A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Effectiveness of adherence to a renal health program in a health network in Peru.

OBJECTIVE To evaluate the effectiveness of adherence to a multidisciplinary renal health program in reducing mortality and progression to hemodialysis. METHODS We used a database that included patient monitoring (2013-2017), dialysis admissions and all cause of mortality in Peru. Adherence to the program was established by meeting minimum visits during the first year of monitoring. The outcome of interest was hemodialysis admissions or all cause-mortality. Kaplan-Meier curves, Log-Rank test and competing survival analysis methods were used to estimate the differential risk between adherent and non-adherent patients. RESULTS A total of 20,354 participants was evaluated; 54.1% were male, 72.1 years old in average, 2.2 years average follow-up, and 15,279 (75.1%) belonged to the early stages (1 to 3a) of Chronic Kidney Disease. Adherence decreased the risk of renal replacement therapy in 41.0% (HR = 0.59, 95%CI 0.41-0.85) in the low-risk group and mortality in the high-risk group was 31.0% (HR = 0.69, 95%CI 0.57-0.83). CONCLUSIONS The multidisciplinary care strategy with standardized assessments by stage is effective in reducing admission to .0when the patient is identified in early stages and in reducing mortality in advanced stages.

[Progression of chronic renal disease in a reference hospital of social security of Peru 2012-2015]. / Progresión de enfermedad renal crónica en un hospital de referencia de la seguridad social de Perú 2012-2015.

OBJECTIVES.: To describe the characteristics of the population with chronic kidney disease (CKD) stage 3 and 4, to determine the factors associated with CKD progression and admission to renal replacement therapy (RRT), as well as renal survival. MATERIALS AND METHODS.: Longitudinal retrospective study of patients referred between January 2012 and December 2015 to the Renal Health Unit of the Hospital Nacional Edgardo Rebagliati Martins (HNERM), who were evaluated and followed by a multidisciplinary team. The clinical and laboratory data for each query were recorded in a software created specifically for the program. A multivariate logistic regression analysis was performed to assess the factors associated with the progression of CKD, a Cox regression model to predict the risk of entering RRT and the Kaplan-Meier method for renal survival analysis. RESULTS.: We assessed 1248 patients in stage 3A: 248 (20%), stage 3B: 548 (44%) and stage 4: 452 (36%). 352 (28%) progressed, being proteinuria the most important progression factor (OR: 3.2; CI 95%: 2,2-4.6). Proteinuria increases the risk of admission to RRT in four times and having a glomerular filtration rate < 30% in 3.6 times. Median follow-up was 12 months (RIC 5-27 months). 92 patients (7%) required to initiate RRT. Renal survival at 12 months of follow-up was 96% and at 24 months was 90%. CONCLUSIONS.: Our study shows that in a specialized center a significant proportion of patients with CKD does not progress in their disease and that the factor that is most associated with progression of disease and at the onset of RRT is proteinuria.

OBJETIVOS.: Describir las características de la población con enfermedad renal crónica (ERC) estadio 3 y 4, determinar los factores asociados a progresión de ERC y a ingreso a terapia de reemplazo renal (TRR), así como la sobrevida renal. MATERIALES Y MÉTODOS.: Estudio retrospectivo longitudinal de pacientes remitidos entre enero de 2012 y diciembre de 2015 a la Unidad de Salud Renal del Hospital Nacional de Edgardo Rebagliati Martins (HNERM), quienes fueron evaluados y seguidos por un equipo multidisciplinario. Los datos clínicos y de laboratorio de cada consulta se registraron en un software creado específicamente para el programa. Se realizó un análisis de regresión logística multivariado para evaluar los factores asociados con la progresión de la ERC, un modelo de regresión de Cox para predecir el riesgo de ingresar al TRR y el método de Kaplan-Meier para el análisis de supervivencia renal. RESULTADOS.: Se evaluó a 1248 pacientes en estadio 3A: 248 (20%), estadio 3b: 548 (44%) y estadio 4: 452 (36%). 352 (28%) progresaron, siendo la proteinuria el factor de progresión más importante (OR: 3,2; IC95%: 2,2-4,6). La proteinuria incrementa el riesgo de ingreso a la TRR en cuatro veces y el tener una tasa de filtración glomerular <30% en 3,6 veces. La mediana de seguimiento fue de 12 meses (RIC 5-27 meses). 92 pacientes (7%) requirieron iniciar TRR. La supervivencia renal a los 12 meses de seguimiento fue del 96% y a los 24 meses de 90%. CONCLUSIONES.: Nuestro estudio muestra que en un centro especializado una proporción significativa de pacientes con ERC no progresa en su enfermedad y que el factor que más se asocia a progresión de enfermedad y a inicio de TRR es la proteinuria.

Effectiveness of adherence to a renal health program in a health network in Peru / Efectividad de la adherencia a un programa de salud renal en una red sanitaria de Perú

ABSTRACT OBJECTIVE To evaluate the effectiveness of adherence to a multidisciplinary renal health program in reducing mortality and progression to hemodialysis. METHODS We used a database that included patient monitoring (2013-2017), dialysis admissions and all cause of mortality in Peru. Adherence to the program was established by meeting minimum visits during the first year of monitoring. The outcome of interest was hemodialysis admissions or all cause-mortality. Kaplan-Meier curves, Log-Rank test and competing survival analysis methods were used to estimate the differential risk between adherent and non-adherent patients. RESULTS A total of 20,354 participants was evaluated; 54.1% were male, 72.1 years old in average, 2.2 years average follow-up, and 15,279 (75.1%) belonged to the early stages (1 to 3a) of Chronic Kidney Disease. Adherence decreased the risk of renal replacement therapy in 41.0% (HR = 0.59, 95%CI 0.41-0.85) in the low-risk group and mortality in the high-risk group was 31.0% (HR = 0.69, 95%CI 0.57-0.83). CONCLUSIONS The multidisciplinary care strategy with standardized assessments by stage is effective in reducing admission to .0when the patient is identified in early stages and in reducing mortality in advanced stages.

