Circulating vascular endothelial growth factor (VEGF) and its soluble receptor 1 (sVEGFR-1) are associated with inflammation and mortality in incident dialysis patients

Abstract

Background: Vascular endothelial growth factor (VEGF) and its soluble receptor 1 (sVEGFR-1) predict mortality in nondialyzed chronic kidney disease (CKD) stage 3-5 patients and prevalent hemodialysis (HD) patients. We investigated determinants of VEGF and sVEGFR-1 as well as their relationship with all-cause mortality in incident dialysis patients.

Methods: In this longitudinal cohort study of 211 CKD 5 patients [64% males, mean age of 54 ± 12 years and median glomerular filtration rate (GFR) 5.9 [interquartile range (IQR), 4.6-7.2 mL/min/1.73 m2] who were enrolled at initiation of renal replacement therapy, demographics, clinical characteristics, including comorbidities and laboratory data were obtained at the beginning of the study. After 12 months, blood was again drawn from 95 dialysis patients [42 HD patients and 53 peritoneal dialysis (PD) patients]. The 211 patients were followed up for a median of 29 (IQR, 15-37) months for survival analysis. Plasma was also obtained from 47 healthy controls.

Results: VEGF and sVEGFR-1 levels did not change significantly after 12 months on HD or PD. The sVEGFR-1, but not VEGF levels, differed between the patients and the healthy controls. VEGF and sVEGFR-1 correlated with high-sensitivity C-reactive protein (hsCRP; rho = 0.19, P = 0.01 and rho = 0.16, P = 0.03; respectively), leukocyte count (rho = 0.22; P < 0.01 and rho = 0.23; P < 0.01; respectively) and sVEGFR-1 correlated also with interleukin-6 (IL-6) (rho = 0.21, P < 0.01). In Kaplan-Meier analysis, a high VEGF level was associated with increased all-cause mortality (Chi-square = 5.8, P = 0.02) which remained after adjustments for age, gender, body mass index (BMI), IL-6, GFR and comorbidities [hazard ratio, HR: 3.08, 95% confidence intervals (CI) 1.48-6.42]. Whereas sVEGFR-1 per se did not predict mortality, a high sVEGFR-1 level in patients with concomitant high IL-6 was associated with increased all-cause mortality (HR 2.83, 95% CI 1.32-6.06) which remained significant after adjustments for age, gender, BMI and comorbidities (HR 2.33, 95% CI 1.06-5.14) but not after adjusting also for GFR.

Conclusions: The circulating levels of VEGF and sVEGFR-1 are associated with biomarkers of inflammation. VEGF predicts all-cause mortality, independent of inflammation, while an elevated sVEGFR-1 level increased the mortality risk in inflamed patients.

Keywords: chronic kidney disease; inflammation; mortality; sFlt-1.