Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors.

UNLABELLED: There is a robust inverse graded association between glomerular filtration rate (GFR) and cardiovascular risk, but proof of causality is lacking. Emerging data suggest living kidney donation may be associated with increased cardiovascular mortality although the mechanisms are unclear. We hypothesized that the reduction in GFR in living kidney donors is associated with increased left ventricular mass, impaired left ventricular function, and increased aortic stiffness. This was a multicenter, parallel group, blinded end point study of living kidney donors and healthy controls (n=124), conducted from March 2011 to August 2014. The primary outcome was a change in left ventricular mass assessed by magnetic resonance imaging (baseline to 12 months). At 12 months, the decrease in isotopic GFR in donors was -30±12 mL/min/1.73m(2). In donors compared with controls, there were significant increases in left ventricular mass (+7±10 versus -3±8 g; P<0.001) and mass:volume ratio (+0.06±0.12 versus -0.01±0.09 g/mL; P<0.01), whereas aortic distensibility (-0.29±1.38 versus +0.28±0.79×10(-3) mm Hg(-1); P=0.03) and global circumferential strain decreased (-1.1±3.8 versus +0.4±2.4%; P=0.04). Donors had greater risks of developing detectable highly sensitive troponin T (odds ratio, 16.2 [95% confidence interval, 2.6-100.1]; P<0.01) and microalbuminuria (odds ratio, 3.8 [95% confidence interval, 1.1-12.8]; P=0.04). Serum uric acid, parathyroid hormone, fibroblast growth factor-23, and high-sensitivity C-reactive protein all increased significantly. There were no changes in ambulatory blood pressure. Change in GFR was independently associated with change in left ventricular mass (R(2)=0.28; P=0.01). These findings suggest that reduced GFR should be regarded as an independent causative cardiovascular risk factor. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01028703.

Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans.

BACKGROUND AND PURPOSE: Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature. EXPERIMENTAL APPROACH: The role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration-response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors. KEY RESULTS: Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF. CONCLUSIONS AND IMPLICATIONS: In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms.