Research On The Relationship Of Serum Galectin-3 And Fibroblast Growth Factor 23 With Cardiovascular Risk In Patients With Chronic Kidney Disease

Chronic kidney disease(CKD)is now recognized to be a worldwide problem associated with significant morbidity and mortality.Globally,the burden of CKD continues to increase and current estimates suggest that between 8 and 16%of the world’s population are affected.China has a large population and a high prevalence of CKD.The number of patients with CKD in China is estimated to be approximately 119 million.It has long been known that impaired kidney function have been associated with increased adverse clinical outcomes(i.e.,congestive heart failure,acute myocardial infarction,arrhythmia,stroke and peripheral vascular disease)in the CKD population.Compared with the general population,cardiovascular incident event hazard rates among patients with CKD in stage 3 and 5increased to 1.43 and 10 times,respectively.Also,patients with CKD have higher-than-expected death rates,even after adjustment for adverse prognostic factors that co-occur with CKD,such as older age,diabetes,and previous cardiovascular disease(CVD).Enumerating the degree by which CKD magnifies the risk for CVD might inform screening and management strategies.Thus,better understanding of the?risk of CVD events in CKD could help focus efforts that target prevention strategies or disease management in those with CKD.The cardiac biomarkers B-type natriuretic peptide(BNP)/N-terminal pro-B-type natriuretic peptide(NT-proBNP)and troponin I/T(TnI/TnT)have been shown to predict risk of CVD events in the general population.NT-proBNP is secreted from cardiac myocytes in response to myocardial stretch from pressure or volume overload,and levels increase with increasing left ventricular mass.Through complementary physiologic pathways,concentrations of TnT may become elevated in response to myocardial injury or remodeling or left ventricular hypertrophy(LVH).The use of NT-proBNP and TnT to evaluate risk of CVD events among patients with CKD has been limited because of concerns that elevated levels may be caused by reduced renal excretion.According to Kidney Disease:Improving Global Outcomes(KDIGO)2012 clinical practice guideline for the evaluation and management of CKD,in people with GFR<60ml/min/1.73 m~2,it is recommend that serum concentrations of NT-proBNP and troponin be interpreted with caution and in relation to GFR with respect to assessment of risk of CVD events.Anomalies of the left ventricular structure are quite frequent in CKD patients.Subclinical cardiac changes in LV structure is predictive of an increased cardiovascular death and confers poor prognosis.LVH is associated with various pathophysiological and biochemical disorders.No single biomarker is able to display all these characteristics.Galectin-3 is a member of theβ-galactosidase binding lectin family,which plays many important regulatory roles in inflammation,immunological response,and cancer.Fibroblast growth factor-23(FGF-23)is secreted by osteocytes and regulates phosphate and vitamin D homeostasis by stimulating phosphaturia and inhibiting activation of vitamin D in the kidney.Multiple studies have demonstrated that higher Galectin-3 and FGF-23 levels are independently associated with greater risk of prevalent and incident LVH.However,studies focused on comparison of these measurements are limited in regard to CKD.In the present study we evaluated the value of Galectin-3 and FGF-23levels in a cohort of patients with CKD and whether the incorporation of Galectin-3 and FGF-23 on top of established mortality risk factors and NT-proBNP improved cardiovascular risk stratification.This was a cross-sectional study.Patients aged 16-65 years with baseline CKD stages2 to 5 were enrolled in this study.Baseline clinical characteristics such as gender,age,smoking,diabetes,blood pressure,body surface area(BSA),body mass index(BMI)were obtained.Estimated glomerular filtration rate(eGFR)was calculated using the CKD-EPI formula.Serum NT-proBNP,High-sensitivity troponin T(hs-TnT),Galectin-3 and FGF-23levels were measured by using standard laboratory tests.All patients were examined by transthoracic echocardiography to measure the diameter of the left ventricle.Left ventricular mass index(LVMI)and relative wall thickness(RWT)were obtained by calculation.Based on the measurements of LVMI and RWT,normal LV geometry was defined as RWT≤0.42 with LVMI≤95g/m~2 in woman and 115g/m~2 in man.Patients with either concentric hypertrophy(increased LV mass with RWT>0.42)or eccentric hypertrophy(increased LV mass with RWT≤0.42)were enrolled into LVH group.Participants with concentric remodeling(normal LV mass with increased RWT>0.42)and those with normal LV geometry were enrolled into Non-LVH group.The relation between NT-proBNP,Galectin-3 and FGF-23 levels with left?ventricular?geometry?remodeling was evaluated by Logistic regression and receiver operating characteristic curve(ROC).The main findings of this study are:(1)Median Galectin-3 and FGF-23 levels in patients with CKD stage 2 were significantly higher than those in control group(both P<0.001).Galectin-3 and FGF-23 concentrations increased in parallel with decreasing kidney function,respectively(both P<0.001).However,median NT-proBNP and hs-TnT levels in patients with CKD stage 2 and 3 were within normal range,and significantly increased in patients with advanced CKD stage(both P<0.001).(2)After adjustment for age and sex,natural log transformed Galectin-3 levels correlated with both traditional risk factors and these novel predictors including diabetes,systolic blood pressure(SBP),24h proteinuria,hemoglobin,albumin,CysC,uric acid,phosphate,iPTH,NT-proBNP,hs-TnT and eGFR levels(all P<0.05).Higher Galectin-3 concentrations showed a higher indices of LV structure,including LVM and LVMI(both P<0.01).There was negative correlation between Galectin-3 with LVEF that didn’t reach significance(P=0.110).(3)After adjustment for age and sex,natural log transformed FGF-23 levels correlated with those CVD risk factors including SBP,hemoglobin,Cys C,uric acid,phosphate,i PTH,NT-proBNP,hs-TnT,Galectin-3 and eGFR levels(all P<0.05).Higher FGF-23concentrations showed a higher indices of LV structure,including LVM and LVMI(both P<0.01).There was negative correlation between FGF-23 with LVEF that reached significance(r=-0.166,P<0.01).(4)According to the criteria defined as LVH,areas under the ROC curve(AUC)for NT-proBNP,Galectin-3 and FGF-23 were[0.766(95%CI:0.701,0.830)],[0.672(95%CI:0.599,0.745)]and[0.670(95%CI:0.597,0.743)],respectively,with no significant difference between Galectin-3 and FGF-23(P>0.05).Correlation between Galectin-3 and FGF-23 with LVH were substantially attenuated after adjustment for sex,diabetes and eGFR.The C-statistic for the basic prediction model for LVH diagnosis,comprising age,sex,diabetes,SBP,Hb,eGFR and NT-proBNP,was 0.817(95%CI:0.758,0.875).The addition of Galectin-3 and FGF-23 improved the C-statistic to0.832(95%CI:0.776,0.889),which didn’t reach significance(P>0.05).Clonclusion:Higher levels of Galectin-3 and FGF-23 were associated with several cardiovascular risk factors and left?ventricular?geometry?remodeling in CKD patients.Emerging cardiac biomarkers with different pathophysiological background incorporated may offer important prognostic information in the setting of CKD.