| Objective: To measure the relevant biomarkers of kidney function,glucose metabolism and lipid metabolism in healthy control subjects(HC)and patients with diabetes mellitus(DM)[including simple diabetes mellitus(SDM)and diabetic kidney disease(DKD)],then to discuss the correlation of the occurrence of DKD with these observed biomarkers,and to compare the diagnostic performance of neutrophil gelatinase associated lipocalin(NGAL)with other observed biomarkers in DKD,finally to evaluate the clinical value of NGAL in diagnosis of DKD with different albuminuria levels.Methods: 1892 DM patients(including 866 cases of SDM and 1026 cases of DKD)and 2471 HC from the Mianyang Central Hospital during Jan.2018 to Sep.2018 were included in this study.In the morning,the following blood samples were collected: about 2ml anticoagulant blood used to measure glycohemoglobin(Hb A1c),about 5ml non-anticoagulant blood used to measure urea(Urea),serum creatinine(s Cr),Cystatin C(Cys C),estimated glomerular filtration rate(eGFR),NGAL,triglyceride(TG),cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),homocysteine(HCY),fasting blood glucose(GLU),and two-hour postprandial blood glucose(GLU-2h).And then,about 10 ml urine sample was collected within 1 hour before or after blood sample collection,which was used to measure urinary albumin(u Alb)and urinary creatinine(u Cr).Binary and multiple Logistic regression model were adopted to screen out those biomarkers closely related to DKD and its subgroups with different albuminuria levels,respectlly;receiver operating characteristic curve(ROC)was adopted to evaluate the diagnostic performance in DKD with different albuminuria levels,when the biomarkers were detected alonely and/or combined;and stratified risk analysis was adopted to compare the risk of NGAL and other closely-related biomarkers with DKD in different albuminuria levels.Results:(1)In this DM population,the ratio of patients with nor-albuminuric DKD(NADKD),high level albuminuric DKD(HADKD)and very high level albuminuric DKD(VADKD)were 13.37%,28.38% and 12.47%,respectively.(2)By One-way ANOVA or Kruskal-Wallis test,the differences of kindey function,glucose metabolism and lipid metabolism biomarkers were statistically significant among SDM,DKD and HC groups(F/χ2=11.943~1796.787,all P<0.001).(3)Except Glu-2h(F=1.727,P=0.162),the differences of kindey function,glucose metabolism and lipid metabolism biomarkers were statistically significant among NADKD,HADKD and VADKD groups(χ2=53.063~1926.410,all P<0.001).The levels of u ACR(z=-19.120 and-22.163,all P<0.001),GLU(z=-5.269 and-2.950,all P<0.001)and Hb A1c(z=-5.577 and-2.914,all P<0.001)in VADKD group were significantly higher than those of NADKD and HADKD groups,and the levels of u ACR(z=-22.700,P<0.001),TC(z=-5.176,P<0.001),LDL-C(z=-4.396,P<0.001),GLU(z=-3.536,P<0.001)and Hb A1c(z=-3.885,P<0.001)in HADKD group weresignificantly higher than those of NADKD group.(4)By binary Logistic regression analysis,only u ACR,e GFR,HDL-C and NGAL were closely related to DKD(P<0.001),the OR values were 1.082(Wald χ2=412.801,P<0.001),0.925(Wald χ2=358.157,P<0.001),0.669(Wald χ2=3.956,P=0.047)and 1.008(Wald χ2=81.560,P<0.001)before gender and age adjustment,respectively;and were 1.090(Wald χ2=389.944,P<0.001),0.927(Wald χ2=206.206,P<0.001),0.582(Wald χ2=6.038,P=0.014)and 1.009(Wald χ2=75.062,P<0.001)after gender and age adjustment,respectively.(5)By multiple Logistic regression analysis,u ACR(OR=0.940 and 1.108,both P<0.001),e GFR(OR=0.860 and 0.963,both P<0.001)and NGAL(OR=1.009 and 1.007,both P<0.001)were closely related to NADKD and HADKD occurrence,only u ACR(OR=1.318,P<0.001)was closely related to VADKD occurrence.