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Objective Nephrectomy, the standard of care for localized renal cell carcinoma (RCC), may lead to kidney function loss. Our goal was to identify prognostic biomarkers of postoperative renal function using metabolomics. Methods Metabolomics data from benign kidney parenchyma were collected prospectively from 138 patients with RCC who underwent nephrectomy at a single institution. The primary endpoint was the difference between the postoperative and preoperative estimated glomerular filtration (eGFR) rate divided by the elapsed time (eGFR slope). eGFR slope was calculated ∼2   years post-nephrectomy (GFR1), and at last follow-up (GFR2). A multivariate regularized regression model identified clinical characteristics and abundance of metabolites in baseline benign kidney parenchyma that were significantly associated with eGFR slope. Findings were validated by associating gene expression data with eGFR slope in an independent cohort (n  =   58). Results Data were compiled on 78 patients (median age 62.6 years, 65.4% males). The mean follow - up was 25 ± 3.4 months for GFR1 and 69.5 ± 23.5 months for GFR2 and 17 (22%) and 32 (41%) patients showed eGFR recovery, respectively. Nephrectomy type, blood lipids, gender and 23 metabolites from benign parenchyma were significantly associated with eGFR slope. Some metabolites associated with eGFR slope overlapped with previously reported chronic kidney disease - related processes. Subgroup analysis identified unique 'metabolite signatures' by older age, nephrectomy type and preoperative eGFR. Conclusions Nephrectomy type, gender, blood lipids and benign parenchyma metabolites at nephrectomy were associated with long-term kidney function. On further study, these metabolites may be useful as potential biomarkers and to identify novel therapeutic targets for malignancy-associated renal disease. [ABSTRACT FROM AUTHOR]

BACKGROUND Current treatment for the secondary prevention of cardiovascular diseases frequently involves the prescription of several combination therapies, particularly antihypertensive medications and HMG-CoA reductase inhibitor. We have previously shown that in salt-sensitive hypertension either a statin or the calcium channel blocker amlodipine (Aml) have vasoprotective effects. Here, we investigated in aortas from Dahl salt-sensitive (DS) rats the effects of Aml, the statin atorvastatin (AT), and their combination on endothelial function, superoxide (O2−) production, and the expression of endothelial nitric oxide synthase (eNOS), chemokine monocyte chemoattractant protein-1 (MCP-1), and lectin-like oxidized LDL receptor-1 (LOX-1). METHODS Groups of DS rats were fed either normal-salt (NS, 0.5% NaCl) or high-salt (HS, 4% NaCl) diet or a HS diet with AT (15mg/kg/day), Aml (5mg/kg/day) or combination of AT/Aml for 6 weeks. RESULTS Rats on the HS diet developed hypertension, aortic hypertrophy, accompanied by increased plasma C-reactive protein (CRP), aortic O2−, MCP-1 (80%), and LOX-1 (55%) expression and reduced eNOS and endothelial-dependent relaxation to acetylcholine (EDR). Aml reduced systolic blood pressure (SBP), aortic hypertrophy, plasma CRP, vascular O2−, and MCP-1 expression and improved eNOS and EDR. AT reduced aortic hypertrophy and plasma CRP, improved EDR, and normalized vascular O2−, eNOS, and proinflammatory gene expression with mild reduction in SBP. Combination therapy further reduced the SBP and normalized aortic hypertrophy, EDR, and plasma CRP. CONCLUSIONS The combination therapy of Aml/AT has an additive beneficial effect on the vasculature. These novel findings may provide scientific basis for the combination therapy of statins with antihypertensive agents to reduce and prevent cardiovascular diseases. [ABSTRACT FROM AUTHOR]

: BackgroundCalcium channel blockers such as amlodipine are effective antihypertensive agents. In this study we investigated the effects of amlodipine on vascular oxidative stress, expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1), and endothelial function in angiotensin (Ang) II-infused rats.: MethodsSprague-Dawley rats were treated with Ang II (0.7 mg/kg/day subcutaneously injected by mini-pump), with or without amlodipine (10 mg/kg/day by gavage), for 5 days and compared with control rats. Levels of aortic ring superoxide (O2−) and peroxynitrite (ONOO−) were determined, and systolic blood pressure (SBP) and endothelium-dependent relaxation were evaluated.: ResultsCompared with control rats, Ang II-infused rats developed hypertension (175 ± 3 v 135 ± 2 mm Hg, P < .05), aortic hypertrophy (16.9 ± 1.3 v 13.2 ± 0.3 mg/cm, P < .05), left ventricular hypertrophy (0.236 ± 0.003 v 0.204 ± 0.004 g/100 g body weight, P < .05), and impaired endothelium-dependent relaxation (ED50: 6.6 ± 0.2 v 8.0 ± 0.2 −log mol/L acetylcholine concentration, P < .05). Compared with control rats, Ang II-infused rats also had higher aortic levels of LOX-1 mRNA expression, O2−production (1005 ± 140 v 608 ± 159 counts/min/mg, P < .05), ONOO− production (1875 ± 295 v 782 ± 115 counts/min/mg, P < .05), and plasma free 8-F2α-isoprostanes (67.4 ± 19.1 v 27.2 ± 6.1 pg/mL, P < .05). In Ang II-infused rats SBP, aortic hypertrophy, endothelial dysfunction, LOX-1 expression, aortic O2− and ONOO− production, and plasma free 8-F2α-isoprostane levels were significantly reduced by amlodipine treatment.: ConclusionsAmlodipine has antihypertensive and antioxidant activity in vivo, which effectively inhibits many of the oxidative stress-dependent mechanisms involved in Ang II-mediated cardiovascular injury. [Copyright &y& Elsevier]