Neovascularization And Venous Neointimal Hyperplasia In Arteriovenous Fistulas Among End-stage Renal Disease Patients

Background and objective:Autologous arteriovenous fistula(AVF)is the preferred access and the lifeline for end-stage renal disease(ESRD)patients receiving maintenance hemodialysis.However,AVF failure restricts AVF clinical application.Juxta-anastomotic stenosis is the frequent cause of AVF failure,and its main pathological basis is anastomotic neointimal hyperplasia(NIH).The mechanisms of NIH are still quite unclear.Thus,identifying influential factors and examining the mechanisms underlying NIH is of great significance with regard to maintaining AVF patency.AVF maturation involves the ’arterialization’ of the venous outflow tract,and it has been demonstrated that NIH in arterialized veins and atherosclerosis share several common histological features.It has been discovered that vasa vasorum(VV)neovascularization is associated with the increases in the thickness of carotid intima-media and the formation of unstable plaque in atherosclerosis.Besides,it has also been reported that neovascularization of the vessel wall can also be observed during the NIH development of AVF.However,the association between the VV neovascularization of the vessel wall and NIH in AVF remains undetermined.The purpose of this study is to further explore the correlation between neovascularization and venous NIH in AVF and provide a new theoretical basis for the prevention and treatment of AVF failure.Methods:A total of 82 ESRD patients were included in our study,of which 43 patients received a first AVF creation(control group),and another 39 patients underwent reconstruction of the failed AVF(failed AVF group).The newly created AVFs and failed AVFs for reconstruction were both radiocephalic AVFs created by end-to-side anastomosis in the forearm.A 5-10 mm segment of the vein immediately adjacent to the anastomic site was surgically removed.Demographic characteristics were recorded,and their relationships with NIH and their differences between the two groups were analyzed.Morphometric analyses and intimal and medial thickness measurement were carried out using HE staining,Masson staining,and EVG staining.Vasa vasorum densities(VVDs)within the venous outflow tract at arteriovenous anastomosis was quantified by immunohistochemistry with CD31 and factor Ⅷ staining,and their relationships with NIH and their differences between the two groups were analyzed.The level of vascular endothelial growth factor A(VEGFA)expression was also evaluated immunohistochemically.Results:In this study,the mean age was 53.5±14.5 years,and 63.4%were males.Hemoglobin,serum albumin,calcium,and creatinine levels were higher in failed AVF group than in control group(P<0.05),while low-density lipoprotein and D-dimer levels were higher in control group than in failed AVF group(P<0.05).Both the intimal thickness and the intimal/medial thickness ratio were higher in failed AVF group than in control group(70.68[28.81-99.54]vs.4.53[2.69-7.30]μm,P<0.001;2.20[0.77-4.36]vs.0.15[0.10-0.30],P<0.001),and the intimal/medial thickness ratio was positively associated with hemoglobin(P<0.001)according to the Spearman analysis.Immunohistochemistry demonstrated that CD31 marked VVDs both in the intima and media,and the intimal/medial VVD ratios were significantly higher in failed AVF group than in control group(6.31[1.62-12.53]vs.0.0[0.0-0.0],P<0.001;10.0[7.59-12.95]vs.3.71[2.44-4.87],P<0.001;0.67[0.19-1.08]vs.0.0[0.0-0.0],P<0.001),and factor Ⅷ marked VVDs both in the intima and media,and the intimal/medial VVD ratios were also significantly higher in failed AVF group than in control group(7.82[3.33-11.61]vs.0.0[0.0-0.0],P<0.001;8.33[5.55-13.0]vs.3.57[2.53-4.82],P<0.001;0.71[0.39-1.14]vs.0.0[0.0-0.0],P<0.001).Furthermore,there was also a positive relationship between the intimal/medial VVD ratio and the intimal/medial thickness ratio(P<0.001).In addition,vascular endothelial cell growth factor A(VEGFA)expression was higher in failed AVFs than in preaccess veins.Conclusions:(1)NIH was noticeably more developed in the venous outflow tract of failed AVFs,and failed AVFs exhibited significantly larger intimal thickness than preaccess veins in the control group.It was demonstrated that hemoglobin level was associated with NIH of AVF outflow veins.(2)Vasa vasorum vascularization of the vessel wall and VEGFA expression level were obviously developed in the arterialized veins in failed AVFs,especially among the NIH region.