años con historia de sensibilidad aumentada a Als. En este escenario, se le ofreció un estudio genético para excluir una disfunción específica a nivel de canal Nav

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway.

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.

Dendritic cells are crucial for cardiovascular remodeling and modulate neutrophil gelatinase-associated lipocalin expression upon mineralocorticoid receptor activation.

BACKGROUND: Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage. However, the interrelationship among dendritic cells, target organs inflammation/fibrosis induced by mineralocorticoid receptor, and NGAL-dependence remains unknown. OBJECTIVE: We studied the role of dendritic cells in mineralocorticoid receptor-dependent tissue remodeling and whether NGAL can modulate the inflammatory response of dendritic cells after mineralocorticoid receptor activation. METHODS: Cardiovascular and renal remodeling induced by Aldo and high-salt diet [nephrectomy-Aldo-salt (NAS) model] were analyzed in CD11c.DOG mice, a model which allows dendritic cells ablation by using diphtheria toxin. In addition, in-vitro studies in NGAL-knock out dendritic cells were performed to determine the immunomodulatory role of NGAL upon Aldo treatment. RESULTS: The ablation of dendritic cells prevented the development of cardiac hypertrophy, perivascular fibrosis, and the overexpression of NGAL, brain natriuretic peptide, and two profibrotic factors induced by NAS: collagen 1A1 and connective tissue growth factor. We determined that dendritic cells were not required to prevent renal hypertrophy/fibrosis induced by NAS. Between different immune cells analyzed, we observed that NGAL abundance was higher in antigen-presenting cells, while in-vitro studies showed that mineralocorticoid receptor stimulation in dendritic cells favored NGAL and IL-23 expression (p19 and p40 subunits), which are involved in the development of fibrosis and the Th17-driven response, respectively. CONCLUSION: NGAL produced by dendritic cells may play a pivotal role in the activation of adaptive immunity that leads to cardiovascular fibrosis during mineralocorticoids excess.

TRPM4 channel is involved in regulating epithelial to mesenchymal transition, migration, and invasion of prostate cancer cell lines.

Transient Receptor Potential Melastatin 4 (TRPM4) is a Ca2+ -activated and voltage-dependent monovalent cation channel, which depolarizes the plasma cell membrane, thereby modulating Ca2+ influx across Ca2+ -permeable pathways. TRPM4 is involved in different physiological processes such as T cell activation and the migration of endothelial and certain immune cells. Overexpression of this channel has been reported in various types of tumors including prostate cancer. In this study, a significant overexpression of TRPM4 was found only in samples from cancer with a Gleason score higher than 7, which are more likely to spread. To evaluate whether TRPM4 overexpression was related to the spreading capability of tumors, TRPM4 was knockdown by using shRNAs in PC3 prostate cancer cells and the effect on cellular migration and invasion was analyzed. PC3 cells with reduced levels of TRPM4 (shTRPM4) display a decrease of the migration/invasion capability. A reduction in the expression of Snail1, a canonical epithelial to mesenchymal transition (EMT) transcription factor, was also observed. Consistently, these cells showed a significant change in the expression of key EMT markers such as MMP9, E-cadherin/N-cadherin, and vimentin, indicating a partial reversion of the EMT process. Whereas, the overexpression of TRPM4 in LnCaP cells resulted in increased levels of Snail1, reduction in the expression of E-cadherin and increase in their migration potential. This study suggests a new and indirect mechanism of regulation of migration/invasion process by TRPM4 in prostate cancer cells, by inducing the expression of Snail1 gene and consequently, increasing the EMT.

l-NIL prevents the ischemia and reperfusion injury involving TLR-4, GST, clusterin, and NFAT-5 in mice.

On renal ischemia-reperfusion (I/R) injury, recruitment of neutrophils during the inflammatory process promotes local generation of oxygen and nitrogen reactive species, which, in turn, are likely to exacerbate tissue damage. The mechanism by which inducible nitric oxide synthase (iNOS) is involved in I/R has not been elucidated. In this work, the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine (l-NIL) and the NOS substrate l-arginine were employed to understand the role of NOS activity on the expression of particular target genes and the oxidative stress elicited after a 30-min of bilateral renal ischemia, followed by 48-h reperfusion in Balb/c mice. The main findings of the present study were that pharmacological inhibition of iNOS with l-NIL during an I/R challenge of mice kidney decreased renal injury, prevented tissue loss of integrity, and improved renal function. Several novel findings regarding the molecular mechanism by which iNOS inhibition led to these protective effects are as follows: 1) a prevention of the I/R-related increase in expression of Toll-like receptor 4 (TLR-4), and its downstream target, IL-1ß; 2) reduced oxidative stress following the I/R challenge; noteworthy, this study shows the first evidence of glutathione S-transferase (GST) inactivation following kidney I/R, a phenomenon fully prevented by iNOS inhibition; 3) increased expression of clusterin, a survival autophagy component; and 4) increased expression of nuclear factor of activated T cells 5 (NFAT-5) and its target gene aquaporin-1. In conclusion, prevention of renal damage following I/R by the pharmacological inhibition of iNOS with l-NIL was associated with the inactivation of proinflammatory pathway triggered by TLR-4, oxidative stress, renoprotection (autophagy inactivation), and NFAT-5 signaling pathway.

Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury.

It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI.

Myeloid CD11c+ Antigen-Presenting Cells Ablation Prevents Hypertension in Response to Angiotensin II Plus High-Salt Diet.

Increasing evidence shows that antigen-presenting cells (APCs) are involved in the development of inflammation associated to hypertension. However, the potential role of APCs in the modulation of renal sodium transport has not been addressed. We hypothesized that APCs participate in renal sodium transport and, thus, development of high blood pressure in response to angiotensin II plus a high-salt diet. Using transgenic mice that allow the ablation of CD11chigh APCs, we studied renal sodium transport, the intrarenal renin-angiotensin system components, blood pressure, and cardiac/renal tissue damage in response to angiotensin II plus a high-salt diet. Strikingly, we found that APCs are required for the development of hypertension and that the ablation/restitution of APCs produces rapid changes in the blood pressure in mice with angiotensin II plus a high-salt diet. Moreover, APCs were necessary for the induction of intrarenal renin-angiotensin system components and affected the modulation of natriuresis and tubular sodium transporters. Consistent with the prevention of hypertension, the ablation of APCs also prevented cardiac hypertrophy and the induction of several indicators of renal and cardiac damage. Thus, our findings indicate a prominent role of APCs as modulators of blood pressure by mechanisms including renal sodium handling, with kinetics that suggest the involvement of tubular cell functions in addition to the modulation of inflammation and adaptive immune response.