Study On The Mechanism Of Autologous Arteriovenous Fistula Stenosis In Maintenance Hemodialysis Patients Based On Metabonomic Analysis

ObjectiveTo analyze the differential changes of serum metabolites in patients with autologous arteriovenous fistula(AVF)stenosis during maintenance hemodialysis(MHD),preliminarily explore the relationship and possible mechanism between AVF stenosis and differential metabolites,and provide theoretical basis for seeking biomarkers for diagnosis and new targets for treatment of AVF stenosis in MHD patients.MethodsA total of 100 subjects were recruited in this study,including 35 MHD patients with AVF stenosis;32 MHD patients with AVF non-stenosis;33 non-dialysis patients with chronic kidney disease stage of 5(CKD 5)were matched by age,sex and diabetes prevalence.Sterile tubes were used to collect blood samples from all recruited patients for centrifugation.Serum samples of AVF stenosis group with MHD,AVF non-stenosis group with MHD and non-dialysis group with CKD5 were analyzed by LC-MS/MS.PCA analysis,PLS-DA analysis,heatmap analysis,HMDB compound classification and KEGG pathway enrichment were used to investigate the different metabolites and the different metabolic pathways among the three groups.Receiver operator characteristic(ROC)curve were used to screen potential biomarkers of AVF stenosis.Correlation heatmaps were used to analyze the relationship between different metabolites and clinical parameters in the AVF stenosis group with MHD.Results1.Compared with the AVF non-stenosis group with MHD,Serum creatinine(Scr),serum calcium(Ca),blood phosphorus(P),serum Albumin(ALB),Homocysteine(HCY),Triglyceride(TG)and Hemoglobin(HB)in the AVF stenosis group with MHD were significantly increased(P < 0.05).2.Compared with AVF non-stenosis group with MHD,the concentrations and types of multiple metabolites in the AVF stenosis group with MHD were changed,and their metabolic pathways were altered accordingly.These different metabolites are mainly involved in choline metabolism,α-linolenic acid metabolism,linoleic acid metabolism,glycerol-phospholipid metabolism,biliary secretion,inflammatory mediators regulation and histidine metabolism.The differential metabolic compounds mainly include lipid and lipid molecules,organic acids and derivatives,organoheterocyclic compounds and benzenoids.3.Compared with the non-dialysis group with CKD5,the differential metabolites in the AVF stenosis group with MHD were mainly involved in tyrosine metabolism,arginine metabolism,proline metabolism,arginine biosynthesis,tryptophan metabolism,choline metabolism and α-linolenic acid metabolism.The differential metabolites mainly included lipid and lipid molecules,organic acids and derivatives.4.Compared with the non-dialysis group with CKD5,the differential metabolites in the AVF non-stenosis groups with MHD were mainly involved in arginine metabolism,proline metabolism,tyrosine metabolism,tryptophan metabolism,phenylalanine metabolism,choline metabolism and α-linolenic acid metabolism.The differential metabolites mainly included lipids and lipid molecules,organic acids and derivatives.5.The ROC curve screen out eight different metabolites,including 4-Ethyl-7,11-dimethyldodeca-trans-2-trans-6-1-o-trien-1-al,Monooctyl phthalate,5α-Pregnan-20α-ol-3-one,3-Hydroxydodec-9-enedioylcarnitine,PC(20:5(5Z,8Z,11 Z,14Z,16E)-OH(18R)/17:0),Lyso PA(0:0/18:2(9Z,12Z)),N-Formyl-L-aspartate,Dioctyl Phthalate,which are potential biomarkers for MHD patients with AVF stenosis.6.Correlation heatmap analysis shows between different metabolites and clinical parameters in AVF stenosis group with MHD : Indoxyl was positively correlated with Scr,BUN and P;Carnitine was positively correlated with ALB,Scr,HB,BUN,TG,Ca and P;3,11,12-Trihydroxy-1(10)-spirovetiven-2-one was positively correlated with Scr,BUN,P and TG;Phenylacetylglutamine was positively correlated with Scr and BUN;Lyso PC(0:0/16:0)was positively correlated with ALB,HB,total cholesterol(TC)and Ca;N,N-Dimethylbutylamine was negatively correlated with ALB,Scr,Ca and P;Edetic Acid was negatively correlated with ALB,Scr and HB,and cholines were negatively correlated with Scr,BUN,P and TG.Conclusions1.There were significant differences in serum metabolites between AVF stenosis patients with MHD,AVF non-stenosis patients with MHD and non-dialysis patients with CKD5.There were significant differences in lipid or lipid molecules,organic acids and their derivatives and other metabolites in the AVF stenosis group with MHD,and its metabolites mainly participate in choline metabolism,linoleic acid metabolism,α-linolenic acid metabolism,glycerol-phospholipid metabolism,biliary secretion,inflammatory mediators regulation and histidine metabolism.2.There are eight different metabolites,including 4-Ethyl-7,11-dimethyldodecatrans-2-trans-6-1-o-trien-1-al,Monooctyl phthalate,5α-Pregnan-20α-ol-3-one,3-Hydroxydodec-9-enedioylcarnitine,PC(20:5(5Z,8Z,11 Z,14Z,16E)-OH(18R)/17:0),Lyso PA(0:0/18: 2(9Z,12Z)),N-Formyl-L-aspartate,Dioctyl Phthalate,which may be potential biomarkers for predicting the occurrence of AVF stenosis.3.Some of the different metabolites in the AVF stenosis patients with MHD were correlated with clinical parameters.