RESUMEN
Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 µg/d×12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (-75 pg/mL; 95% confidence interval, -90 to -60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5-36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6±2.9%) and placebo (3.6±2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the between-group difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3-3.1%) was significant (P=0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitol-treated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment. No effect of paricalcitol on endothelium-independent vasodilatation was registered. Paricalcitol improves endothelium-dependent vasodilatation in patients with stage 3 to 4 CKD. Findings in this study support the hypothesis that vitamin D may exert favorable effects on the cardiovascular system in patients with CKD.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Ergocalciferoles/farmacología , Insuficiencia Renal Crónica/fisiopatología , Anciano , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Calcio/metabolismo , Método Doble Ciego , Endotelio Vascular/metabolismo , Ergocalciferoles/efectos adversos , Ergocalciferoles/uso terapéutico , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/metabolismo , Fosfatos/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Índice de Severidad de la Enfermedad , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Essential hypertension is associated with endothelial dysfunction, which is caused by decreased nitric oxide (NO) availability, resulting in an impairment of its beneficial and protective effects on the vessel wall. In prospective studies endothelial dysfunction is associated with increased incidence of cardiovascular events. Antihypertensive drugs show contrasting effects in terms of improvement or restoration of endothelial function in peripheral conduit arteries. Little evidence is available with diuretics. Treatment with the B-adrenoceptor antagonists atenolol and nebivolol is negative. Insufficient evidence is available to establish whether new compounds such as carvedilol, which has strong antioxidant activity, can improve endothelial function in hypertensive patients. Calcium antagonists that can reverse impaired endothelium-dependent vasodilation in different vascular districts, including epicardial and forearm microcirculation, show conflicting results in the brachial artery of essential hypertensive patients. ACE-inhibitors, on the other hand, seem to improve endothelial function in epicardial and peripheral conduit arteries, whereas they are ineffective in the peripheral microcirculation. However, they selectively improve endothelium-dependent vasodilation to bradykinin, an effect probably related to hyper- polarization. Finally, evidence concerning the effect of angiotensin II receptor antagonists on the brachial artery in patients with hypertension and atherosclerosis is inconclusive. In conclusion, despite the considerable evidence that impaired endothelium-dependent vasodilation can be improved by appropriate antihypertensive treatment, no clinical data are available to demonstrate that reversal of endothelial dysfunction is associated with a reduction in cardiovascular events. To acquire further knowledge on this issue, large scale clinical trials will be required to demonstrate that treatment of endothelial dysfunction can lead to better prognosis in essential hypertensive patients.