Impaired endothelial function in patients with nephrotic range proteinuria

Abstract

Proteinuria is associated with increased cardiovascular morbidity and mortality. Release of nitric oxide by the endothelium has been advanced as an important defense mechanism against vessel-wall damage. In the present study we therefore tested the hypothesis that proteinuria is associated with a defect in nitric oxide-dependent vasodilation, by using venous occlusion plethysmography of the forearm in nine patients with nephrotic range proteinuria (>3.5 g/24 hr) and normal renal function (creatinine 83.1 ± 8.7 μmol/liter), eight patients with active glomerulonephritis but normal renal function (creatinine 81.2 ± 5.4 μmol/liter) and low range proteinuria (<1.0 g/24 hr), and ten healthy volunteers. We infused L-NMMA (2 mg/min) to inhibit basal nitric oxide production, serotonin, 0.1, 0.3 and 1.0 ng/kg/min) as an endothelium-dependent vasodilator, and nitroprusside (1, 10, 30 and 100 ng/kg/min) as an endothelium-independent vasodilator into the brachial artery. Administration of L-NMMA decreased basal forearm vascular resistance (FVR) By 30 ± 4% in the nephrotic subjects, 38 ± 4% in the non-nephrotic patients and by 37 ± 2% in the healthy controls (P = 0.15). Upon the highest dose of serotonin FVR decreased in nephrotic subjects by 40 ± 5%, which was less than in non-nephrotic patients (56 ± 3%; P < 0.05) or in healthy controls (55 ± 3%; P < 0.05). The maximal decrease in FVR upon nitroprusside infusion was not different between the groups (respectively 84 ± 2, 84 ± 3 and 84 ± 2%). The impaired serotonin-induced vasodilation could be attributed to a defect in nitric oxide production, since L-NMMA almost completely prevented serotonergic vasodilation. The defect in agonist-induced nitric oxide release or activity could not be explained by decreased substrate availability, as infusion of excess L-arginine (0.2 mg/kg/min) did not improve vasodilation. The nephrotic suhjects also had an increased lysophosphatidylcholine content in the low-density-lipoprotein fraction, which has been shown to interfere with Gi-protein-dependent signal transduction pathways, including serotonin-induced vasodilation. In conclusion, nephrotic-range proteinuria is accompanied by impaired endothelium-dependent vasomotion.