| PART ONE Expression of Serum Angiogenic factors in Patients with End-stage Renal DiseaseObjective: To evaluate the effect of angiogenic factors in End stage renal disease(ESRD) patients based on analysis of circulating transforming growth factor β1(TGF-β1), vascular endothelial growth factor-A(VEGF-A), soluble neural cadherin(s N-cadherin) and soluble vascular endothelial cadherin(s VE-cadherin).Methods: 72 patients(45 male and 27 female, average age 54±17), diagnosed as ESRD according to KDIGO guideline between August 2014 and February 2015 from the blood purification center of the 1st Affiliated Hospital of Soochow University, were enrolled in this study. 39 healthy individuals(male 27, female 12, average age 55±18) served as controls. Hemoglobin and Hematocrit was carried out on an automated hematology analyzer. Biochemical parameters such as serum creatinine(Cr), urea, high sensitivity C-reactive protein(hs CRP), calcium(Ca), phosphorus(P), total cholesterol(TC), triglycerides(TG), low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol(HDL-C) were estimated using an automated biochemical analyzer. Serum parathyroid hormone(PTH), vitamin D3(Vit D3), ferritin(Fer) and β2-microglobin(β2-MG) were determined using a Chemiluminescence Immunoassay system. Serum TGF-β1, VEGF-A, soluble N-cadherin and soluble VE-cadherin were measured by enzyme-linked immunosorbent assay(ELISA), respectively. The differences and relationships between each parameter were analyzed.Results:(1) Except serum Cr and urea(P<0.01), no significant differences between ESRD patients and healthy controls were found in age, gender, body mass index, Ca, P, TC, TG, LDL-c and HDL-c(P>0.05). Serum concentrations of TGF-β1, VEGF-A and s N-cadherin were significant higher in ESRD patients than in healthy controls(P<0.01). In contrast, serum s VE-cadherin level and the ratio of s VE-cadherin to s N-cadherin in ESRD patients were significant lower when comparing to healthy controls(P<0.01).(2) Of the ESRD patients, 23.6% of them were innon-inflammatory state, 76.4% were in a state of micro inflammation. Instead of TGF-β1, VEGF-A, s N-cadherinand s VE-cadherin/s N-cadherin(P>0.05), serum s VE-cadherin concentration was significant higher in micro-inflamed patients in comparison with non-inflammatory patients(P<0.01).(3) Of the ESRD cohort, 16.6% of patients were Vit D3 deficient, 41.7% had inadequate Vit D3 values whereas 41.7% had optimal Vit D3 values. Serum concentrations of VEGF-A, s VE-cadherin as well as s VE-cadherin/s N-cadherin(P<0.01) did differ significantly between the subgroups by Vit D3 category, whereas neither TGF-β1 nor s N-cadherin was found significant difference among each group(P>0.05). Furthermore, Serum concentration of s VE-cadherin as well as s VE-cadherin/s N-cadherin was positively correlated with Vit D3(r=0.324,P=0.006; r=0.28,P=0.017).(4) In univariate analysis of ESRD patients, significant positive correlations with TGF-β1 were found for PTH and LDL-c(r=0.328,P=0.0049;r=0.2319,P=0.0499). Of the angiogenic factors studied, serum TGF-β1 was positive associated with VEGF-A and s N-cadherin(r=0.258,P=0.028; r=0.306,P=0.009), while aninverse correlation was noted between s N-cadherin and s VE-cadherin(r=-0.255,P=0.039). The ratio of s VE-cadherin to s N-cadherin was significant negatively associated with dialysis therapy duration and Vit D3 state, r=-0.454, P<0.01, r=0.246, P=0.019, respectively.(5) In multiple regressions, dialysis therapy duration and Vit D3 were the independent explanation variables of s VE-cadherin/s N-cadherin(r=-0.454, P<0.01; r=0.246, P=0.019).Conclusions:(1) Elevated serum TGF-β1 and s N-cadherin indicated possible EMT or End MT in ESRD patients. In terms of high levels of VEGF-A, there was a possibility of angiogenesis in kidney also.(2) Increased concentration of serum s VE-cadherin in ESRD patients under micro-inflamed state suggested that the shedding of VE-cadherin from endothelial cell membrane was associated with inflammation.(3) The positive correlations with Vit D3 between s VE-cadherin and s VE-cadherin/s N-cadherin indicated Vit D3 was involved in the pathophysiological process of the repair of dysfunctional endothelial cells.(4) The dialysis therapy duration and serum Vit D3 levels were the independent predictors of the ratio of s VE-cadherin to s N-cadherin in ESRD patients. The longer dialysis therapy duration and lower levels of Vit D3, the more severe of renal endothelial cells dysfunction.PART TWO The Analysis of Serum TGF-β1, VEGF-A, s N-cadherin and s VE-cadherin in End-stage Renal Disease Patients upon HemodialysisObjective: To compare the angiogenic profile of ESRD patients before and after polyethersulfone(PES) hemodialysis based on the analysis of serum TGF-β1, VEGF-A, s N-cadherin and s VE-cadherin.Methods: Serum concentrations of TGF-β1, VEGF-A, s N-cadherin and s VE-cadherin were measured in 66 ESRD patients(male 43 and female 23, average age 52±19) pre- and post- PES dialysis and 39 healthy controls(male 27, female 12, average age 55±18).Results: After a duration of hemodialysis in ESRD patients, serum levels of VEGF-A, s VE-cadherin and the ratio of s VE-cadherin to s N-cadherin were significantly higher(P<0.01), whereas serum concentrations ofs N-cadherin were significantly lower(P<0.01). However, no significant change was observed in terms of serum TGF-β1 levels(P>0.05).Conclusion: Increased concentrations of serum TGF-β1 in ESRD patients could not be attenuated by PES hemodialysis therapy. However, after hemodialysis, elevated serum levels of VEGF-A may promote angiogenesis activity, and the balance between VE-cadherin and N-cadherin was tend to normalization, suggesting PES hemodialysis therapy may contribute to the improvement of endothelial function and thus facilitated effective angiogenesis. |
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