RESUMEN OBJETIVO Evaluar la efectividad de la adherencia a un programa de salud renal en la reducción de mortalidad y progresión a hemodiálisis. MÉTODOS Utilizamos una base de datos que condensaba el seguimiento de los pacientes (2013-2017), los ingresos a diálisis de los mismos y la mortalidad por todas las causas en Perú. La adherencia al programa se estableció con el cumplimiento de visitas mínimas durante su primer año de seguimiento. La efectividad de la adherencia al programa se midió en términos de debut a hemodiálisis o muerte por todas las causas. Se utilizaron curvas de Kaplan-Meier, test de diferencias en la distribución (Log-Rank test) y métodos de análisis de supervivencia. Los análisis se realizaron utilizando R estudio 3.5.0 RESULTADOS Fueron evaluados 20.354 participantes, 54,1% varones, edad media de 72,1 años, con un seguimiento medio de 2,2 años; 15.279 (75.1%) tuvieron ERC en estadios tempranos (estadio 1 al 3a). La adherencia disminuyó en un 41,0% el riesgo de terapia de reemplazo renal (HR = 0,59; IC95% 0,41-0,85) en el grupo de bajo riesgo y en un 31,0% (HR = 0,69; IC95% 0,57-0,83) la mortalidad en el grupo de alto riesgo. CONCLUSIONES La estrategia de cuidado multidisciplinario con evaluaciones estandarizadas según estadio es efectiva en reducir el ingreso a terapia de reemplazo renal cuando se identifica al paciente en estadios tempranos y en reducir la mortalidad en estadios avanzados.

Progresión de enfermedad renal crónica en un hospital de referencia de la seguridad social de Perú 2012-2015 / Progression of chronic renal disease in a reference hospital of social security of Peru 2012-2015

RESUMEN Objetivos. Describir las características de la población con enfermedad renal crónica (ERC) estadio 3 y 4, determinar los factores asociados a progresión de ERC y a ingreso a terapia de reemplazo renal (TRR), así como la sobrevida renal. Materiales y métodos. Estudio retrospectivo longitudinal de pacientes remitidos entre enero de 2012 y diciembre de 2015 a la Unidad de Salud Renal del Hospital Nacional de Edgardo Rebagliati Martins (HNERM), quienes fueron evaluados y seguidos por un equipo multidisciplinario. Los datos clínicos y de laboratorio de cada consulta se registraron en un software creado específicamente para el programa. Se realizó un análisis de regresión logística multivariado para evaluar los factores asociados con la progresión de la ERC, un modelo de regresión de Cox para predecir el riesgo de ingresar al TRR y el método de Kaplan-Meier para el análisis de supervivencia renal. Resultados. Se evaluó a 1248 pacientes en estadio 3A: 248 (20%), estadio 3b: 548 (44%) y estadio 4: 452 (36%). 352 (28%) progresaron, siendo la proteinuria el factor de progresión más importante (OR: 3,2; IC95%: 2,2-4,6). La proteinuria incrementa el riesgo de ingreso a la TRR en cuatro veces y el tener una tasa de filtración glomerular <30% en 3,6 veces. La mediana de seguimiento fue de 12 meses (RIC 5-27 meses). 92 pacientes (7%) requirieron iniciar TRR. La supervivencia renal a los 12 meses de seguimiento fue del 96% y a los 24 meses de 90%. Conclusiones. Nuestro estudio muestra que en un centro especializado una proporción significativa de pacientes con ERC no progresa en su enfermedad y que el factor que más se asocia a progresión de enfermedad y a inicio de TRR es la proteinuria.

ABSTRACT Objectives. To describe the characteristics of the population with chronic kidney disease (CKD) stage 3 and 4, to determine the factors associated with CKD progression and admission to renal replacement therapy (RRT), as well as renal survival. Materials and methods. Longitudinal retrospective study of patients referred between January 2012 and December 2015 to the Renal Health Unit of the Hospital Nacional Edgardo Rebagliati Martins (HNERM), who were evaluated and followed by a multidisciplinary team. The clinical and laboratory data for each query were recorded in a software created specifically for the program. A multivariate logistic regression analysis was performed to assess the factors associated with the progression of CKD, a Cox regression model to predict the risk of entering RRT and the Kaplan-Meier method for renal survival analysis. Results. We assessed 1248 patients in stage 3A: 248 (20%), stage 3B: 548 (44%) and stage 4: 452 (36%). 352 (28%) progressed, being proteinuria the most important progression factor (OR: 3.2; CI 95%: 2,2-4.6). Proteinuria increases the risk of admission to RRT in four times and having a glomerular filtration rate < 30% in 3.6 times. Median follow-up was 12 months (RIC 5-27 months). 92 patients (7%) required to initiate RRT. Renal survival at 12 months of follow-up was 96% and at 24 months was 90%. Conclusions. Our study shows that in a specialized center a significant proportion of patients with CKD does not progress in their disease and that the factor that is most associated with progression of disease and at the onset of RRT is proteinuria.