#555 Stromal cell-derived factor-1, P-selectin, and advanced oxidation protein products may be associated with cerebral vessels in normoalbuminuric diabetic kidney disease

Abstract Background and Aims The kidney and the brain share similarities in terms of structure and function, and are coordinated by common pathogenic mechanisms, such as inflammation, endothelial dysfunction, oxidative stress, and mitochondrial dysfunction. The aim of our study was to evaluate the interrelation of these pathogenic pathways with proximal tubule (PT) dysfunction, podocyte damage, and cerebral vessels remodeling in normoalbuminuric DKD in type 2 diabetes mellitus (DM) patients. Method A cohort of 223 patients (64 patients with normoalbuminuria, 59 patients with microalbuminuria, and 61 patients with macroalbuminuria) and 39 age- and gender-matched healthy controls were enrolled in this case series study. All patients were assessed concerning urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule dysfunction (kidney injury molecule-1-KIM-1, N-acetyl-β-(D)-glucosaminidase-NAG), serum and urinary stromal cell-derived factor-1 (SDF-1), P-selectin, advanced oxidation protein products (AOPPs). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR (ABI 7900-HT–Applied BioSystem). TaqMan assays were utilized for the assessment of cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and of beta 2 microglobulin nuclear gene (B2M). mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio. The cerebrovascular hemodynamic indices were evaluated by an ultrasound equipment with high resolution (MYLAB 8-ESAOTE Italy) equipped with a colour ultrasound system. Subclinical atherosclerosis and arteriosclerosis were assessed by intima-media thickness (IMT) in the common carotid arteries (CCAs), the pulsatility index (PI) and the resistivity index (RI) in the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), bilaterally. Cerebrovascular reactivity (CVR), which represents the vasodilatory reactivity of cerebral vessels in response to a vasodilatory stimulus, was assessed by the breath-holding test and the breath-holding index (BHI). Results In multivariable regression analysis, serum mtDNA correlated directly with eGFR and negatively with serum P-selectin and serum SDF-1 (R2 = 0.6564; P < 0.0001). Urinary mtDNA correlated directly with podocalyxin, urinary P-selectin, and urinary SDF-1 (R2 = 0.6280; P < 0.0001). IMT-CCAs correlated negatively with eGFR and directly with UACR, synaptopodin, serum P-selectin, and serum AOPPs (P < 0.0001; R2 = 0.7020). PI-ICAs correlated indirectly with eGFR and directly with serum P-selectin and serum SDF-1 (P < 0.0001; R2 = 0.5113). PI-MCAs had a negative correlation with eGFR and direct correlations serum P-selectin and serum SDF-1(P < 0.0001; R2 = 0.5886). RI-ICAs was included in a complex model which displayed an indirect correlation with eGFR and direct correlations with NAG, serum P-selectin, serum SDF-1, and UACR (P < 0.0001; R2 = 0.7629). RI-MCAs were included in a model which showed a negative correlation with eGFR and direct correlations with NAG, KIM-1, synaptopodin, podocalyxin, serum P-selectin and serum SDF-1 (P < 0.0001; R2 = 0.8482). The CVR the BHI correlated negatively with eGFR and directly with podocalyxin, serum P-selectin, and serum SDF-1 (P < 0.0001; R2 = 0.7897). Conclusion The study demonstrates a concurrent association of SDF-1, P-selectin, AOPPs, and mitochondrial dysfunction with early DKD and significant cerebrovascular modifications in neurologically asymptomatic patients with type 2 DM and normoalbuminuric DKD.