Showing papers by "Luis M. Ruilope published in 2019"

Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry.

Abstract: AIMS Several studies and registries have demonstrated sustained reductions in blood pressure (BP) after renal denervation (RDN). The long-term safety and efficacy after RDN in real-world patients with uncontrolled hypertension, however, remains unknown. The objective of this study was to assess the long-term safety and efficacy of RDN, including its effects on renal function. METHODS AND RESULTS The Global SYMPLICITY Registry is a prospective, open-label registry conducted at 196 active sites worldwide in hypertensive patients receiving RDN treatment. Among 2237 patients enrolled and treated with the SYMPLICITY Flex catheter, 1742 were eligible for follow-up at 3 years. Baseline office and 24-h ambulatory systolic BP (SBP) were 166 ± 25 and 154 ± 18 mmHg, respectively. SBP reduction after RDN was sustained over 3 years, including decreases in both office (-16.5 ± 28.6 mmHg, P < 0.001) and 24-h ambulatory SBP (-8.0 ± 20.0 mmHg; P < 0.001). Twenty-one percent of patients had a baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Between baseline and 3 years, renal function declined by 7.1 mL/min/1.73 m2 in patients without chronic kidney disease (CKD; eGFR ≥60 mL/min/1.73 m2; baseline eGFR 87 ± 17 mL/min/1.73 m2) and by 3.7 mL/min/1.73 m2 in patients with CKD (eGFR <60 mL/min/1.73 m2; baseline eGFR 47 ± 11 mL/min/1.73 m2). No long-term safety concerns were observed following the RDN procedure. CONCLUSION Long-term data from the Global SYMPLICITY Registry representing the largest available cohort of hypertensive patients receiving RDN in a real-world clinical setting demonstrate both the safety and efficacy of the procedure with significant and sustained office and ambulatory BP reductions out to 3 years.

Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial

Abstract: Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial.

Abstract: Background: Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of finerenone on renal and CV outcomes has not been investigated in long-term trials yet. Methods: The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease ­(FIDELIO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25–<75 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30–≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death. Conclusion: FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.

Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and meta-analysis of randomized controlled trials.

Abstract: Background Reductions in albuminuria of more than 30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin-angiotensin system (RAS) blockade represents the cornerstone of CKD treatment. However, as CKD progression still occurs, other nephroprotective options were explored; mineralocorticoid receptor antagonists (MRA) were tested with generally positive results. Methods We conducted a systematic review and meta-analysis on the effects of MRAs on albuminuria/proteinuria, and adverse events, such as change in renal function and hyperkalemia incidence. A detailed search in electronic databases, clinical trial registries and grey literature was performed to retrieve randomized controlled trials (RCTs) in which administration of an MRA alone or on-top of ACEi/ARB was compared with placebo or active treatment. Results Of the 45 initially identified reports, 31, with 2767 participants, were included in analysis of the primary outcome. The use of MRAs (alone or on top of RAS blockade) compared with placebo decreased urine albumin-to-creatinine ratio (UACR) by -24.55% (95% CI -29.57 to -19.53%), urine protein-to-creatinine ratio (UPCR) by -53.93% (95% CI -79% to -28.86%) and 24 h albumin excretion by -32.47% (95% CI -41.1 to -23.85%). MRAs also reduced UACR by -22.48% (95% CI -24.51 to -20.44%) compared with calcium-channel-blockers (CCBs), whereas no differences were found compared with a second ACEi/ARB or nonpotassium-sparing diuretics. Addition of an MRA was associated with change in estimated glomerular filtration rate (eGFR) of -2.38 ml/min per 1.73 m (95% CI -3.51 to -1.25), rise in potassium by 0.22 mEq/l (95% CI 0.16-0.28 mEq/l) and a 2.6-fold increase in hyperkalemia risk (RR 2.63, 95% CI 1.69-4.08) compared with placebo/active control. Conclusion Use of MRAs alone or on top of RAS blockade confers important antiproteinuric effects in patients with CKD, with a slight increase in mean potassium levels.

Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints

Abstract: Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

Guía ESC/ESH 2018 sobre el diagnóstico y tratamiento de la hipertensión arterial

Abstract: Autores/Miembros del Grupo de Trabajo: Bryan Williams* (coordinador de la ESC) (Reino Unido), Giuseppe Mancia* (coordinador de la ESH) (Italia), Wilko Spiering (Países Bajos), Enrico Agabiti Rosei (Italia), Michel Azizi (Francia), Michel Burnier (Suiza), Denis L. Clement (Bélgica), Antonio Coca (España), Giovanni de Simone (Italia), Anna Dominiczak (Reino Unido), Thomas Kahan (Suecia), Felix Mahfoud (Alemania), Josep Redon (España), Luis Ruilope (España), Alberto Zanchetti† (Italia), Mary Kerins (Irlanda), Sverre E. Kjeldsen (Noruega), Reinhold Kreutz (Alemania), Stephane Laurent (Francia), Gregory Y.H. Lip (Reino Unido), Richard McManus (Reino Unido), Krzysztof Narkiewicz (Polonia), Frank Ruschitzka (Suiza), Roland E. Schmieder (Alemania), Evgeny Shlyakhto (Rusia), Costas Tsioufis (Grecia), Victor Aboyans (Francia) e Ileana Desormais (Francia)

Fibroblast growth factor-23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes

Abstract: Background Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation-contraction (EC) coupling. Methods We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram. Results Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho). Conclusions Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD.

Microalbuminuria and cardiorenal risk: old and new evidence in different populations.

Abstract: Since the association of microalbuminuria (MAU) with cardiovascular (CV) risk was described, a huge number of reports have emerged. MAU is a specific integrated marker of CV risk and targets organ damage in patients with hypertension, chronic kidney disease (CKD), and diabetes and its recognition is important for identifying patients at a high or very high global CV risk. The gold standard for diagnosis is albumin measured in 24-hour urine collection (normal values of less than 30 mg/day, MAU of 30 to 300 mg/day, macroalbuminuria of more than 300 mg/day) or, more practically, the determination of urinary albumin-to-creatinine ratio in a urine morning sample (30 to 300 mg/g). MAU screening is mandatory in individuals at risk of developing or presenting elevated global CV risk. Evidence has shown that intensive treatment could turn MAU into normoalbuminuria. Intensive treatment with the administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, in combination with other anti-hypertensive drugs and drugs covering other aspects of CV risk, such as mineralocorticoid receptor antagonists, new anti-diabetic drugs, and statins, can diminish the risk accompanying albuminuria in hypertensive patients with or without CKD and diabetes.

Oxidative Status before and after Renal Replacement Therapy: Differences between Conventional High Flux Hemodialysis and on-Line Hemodiafiltration.

Abstract: Hemodialysis patients experience high oxidative stress because of systemic inflammation and depletion of antioxidants. Little is known about the global oxidative status during dialysis or whether it is linked to the type of dialysis. We investigated the oxidative status before (pre-) and after (post-) one dialysis session in patients subjected to high-flux dialysis (HFD) or on-line hemodiafiltration (OL-HDF). We analyzed carbonyls, oxidized LDL (oxLDL), 8-hydroxy-2'-deoxyguanosine, and xanthine oxidase (XOD) activity as oxidative markers, and total antioxidant capacity (TAC), catalase, and superoxide dismutase activities as measures of antioxidant defense. Indices of oxidative damage (OxyScore) and antioxidant defense (AntioxyScore) were computed and combined into a global DialysisOxyScore. Both dialysis modalities cleared all markers (p < 0.01) except carbonyls, which were unchanged, and oxLDL, which increased post-dialysis (p < 0.01). OxyScore increased post-dialysis (p < 0.001), whereas AntioxyScore decreased (p < 0.001). XOD and catalase activities decreased post-dialysis after OL-HDF (p < 0.01), and catalase activity was higher after OL-HDF than after HFD (p < 0.05). TAC decreased in both dialysis modalities (p < 0.01), but remained higher in OL-HDF than in HFD post-dialysis (p < 0.05), resulting in a lower overall DialysisOxyScore (p < 0.05). Thus, patients on OL-HDF maintain higher levels of antioxidant defense, which might balance the elevated oxidative stress during dialysis, although further longitudinal studies are needed.

Effect of angiotensin receptor blockers on blood pressure and renal function in patients with concomitant hypertension and chronic kidney disease: a systematic review and meta-analysis

Abstract: Objective: Angiotensin receptor blockers (ARB) are among the recommended first-line treatment options in patients with hypertension and chronic kidney disease (CKD). This meta-analysis evaluated th...

Frequency and Prognosis of Treated Hypertensive Patients According to Prior and New Blood Pressure Goals.

Abstract: United States and European guidelines have recommended new treatment goals for office blood pressure (BP). We examined 9784 hypertensives of the Spanish Ambulatory BP Monitoring (ABPM) registry wit...

