The Role Of SCD146 In Assessing Hydration State Of Hemodialysis Patients

Background:Dialysis is a treatment for patients with End Stage Renal Disease（ESRD）to remove excess water,toxins and maintaining electrolyte balance.It includes hemodialysis（HD）and peritoneal dialysis（PD）.Hydration State is associated with the quality of life,incidence of complications and prognosis of dialysis patients.Overhydration（OH）could lead to heart failure,hypertension,edema and other complications.Studies have shown that OH is an independent risk factor for death in ESRD patients.Dehydration could cause hypotension and the decrease of residual renal function.Studies have shown that hypotension is an independent risk factor for the death of hemodialysis patients.Strict control of hydration state could reduce blood pressure and improve survival rate of patients.Evulating the hydration state in dialysis patients is very important to the management of dialysis patients and the formulation of good dialysis programs,and to improve the prognosis of dialysis patients.Currently,clinical assessment of hemodialysis patients’hydration state is mainly based on their symptoms and signs,which is not accurate.Extracellular Fluid Volume（ECV）and Total Body Water（TBW）can be quantitatively measured by tracer dilution method.Bioelectrical Impedance Analysis（BIA）can quantitatively measure ECV,Intracellular Fluid Volume（ICV）and TBW.Tracer dilution is the gold standard,but it’s implementation is complex,invasive and expensive.The results of different tracers may be different with each other,and it can not evaluate the hydration state,so BIA is the most potential manner.OH in dialysis patients may be related to water and sodium retention,insufficient dialysis,congestive heart failure and other factors.Clarifying the hydration state of dialysis patients and what factors it belongs to can guide clinicians to implement different treatment schemes according to different reasons.BIA can evaluate ECV,ICV and excess water（MEXF）in patients as a whole,however,the evaluation of bioelectrical impedance needs professional instruments,which are expensive and difficult to popularize.Biomarkers may be able to compensate for this defect.B-type natriuretic Peptide（BNP）and N-terminal brain natriuretic peptide precursor（NT-proBNP）are released by myocardial cells if the intracardiac pressure increase.They are often used as biomarkers to reflect the severity of heart failure in patients.Studies have shown that BNP has a short half-life in vivo and poor stability in vitro,while NT-proBNP is more stable than BNP.Therefore,NT-proBNP is often measured clinically.Some previous studies have suggested that BNP or NT-pro-BNP is an effective indicator for assessing hydration state in dialysis patients,but other studies have concluded that BNP is not a good indicator for hydration state.Therefore,it is still controversial whether BNP and NT-proBNP are effective in assessing OH in dialysis patients.CD146 is a kind of intercellular adhesion molecule found in recent years,which is widely distributed,including all vascular endothelial cells,smooth muscle cells,activated T lymphocyte and so on.The free form sCD146（soluble CD146）releases more when the vascular endothelial cells are stretched.At present,many studies have shown that sCD146 is a marker of endothelial cell injury and also a biomarker of systemic circulation congestion.Overseas studies have found that in dialysis patients with low NT-proBNP level but high sCD146 level,nearly 3/4 of them still have OH,suggesting that OH exists in most dialysis patients and has no good correlation with BNP level in vivo.This study also found that the incidence of cardiac systolic dysfunction in patients with high BNP level is 2-3 times higher than that in patients with low BNP level,while there was no significant correlation between sCD146 level and systolic dysfunction.Significant correlation suggested that sCD146 was almost independent of cardiogenic factors and could better reflect the condition of systemic circulation congestion.Enzyme-linked Immunosorbent Assay（ELISA）and electrochemoluminescence immunoassay（ECLIA）was used to determine the concentration of sCD146 and NT-proBNP.Currently,there is no study on the relationship between sCD146 and hydration state in Chinese dialysis patients.Based on this,we will study the relationship between sCD146,NT-proBNP levels and hydration state in dialysis patients.Grouping based on BIA measurements,we will study the role of sCD146 and NT-proBNP in assessing hydration state in hemodialysis patients.Purpose:1.We will investigate the expression level of sCD146 in dialysis patients and healthy people.2.The correlation between sCD146,NT-proBNP and hydration state of hemodialysis patients will be explored.3.We will explorethe specificity and sensitivity of sCD146 and NT-proBNP in diagnosing hydration state.Methods:1.Screening ESRD patients who receive maintenance hemodialysis in the outpatient department of Blood Purification Center of the First Affiliated Hospital of Zhengzhou University and the end ESRD maintenance hemodialysis patients who were hospitalized in the nephrology ward of the First Affiliated Hospital of Zhengzhou University from September 2018 to January 2019.At the same time,10healthy people were screened to take blood from elbow vein to measure