RESUMEN
Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers, and mineralocorticoid receptor antagonists in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for heart failure. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin-angiotensin-aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.
Asunto(s)
Insuficiencia Cardíaca , Aminobutiratos , Compuestos de Bifenilo , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Volumen Sistólico , Tetrazoles/efectos adversos , Valsartán/uso terapéuticoRESUMEN
OBJECTIVE: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT in epidemiological studies. Since vitamin D is also implicated in vascular protection and affects IGF-1 biology, we hypothesized that it would influence the effect of IGF-1 on IMT. METHODS: The relationship between carotid IMT and fasting serum IGF-1 was examined across strata of 25-hydroxyvitamin D [25(OH)D] in 472 participants in the Baltimore Longitudinal Study of Aging (BLSA) with well-controlled blood pressure and in 165 treatment-naive patients with essential hypertension from the Microalbuminuria: A Genoa Investigation on Complications (MAGIC) study. Moreover, the interplay between vitamin D and IGF-1 was preliminarily explored in EA.hy926 endothelial cells. RESULTS: After adjusting for age, sex, BMI, renal function, smoking, systolic blood pressure, LDL-cholesterol, glycemia, antihypertensive or lipid-lowering therapy, season, parathyroid hormone, and vitamin D supplementation, IGF-1 was significantly and negatively associated with carotid IMT only within the lowest 25(OH)D quartile (range 6.8-26 ng/mL) of the BLSA (ß -0.095, p = 0.03). Similarly, a significant negative correlation between IGF-1 and carotid IMT was found after full adjustment only in MAGIC patients with 25(OH)D concentrations below either the deficiency cut-off of 20 ng/mL (ß -0.214, p = 0.02) or 26 ng/mL (ß -0.174, p = 0.03). Vitamin D dose-dependently decreased hydrogen peroxide-induced endothelial cell oxidative stress and apoptosis, which were further inhibited by IGF in the presence of low, but not high vitamin D concentration. CONCLUSIONS: Circulating IGF-1 is vasoprotective primarily when vitamin D levels are low. Future studies should address the mechanisms of vitamin D/IGF-1 interaction.
Asunto(s)
Grosor Intima-Media Carotídeo , Factor I del Crecimiento Similar a la Insulina/análisis , Vitamina D/análogos & derivados , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Albuminuria/sangre , Albuminuria/epidemiología , Aldosterona/sangre , Apoptosis , Baltimore/epidemiología , Índice de Masa Corporal , Células Endoteliales/patología , Endotelio Vascular/fisiopatología , Ayuno/sangre , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Factor I del Crecimiento Similar a la Insulina/farmacología , Italia/epidemiología , Lípidos/sangre , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Factores de Riesgo , Vitamina D/sangre , Vitamina D/farmacología , Vitamina D/fisiologíaRESUMEN
The prevalence of chronic kidney disease, currently estimated to vary between 8 and 12 % in the general population, is steadily rising due to aging and to the ongoing epidemic of hypertension and type 2 diabetes. Even in its early stages, chronic kidney disease entails a greater risk for cardiovascular mortality, and its prevention and treatment is rapidly becoming a key medical issue for many health care systems worldwide. Adequate blood pressure control and reduction of urine protein excretion, preferably obtained by the use of renin-angiotensin-aldosterone system inhibitors, have traditionally been considered the mainstay of therapeutic strategies in patients with renal disease. Given the pivotal role of renin-angiotensin-aldosterone system activity in the pathogenesis and progression of renal and cardiovascular damage, a more profound inhibition of the system, either by the use of multiple agents or by a single agent at high dosage has recently been advocated, especially in the presence of proteinuria. Recent trials, however have failed to confirm the usefulness of this therapeutic approach, at least in unselected patients. This article will critically review the current literature and will discuss the clinical implications of targeting the renin-angiotensin-aldosterone system in order to provide the greatest renal protection.
Asunto(s)
Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Enfermedades Renales/prevención & control , Sistema Renina-Angiotensina/efectos de los fármacos , Algoritmos , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Hypertension is an important modifiable risk factor for cardiovascular disease; its prevention and treatment currently represent major health concerns around the world, especially in western countries. Effective, well-tolerated drugs such as dihydropyridine calcium channel blockers, to be used either alone or in combination treatments, play a key role in reducing cardiovascular morbidity and mortality. The extended-release formulation of nifedipine given once daily provides a relatively constant concentration profile and has proved to be effective in reducing blood pressure values. In the International Nifedipine gastrointestinal therapeutic system Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study, it was demonstrated that nifedipine confers cardiovascular protection as effectively as diuretics in high-risk patients, with a smaller incidence of adverse metabolic consequences. Furthermore, two INSIGHT substudies demonstrated that nifedipine prevents the progression of carotid atherosclerosis and reduces the worsening of coronary calcifications, supporting the use of calcium channel blockers in hypertensive patients--especially those at high cardiovascular risk. This review discusses the existing clinical evidence supporting the use of nifedipine in the treatment of hypertension.
Asunto(s)
Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Nifedipino/uso terapéutico , Antihipertensivos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Ensayos Clínicos como Asunto , Humanos , Nifedipino/farmacologíaRESUMEN
INTRODUCTION: Increased renal vascular resistance and microalbuminuria are associated with hypertensive target organ damage and may be predictors of hypertensive nephrosclerosis. AIM: We investigated changes in renal resistive index (RI) and urinary albumin excretion (UAE) in a group of patients with primary hypertension before and during long-term antihypertensive treatment. METHODS: Thirty-two patients were randomized to receive antihypertensive treatment with either a calcium channel blocker (nifedipine GITS, up to 90 mg/day, n = 16) or an ACE inhibitor (lisinopril, up to 20 mg/day, n = 16), alone or in association with a diuretic (chlortalidone, 25 mg/day). Blood pressure, renal resistive index (by US Doppler) and UAE (mean of three nonconsecutive timed urinary collections, microg/min) were evaluated at baseline and over the course of 24 months of treatment. RESULTS: Both regimens effectively lowered blood pressure (mean blood pressure from 123 +/- 1.8 at baseline to 103 +/- 1.5 mm Hg at 24 months in the lisinopril group and from 122 +/- 1.9 at baseline to 104 +/- 0.8 at 24 months in the nifedipine group, p < 0.001 for both groups). Overall, blood pressure decrease was associated with a reduction in UAE and no change in RI throughout the study. However, despite similar blood pressure reduction, the two regimens showed different specific effects. Lisinopril was associated with a significant decrease in both UAE (33.8 +/- 16.2 at baseline and 9.1 +/- 2.1 at 24 months, p < 0.01) and renal RI (0.61 +/- 0.02 at baseline and 0.56 +/- 0.04 at 24 months, p < 0.05) while nifedipine GITS did not significantly influence UAE (35.7 +/- 12.2 at baseline and 31.2 +/- 12.1 at 24 months, n.s.) or RI (0.61 +/- 0.01 at baseline and 0.59 +/- 0.02 at 24 months, n.s.). CONCLUSION: Effective blood pressure control over a long period of time reduces the severity of organ damage, namely UAE while maintaining renovascular resistance in patients with essential hypertension. Different classes of antihypertensive agents might convey additional specific renal protection beyond blood pressure control. These data could be useful in devising individualized therapeutic strategies in hypertensive patients at increased renal risk.