(6)When the biomarkers related to DKD were detected alonely,the AUC(95%CI)of u ACR,e GFR,NGAL and HDL-C were 0.950(0.943~0.957),0.795(0.783~0.807),0.727(0.714~0.741)and 0.615(0.601~0.630),respectively;the criterion values at the maximized Youden index(YI)were 29.54mg/g Cr,63.7ml/min/1.73m2,193.8μg/L and 1.15mmol/L,respectively;their sensitivity(Se)were 85.0%,56.7%,87.8% and 58.3%,respectively;Specificity(Sp)were 99.8%,94.5%,93.1% and 60.4%,respectively;u ACR had the highest diagnostic performance.(7)When the biomarkers related to NADKD were detected alonely,the AUC(95%CI)of u ACR,e GFR and NGAL were 0.627(0.611~0.643),0.959(0.952~0.965)and 0.811(0.798~0.823),respectively;the criterion values at the maximized YI were 7.31 mg/g Cr,62.8ml/min/1.73m2 and 180.0μg/L,respectively;Se were 64.0%,89.7% and 97.4%,respectively;Sp were 59.4%,97.4% and 78.0%,respectively.e GFR had the highest diagnostic performance.(8)When the biomarkers related to HADKD were detected alonely,the AUC(95%CI)of u ACR,e GFR and NGAL were 0.995(0.992~0.997),0.760(0.746~0.773)and 0.686(0.671~0.701),respectively;the criterion values at the maximized YI were 29.93 mg/g Cr,72.5ml/min/1.73m2 and 206.9μg/L 7.31 mg/g Cr,respectively;Se were 100.0%,55.6% and 43.3%,respectively;Sp were 98.8%,87.5% and 88.7%,respectively.u ACR has the highest diagnostic performance.(9)Only u ACR was related to the diagnosis of VADKD,whose AUC(95% CI)was 1.000(0.900~1.000),criterion value at the maximized YI was 149.42mg/g Cr,Se was 100%,and Sp was 99.9%.(10)When u ACR,e GFR,NGAL and HDL-C were combined for screening the performance of DKD,the AUC of quadruple-test(u ACR/e GFR/NGAL/HDL-C)and triple-test1(u ACR/e GFR/NGAL)were both 0.981(0.976~0.985),whose results were the same(z=0.375,P=0.707)and the highest(z=2.990~25.115,all P<0.05);the AUC of triple-test2(u ACR/e GFR/HDL-C)and duplex-test1(u ACR/e GFR),were 0.976(0.971~0.980)and 0.975(0.970~0.980),respectively,which were equivalent(z=1.279,P=0.201)and higher than the else seven modes except quadruple-test and triple-test1 modes(z=5.261~23.292,all P<0.01).(11)When combined test of u ACR,e GFR,and NGAL for screening NADKD,the AUC of triple-test1 and duplex-test3(e GFR/NGAL)were both 0.977(0.971~0.981),whose results were the same(z=0.189,P=0.985)and the highest(z=3.107~21.284,all P<0.01).(12)When u ACR,e GFR,and NGAL were combined for screening HADKD,the differences of AUC among triple-test1 and duplex-test1 and duplex-test2(u ACR/NGAL)were no statistically significant(z=0.195~0.968,P=0.333~0.846),but higher than duplex-test3(z=17.036~17.134,all P<0.001).(13)By risk stratification analysis,NGAL was a risk factor for both NADKD(OR=8.817,P<0.001)and HADKD(OR=2.511,P=0.014),while HDL-C was a risk factor only for NADKD(OR=2.919,P<0.001).Conclusion:(1)The proportion of NADKD patients in the DM patients observed is 13.37%,which is approximate to the results of domestic and foreign reports.(2)The decreased HDL-C is related closely to DKD,indicating that lipid metabolism disorder maybe promote the occurrence of DKD.(3)The levels of HCY in DKD patients with different albuminuria levels show a vshaped increase trend,it indicates that atherosclerosis may not only be an important risk factor for the occurrence and development of DKD,but also play a important role in the mechanism of NADKD occurrence,which may be a breakthrough in furtherly exploring the difference of the pathogenesis between NADKD and HADKD.(4)The preferred biomarker for screening DKD is u ACR,if which <30mg/g Cr,duplex-test3(e GFR/NGAL)should be suggested in order to avoid the missed diagnosis of NADKD;if which ≥30mg/g Cr,duplex-test1(u ACR/e GFR)recommended by the KIDGO guideline is allright.(5)Compared with HDL-C,NGAL has a higher predictive value for NADKD risk. |
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