the level of sCD146 as control.The inclusion criteria were as follows:age≥18 years old,the dialysis time≥3 months,urine volume<400 ml/d,sign informed consents.Exclusion criteria were as follows:Complicated with nephrotic syndrome,cirrhosis or other autoimmune diseases,tumors,heart failure,implants and pacemakers in the heart,pregnant women,amputation,hospitalization because acute disease attack in the past week.At the same time,10 healthy people who were checked up in Zhengzhou University Hospital in January 2019 were screened to take blood from elbow vein to measure the level of sCD146 as control.Inclusion criteria were as follows:age≥18 years old,sign informed consents.Exclusion criteria:Patients with abnormal physical or laboratory examinations.2.Clinical data were collecting,including sex,age,height,type of dialysis pathway,systolic blood pressure（sBP）,hemoglobin（Hb）,serum albumin（Alb）,blood urea nitrogen（blood Urea Nitrogen,BUN）,uric acid（UA）,creatinine（Serum Creatinine）,total cholesterol（TC）were collected.Triglycerid（TG）,potassium,phosphorus,dialysis effectiveness index Kt/V,parathyroid Hormone（PTH）and the main indicators of color Doppler ultrasound results.3.Healthy people:Cubital vein blood was taken in the morning to measure the concentration of sCD146 and NT-proBNP.Hemodialysis patients:Body weight was measured before and after dialysis on dialysis day,and bioelectrical impedance was measured by Xitro4200 bioelectrical impedance meter and electrodes.Blood plasma was taken to detect sCD146 and NT-proBNP.Ultrafiltration volume was recorded.Diet was forbidden during dialysis.According to the measured values of height,weight,resistance and reactance,TBW,ECV and Chamney of patients were calculated according to Moissl Equation（ME）based on Hanai theory.According to the three-compartment model of tissues,the model for calculating MEXF in vivo was proposed,M_EXF=1.136*ECV-0.430*ICV-0.114*BW,and M_EXF in vivo was calculated according to this formula.4.Statistical Analyses:SPSS17.0 of IBM was used for all the statistical analysis.Quantitative data were described by mean±standard deviation or median（quartile spacing）,and categorical variables were described by percentages.T test（or Mann-Whitney U test）and chi-square test were used to compare and analyze clinical data.Pearson or Spearman test was used to compare and analyze the correlation between NT-proBNP and sCD146,ECV,excess water in vivo,and sCD146,NT-proBNP.Pearson or Spearman correlation analysis was also used to analyze the correlation between the changes of body weight and the changes of sCD146 and NT-proBNP before and after dialysis.ROC curve is used to evaluate the accuracy of sCD146 and NT-proBNP in diagnosing water load.P<0.05 was defined as significant difference.Results:1.Compared with 10 healthy controls,plasma sCD146 levels in hemodialysis patients increased before and after dialysis（275.58[209.00,370.80]VS.182.03[152.01,214.09]ng/ml,P<0.05）,（233.00[172.50,442.59]VS.182.03[152.01,214.09]ng/ml,P<0.05）.Moreover,the levels of sCD146 and NT-proBNP before and after dialysis in the water overload group were higher than those in the water overload group（P<0.05）.2.Pearson or Spearman correlation analysis showed that sCD146 before dialysis was positively correlated with M_EXF（r=0.400,P<0.05）before dialysis,negatively correlated with age（r=0.394,P<0.05）,but not with pre-dialysis body weight（r=0.030,P=0.872）,blood pressure（r=-0.085,P=0.646）,ECV/TBW（r=0.269,P=0.136）.NT-proBNP before dialysis was positively correlated with ECV/TBW before dialysis（r=0.382,P<0.05）and M_EXF before dialysis（r=0.347,P<0.05）.There was no significant correlation between sCD146 and NT-proBNP before dialysis（r=0.235,P=0.195）.With the concentration of sCD146 before dialysis as a dependent variable,after adjustment of age,hemoglobin,albumin,pre-dialysis resistance,pre-dialysis reactance,pre-dialysis ECV/TBW value and MEXF,multiple linear regression showed that sCD146 before dialysis was still correlated with MEXF.After logarithmic conversion of NT-proBNP value before dialysis,the logarithmic value was taken as dependent variable.After adjustment of age,hemoglobin,albumin,pre-dialysis resistance,pre-dialysis reactance,pre-dialysis ECV/TBW value and pre-dialysis MEXF,multiple linear regression showed that it was only related to pre-dialysis M_EXF.3.Before dialysis,the area under ROC curve（AUC）of sCD146 and NT-proBNP concentration for diagnosing overhydration was 0.723（95%CI,0.528 to 0.918,P=0.041）and 0.723（95%CI,0.549 to 0.897,P=0041）,respectively.The best cut-off value of sCD146 was 290.15 ng/ml（sensitivity 57.1%,specificity 90.9%）and the best cut-off value of NT-proBNP was 9601 pg/ml（sensitivity 57.1%,specificity99.7%）.It is obvious that sCD146 plays the same role in diagnosing overhydration in hemodialysis patients as NT-proBNP.Conclusions:1.Compared with healthy people,plasma sCD146 level increased in hemodialysis patients.The plasma levels of sCD146 and NT-proBNP in patients with excessive water load were higher than those in patients with normal hydration state.The levels of sCD146 and NT-proBNP were positively correlated with excessive water load.2.The role of sCD146 in diagnosing overhydration in hemodialysis patients is similar to that of NT-proBNP.3.sCD146 may be a new biomarker for the overhydration state in hemodialysis patients.