Oxidative stress and microvascular function in chronic kidney disease
University of Delaware
Patients with chronic kidney disease (CKD) are at risk of progressing towards end stage renal disease (ESRD), however, they are more likely to die from cardiovascular disease (CVD) before reaching ESRD. Endothelial dysfunction has been shown to play a role in the progression of CKD as well as the development of atherosclerosis however, the mechanisms by which endothelial dysfunction occurs in the CKD population are not clear. Therefore, the specific aims of this study were to determine whether oxidative stress or a relative deficit in L-arginine plays a mechanistic role in reducing NO-mediated cutaneous vasodilation in response to local heating in patients with moderate to severe CKD. Methods: We measured red blood cell (RBC) flux via laser Doppler flowmetry in conjunction with intradermal microdialysis of 1) Ringer’s solution, 2) 20 mM ascorbic acid, 3) 10 mM L-arginine, and 4) 10 mM NG-nitro-L-arginine methyl ester (L-NAME). We hypothesized that nitric-oxide mediated cutaneous vasodilation would be impaired in the CKD population but normalized by the intradermal microdialysis of ascorbic acid and L-arginine. Eight healthy and eight stage 3-4 CKD patients were instrumented with four microdialysis (MD) fibers in the ventral side of the non-dominant forearm. A standardized non-painful local heating protocol (42˚C) was used to elicit cutaneous vasodilation. 28 mM sodium nitroprusside was perfused into all four MD sites and local temperature was increased to 43˚C in order to achieve a maximal dilation in all sites. Cutaneous vascular conductance (CVC) was calculated at RBC flux/MAP. All data are expressed as a percentage of the maximum CVC achieved in each MD site. Results: There were no differences in baseline %CVCmax among group and treatment; Ringer: CKD; 12 ± 1, HC; 9 ± 1, AA: CKD; 13 ± 3, HC; 11 ± 1, L-arg: CKD; 11 ± 2, HC; 13 ± 2, L-NAME: CKD; 11 ± 2, HC; 12 ± 1; (p > 0.05). The NO-mediated plateau was attenuated in CKD compared to HC’s; CKD: 76 ± 4, HC: 91 ± 2, (p < 0.05). The attenuation was significantly improved by AA and L-arg in the CKD group; AA: 89 ± 2, L-arg: 90 ± 1, (p < 0.05). There was a significant difference in the initial peak between the HC and CKD groups at the control site (R) and L-arg site; R: HC; 71 ± 4, CKD; 53 ± 5 (p <0.05), L-arg: HC: 68 ± 3, CKD; 47 ± 4 (p < 0.01). Conclusion: NO-mediated cutaneous vasodilation and the axon-reflex are impaired in the CKD population compared to healthy age and gender matched controls. The impairment in NO-mediated cutaneous vasodilation was normalized by the perfusion of ascorbic acid and L-arginine, indicating that oxidative stress and a relative deficit of L-arginine are mechanisms by which endothelial dysfunction occurs in stage 3-4 CKD.