Asociación entre disminución de la función renal y actividad metaloproteinasa-9 en el paciente hipertenso

Abstract: Resumen Antecedentes y objetivo Las enzimas metaloproteinasas de matriz (MMP) estan involucradas en el remodelado tisular deletereo asociado al dano de organos diana de la enfermedad renal. El objetivo de este estudio fue explorar la asociacion entre la caida de la funcion renal y la actividad sistemica de la metaloproteinasa inflamatoria MMP-9 en el paciente hipertenso con enfermedad renal cronica (ERC) leve-moderada. Material y metodos Se analizaron los niveles plasmaticos de MMP-9 activa, MMP-9 total, su inhibidor tisular (TIMP-1), el cociente MMP-9/TIMP-1 y la interaccion entre MMP-9 y TIMP-1 en 37 pacientes hipertensos distribuidos segun su tasa de filtracion glomerular estimada (TFGe) en 3 grupos: > 90, 90-60 y 60-30 mL/min/1,73 m2. Resultados La MMP-9 total no fue diferente con respecto a la disminucion en la TFGe. TIMP-1 estaba significativamente incrementado en los pacientes hipertensos con TFGe entre 60-30 mL/min/1,73 m2 (p 90 mL/min/1,73 m2). Estos resultados fueron apoyados por la disminucion significativa de la interaccion MMP-9-TIMP-1 observada en los pacientes con TFGe entre 60-30 mL/min/1,73 m2 (p 90 mL/min/1,73 m2). A pesar de la elevacion sistemica de TIMP-1 encontramos un incremento significativo de MMP-9 activa en los pacientes hipertensos con TFGe entre 60-30 mL/min/1,73 m2 (p 90 y 90-60 mL/min/1,73 m2, respectivamente). Los niveles de TIMP-1, MMP-9 activa e interaccion proteica MMP-9-TIMP-1 correlacionaron significativamente con el deterioro de la funcion renal, lo cual no se observo para la MMP-9 total. Conclusiones La progresion de la ERC, incluso en estadios donde la caida de la funcion renal es aun moderada, se asocia con un aumento especifico de la actividad MMP-9, lo cual podria considerarse como una potencial diana terapeutica.

Estimating the impact of obesity and metabolic phenotype on sickness absence. Results from the ICARIA study.

Abstract: Background and aims To assess the impact of obesity and being overweight on sickness absence (SA) as a function of healthy/unhealthy metabolic phenotype. Methods and results A total of 173 120 healthy workers who underwent a routine check-up, consisting of a structured interview, anthropometric measurements and blood pressure and fasting blood analysis, were included as the study sample (67.1% males; 49.2% manual workers; mean age 40.6 ± 21.9 years). Workers were classified according to their body mass index (BMI) and metabolic phenotype. A metabolically unhealthy phenotype was defined as the presence of three or more of the following criteria: glycaemia ≥110 mg/dL or previously diagnosed type I/II diabetes or treatment for diabetes; triglycerides ≥150 mg/dL or lipid-lowering therapy; HDL 102/88 cm M/F. A one-year follow-up was conducted to evaluate the incidence of work-related and non-work-related SA (WRSA/NWRSA). The association of BMI with SA was tested using Poisson regression (standard error correction), segmenting on the basis of metabolic phenotype. The overall percentages of workers who were overweight, obese and/or had a metabolically unhealthy phenotype were 37.7%, 16.3% and 8.8%, respectively. BMI was associated with increased incidence of NWRSA in both phenotypes. It was also associated with WRSA in subjects with a BMI in the range of 35–39.99 kg/m2 and in metabolically healthy individuals. WRSA was lower in subjects with a BMI ≥40 kg/m2 and among metabolically unhealthy individuals. Conclusion Obesity is associated with health problems that have a significant impact on SA.

Urine Haptoglobin and Haptoglobin-Related Protein Predict Response to Spironolactone in Patients With Resistant Hypertension.

Abstract: Resistant hypertension prevalence is progressively increasing, and prolonged exposure to suboptimal blood pressure control results in higher cardiovascular risk and end-organ damage. Among various antihypertensive agents, spironolactone seems the most effective choice to treat resistant hypertension once triple therapy including a diuretic fails. However success in blood pressure control is not guaranteed, adverse effects are not negligible, and no clinical tools are available to predict patient's response. Complementary to our previous study of resistant hypertension metabolism, here we investigated urinary proteome changes with potential capacity to predict response to spironolactone. Twenty-nine resistant hypertensives were included. A prospective study was conducted and basal urine was collected before spironolactone administration. Patients were classified in responders or nonresponders in terms of blood pressure control. Protein quantitation was performed by liquid chromatography-mass spectrometry; ELISA and target mass spectrometry analysis were performed for confirmation. Among 3310 identified proteins, HP (haptoglobin) and HPR (haptoglobin-related protein) showed the most significant variations, with increased levels in nonresponders compared with responders before drug administration (variation rate, 5.98 and 7.83, respectively). Protein-coordinated responses were also evaluated by functional enrichment analysis, finding oxidative stress, chronic inflammatory response, blood coagulation, complement activation, and regulation of focal adhesions as physiopathological mechanisms in resistant hypertension. In conclusion, protein changes able to predict patients' response to spironolactone in basal urine were here identified for the first time. These data, once further confirmed, will support clinical decisions on patients' management while contributing to optimize the rate of control of resistant hypertensives with spironolactone.

May Measurement Month 2017: an analysis of blood pressure screening in Spain-Europe.

Abstract: May Measurement Month 2017 is a global initiative aimed at raising awareness of high blood pressure (BP) and to act as a temporary solution to the lack of screening programs worldwide, in which Spain participated actively. The primary objective was to raise awareness and increase control of BP in Spain. An opportunistic cross-sectional survey of volunteers aged ≥18 was set up in May 2017. Following the design of the International Society of Hypertension, data were collected from the 17 autonomous communities in which Spain is divided, mainly in community pharmacies, primary care centres and some hypertension (HT) units, and cardiovascular departments in hospitals. No additional training of volunteers was necessary. A total of 3849 individuals were screened. After multiple imputation, our data showed that 1923 (50.0%) had HT. In those not receiving antihypertensive medication, 17.5% were hypertensives, in individuals receiving antihypertensive medication, 33.9% had uncontrolled BP. May Measurement Month 2017 was the largest BP screening campaign undertaken in Spain. In total, 17.5% of people with HT did not receive medication. One-third of hypertensive participants receiving treatment did not have their BP controlled. These results confirm that an opportunistic screening can identify a significant number of subjects with and untreated and inadequately treated BP.

Proteomic investigations into hypertension: what's new and how might it affect clinical practice?

Abstract: Introduction: Hypertension is a multifactorial disease that has, thus far, proven to be a difficult target for pharmacological intervention. The application of proteomic strategies may help to identify new biomarkers for the early diagnosis and prompt treatment of hypertension, in order to control blood pressure and prevent organ damage. Areas covered: Advances in proteomics have led to the discovery of new biomarkers to help track the pathophysiological processes implicated in hypertension. These findings not only help to better understand the nature of the disease, but will also contribute to the clinical needs for a timely diagnosis and more precise treatment. In this review, we provide an overview of new biomarkers identified in hypertension through the application of proteomic techniques, and we also discuss the difficulties and challenges in identifying biomarkers in this clinical setting. We performed a literature search in PubMed with the key words 'hypertension' and 'proteomics', and focused specifically on the most recent literature on the utility of proteomics in hypertension research. Expert opinion: There have been several promising biomarkers of hypertension identified by proteomics, but too few have been introduced to the clinic. Thus, further investigations in larger cohorts are necessary to test the feasibility of this strategy for patients. Also, this emerging field would profit from more collaboration between clinicians and researchers.

The endless story of markers of renal function and cardiovascular risk

Abstract:

Hypertension in Diabetic Kidney Disease

Abstract: The incidence and prevalence of diabetes mellitus (DM) are continuously growing throughout the world especially resulting from the increase in type 2 DM, which in turn is closely related to the increased prevalence of obesity. Both DM and obesity are closely related to arterial hypertension, and DM is the main cause of end-stage renal disease. Chronic kidney disease (CKD) in DM has different origins beyond diabetic nephropathy that requires a renal biopsy to make an adequate diagnosis. Because renal biopsy is not widely performed and since treatment is practically the same for renal protection in the different forms of diabetic CKD, the term diabetic kidney disease (DKD), instead of diabetic nephropathy, is amply used. Arterial hypertension requires to be strictly controlled in patients with DKD. This chapter reviews the adequate diagnosis of elevated blood pressure (BP), the goal BP to be attained, and the way to achieve it through the combination of drugs including new oral antidiabetic drugs in type 2 DM and particularly in DKD.