Renal Outcomes in Anticoagulated Patients With Atrial Fibrillation.

BACKGROUND: Lifelong oral anticoagulation, either with warfarin or a non-vitamin K antagonist oral anticoagulant (NOAC), is indicated for stroke prevention in most patients with atrial fibrillation (AF). Emerging evidence suggests that NOACs may be associated with better renal outcomes than warfarin. OBJECTIVES: This study aimed to compare 4 oral anticoagulant agents (apixaban, dabigatran, rivaroxaban, and warfarin) for their effects on 4 renal outcomes: ≥30% decline in estimated glomerular filtration rate (eGFR), doubling of the serum creatinine level, acute kidney injury (AKI), and kidney failure. METHODS: Using a large U.S. administrative database linked to laboratory results, the authors identified 9,769 patients with nonvalvular AF who started taking an oral anticoagulant agent between October 1, 2010 and April 30, 2016. Inverse probability of treatment weighting was used to balance more than 60 baseline characteristics among patients in the 4 drug cohorts. Cox proportional hazards regression was performed in the weighted population to compare oral anticoagulant agents. RESULTS: The cumulative risk at the end of 2 years for each outcome was 24.4%, 4.0%, 14.8%, and 1.7% for ≥30% decline in eGFR, doubling of serum creatinine, AKI, and kidney failure, respectively. When the 3 NOACs were pooled, they were associated with reduced risks of ≥30% decline in eGFR (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.66 to 0.89; p < 0.001), doubling of serum creatinine (HR: 0.62; 95% CI: 0.40 to 0.95; p = 0.03), and AKI (HR: 0.68; 95% CI: 0.58 to 0.81; p < 0.001) compared with warfarin. When comparing each NOAC with warfarin, dabigatran was associated with lower risks of ≥30% decline in eGFR and AKI; rivaroxaban was associated with lower risks of ≥30% decline in eGFR, doubling of serum creatinine, and AKI; however, apixaban did not have a statistically significant relationship with any of the renal outcomes. CONCLUSIONS: Renal function decline is common among patients with AF treated with oral anticoagulant agents. NOACs, particularly dabigatran and rivaroxaban, may be associated with lower risks of adverse renal outcomes than warfarin.

Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects.

Tetrahydrobiopterin (BH4) is an essential cofactor required for the activity of endothelial nitric oxide (NO) synthase. Suboptimal concentrations of BH4 in the endothelium reduce the biosynthesis of NO, thus contributing to the pathogenesis of vascular endothelial dysfunction. Supplementation with exogenous BH4 or therapeutic approaches that increase endogenous amounts of BH4 can reduce or reverse endothelial dysfunction by restoring production of NO. Improvements in formulations of BH4 for oral delivery have stimulated clinical trials that test the efficacy of BH4 in the treatment of systemic hypertension, peripheral arterial disease, coronary artery disease, pulmonary arterial hypertension, and sickle cell disease. This review discusses ongoing progress in the translation of knowledge, accumulated in preclinical studies, into the clinical application of BH4 in the treatment of vascular diseases. This review also addresses the emerging roles of BH4 in the regulation of endothelial function and their therapeutic implications.

Signaling pathways modulated by fish oil in salt-sensitive hypertension.

Although many studies have indicated that fish oil (FO) improves cardiovascular risk factors and reduces histopathological manifestations of injury in experimental renal injury models, potential mechanisms underlying this protective effect have not been adequately defined. The objective of this study was to identify potential signaling pathways that confer protection in the Dahl rat model of salt-sensitive hypertension. Male Dahl salt-sensitive rats (n = 10/group) were provided with formulated diets containing 8% NaCl, 20% protein, and 25% FO or 25% corn oil (CO) for 28 days. FO reduced blood pressure (-11% at 4 wk; P < 0.05), urine protein excretion (-45% at 4 wk; P < 0.05), plasma cholesterol and triglyceride levels (-54%, P < 0.001; and -58%, P < 0.05), and histopathological manifestations of renal injury, including vascular hypertrophy, segmental and global glomerular sclerosis, interstitial fibrosis, and tubular atrophy. Interstitial inflammation was significantly reduced by FO (-32%; P < 0.001), as assessed by quantitative analysis of ED1-positive cells in sections of the renal cortex. FO reduced tubulointerstitial proliferative activity, as assessed by Western blot analysis of cortical homogenates for PCNA (-51%; P < 0.01) and quantitative analysis of Mib-1-stained sections of the renal cortex (-42%; P < 0.001). Decreased proliferative activity was associated with reduced phospho-ERK expression (-37%; P < 0.005) and NF-kappaB activation (-42%; P < 0.05). FO reduced cyclooxygenase (COX)-2 expression (-63%; P < 0.01) and membrane translocation of the NADPH oxidase subunits p47(phox) and p67(phox) (-26 and -34%; P < 0.05). We propose that FO ameliorates renal injury in Dahl salt-sensitive rats through the inhibition of ERK, decreased NF-kappaB activation, inhibition of COX-2 expression, and decreased NADPH oxidase activation.