尿视黄醇结合蛋白、尿肝型脂肪酸结合蛋白、血成纤维细胞生长因子-21、血转化生长因子-β联合诊断早期糖尿病肾病的价值

Value of urinary retinol binding protein,urinary hepatic fatty acid binding protein,serum fibroblast growth factor-21 and transforming growth factor-βin the diagnosis of early diabetic nephropathy

目的分析尿视黄醇结合蛋白(retinol binding protein,RBP)、尿肝型脂肪酸结合蛋白(liver type fatty acid binding protein,L-FABP)、血成纤维细胞生长因子-21(fibroblast growth factor-21,FGF-21)、转化生长因子-β(transforming growth factor-β,TGF-β)联合诊断早期糖尿病肾病(diabetic nephropathy,DN)的价值。方法选取2019年3月至2020年2月到咸宁市中心医院就诊的2型糖尿病(type 2 diabetes mellitus,T2DM)患者129例,根据尿微量白蛋白/肌酐(urinary albumin/creatinine,UA/CR)比值将所有患者分为DM对照组(n=48)、DN微量蛋白尿组(n=43)及DN大量蛋白尿组(n=38)3组;同期选择于我院体检的39名健康人作为正常对照组。采用免疫比浊法测定各组受检者尿RBP、尿微量白蛋白(microalbumin,mAlb)水平;采用酶联免疫法测定各组受检者尿L-FABP水平,采用酶联免疫法检测各组受检者血FGF-21、TGF-β、三酰甘油(triglyceride,TG)、总胆固醇(total choles⁃terol,TC)、高密度脂蛋白-胆固醇(high density lipoprotein-cholesterol,HDL-C)、低密度脂蛋白-胆固醇(low density lipoprotein-cholesterol,LDL-C)水平;采用全自动生化检测仪检测各组受检者血清空腹血糖(fasting plasma glucose,FPG)、餐后2 h血糖、平均血糖、24 h尿蛋白定量(24 h urinary protein,24 h UP)、糖化血红蛋白(haemoglobin A1c,HbA1c)、血清白蛋白、血红蛋白(hemoglobin,Hb)、血肌酐(se⁃rum creatinine,Scr)、血尿素氮(blood urea nitrogen,BUN)、血尿酸(serum uric acid,SUA)水平;采用改良MDRD方程计算肾小球滤过率(glomerular filtration rate,GFR)。采用Pearson相关性分析尿RBP、尿L-FABP、血FGF-21以及血TGF-2与肾功能的关系。采用受试者工作特征曲线(receiver operator characteristic curve,ROC)曲线分析尿RBP、尿L-FABP、血FGF-21、血TGF-β与四者联合在诊断DN中的价值。结果DM对照组、DN微量蛋白尿组及DN大量蛋白尿组的尿RBP[(56.32±6.24)mg/L、(78.86±14.22)mg/L、(103.25±16.57)mg/L比(37.33±5.13)mg/L]、尿L-FABP[(39.56±4.51)μg/g、(89.69±11.88)μg/g、(196.38±36.21)μg/g比(13.45±1.33)μg/g]、血FGF-21[(254.85±25.19)μg/L、(305.42±30.36)μg/L、(354.12±35.67)μg/L比(209.36±19.32)μg/L]及血TGF-β[(427.36±43.74)ng/L、(543.89±63.45)ng/L、(672.13±82.16)ng/L比(356.24±39.15)ng/L]水平均明显高于正常对照组(P<0.05);DM对照组、DN微量蛋白尿组及DN大量蛋白尿组的Scr[(62.35±18.51)μmol/L、(68.52±27.96)μmol/L、(127.94±109.60)μmol/L比(67.89±11.54)μmol/L]、BUN[(6.01±2.43)mmol/L、(6.37±2.16)mmol/L、(9.65±4.18)mmol/L比(4.16±0.42)mmol/L]、SUA[(356.69±34.51)mmol/L、(359.23±36.42)mmol/L、(364.56±41.43)mmol/L比(288.91±25.77)mmol/L]、24 h UP[(0.05±0.25)g/24h、(0.36±0.26)g/24h、(0.77±0.28)g/24h比(0.03±0.17)g/24h]、mAlb[(6.94±1.63)μg/L、(8.32±1.75)μg/L、(10.46±1.91)μg/L比(3.54±1.02)μg/L]、eGFR[(139.65±51.24)mL·min^(-1)·(1.73m^(2))^(-1)、(134.25±63.81)mL·min^(-1)·(1.73m^(2))^(-1)、(86.99±56.76)mL·min^(-1)·(1.73m^(2))^(-1)比(113.51±24.87)mL·min^(-1)·(1.73m^(2))^(-1)]水平与正常对照组相比,均明显增高(P<0.05);DM对照组、DN微量蛋白尿组及DN大量蛋白尿组FPG[(8.87±3.43)mmol/L、(9.74±4.29)mmol/L、(9.35±3.96)mmol/L比(5.21±0.43)mmol/L]、餐后2 h血糖[(12.42±5.31)mmol/L、(14.86±4.75)mmol/L、(13.71±5.43)mmol/L比(6.12±1.05)mmol/L]、平均血糖[(12.14±4.47)mmol/L、(13.38±4.62)mmol/L、(12.87±4.36)mmol/L比(5.22±0.21)mmol/L]、HbA1c[(8.41±2.31)%、(8.84±2.35)%、(8.76±3.08)%比(5.63±2.02)%]均明显高于正常对照组(P<0.05);DM对照组、DN微量蛋白尿组及DN大量蛋白尿组TG[(1.26±0.88)mmol/L、(1.48±0.11)mmol/L、(1.71±0.09)mmol/L比(0.93±0.97)mmol/L]、TC[(4.67±0.49)mmol/L、(5.23±0.53)mmol/L、(6.81±0.61)mmol/L比(3.41±0.33)mmol/L]、HDL-C[(1.19±0.27)mmol/L、(1.26±0.33)mmol/L、(1.42±0.54)mmol/L比(1.67±0.23)mmol/L]、LDL-C[(2.41±0.66)mmol/L、(2.53±0.81)mmol/L、(3.21±1.27)mmol/L比(2.76±0.33)mmol/L]、血清白蛋白[(42.49±3.96)g/L、(39.64±4.45)g/L、(37.82±4.94)g/L比(39.51±3.08)g/L]水平均明显高于正常对照组(P<0.05),Hb[(129.12±16.23)g/L、(126.33±19.45)g/L、(117.72±24.93)g/L比(134.22±10.13)g/L]水平均明显低于正常对照组(P<0.05)。Pearson相关性分析可得,尿RBP、血FGF-21、血TGF-β与Scr、BUN、SUA、24 h UP、mAlb、eGFR呈显著正相关(P<0.05),尿L-FABP与Scr、BUN无明显相关(P>0.05),与SUA、24 h UP、mAlb、eGFR呈显著正相关(P<0.05)。ROC曲线分析得知,尿RBP、尿L-FABP、血FGF-21、血TGF-β单独诊断DN的曲线下面积(area under curve,AUC)分别为0.725、0.756、0.749、0.715,四者联合诊断的DN的AUC为0.901。结论DN患者尿RBP、尿L-FABP、血FGF-21及血TGF-β表达水平明显异常,四者联合应用对早期DN具有显著的诊断价值。

Objective To explore the value of urinary retinol binding protein(RBP),urinary he⁃patic fatty acid binding protein(L-FABP),serum fibroblast growth factor-21(FGF-21)and transforming growth factor-β(TGF-β)in the diagnosis of early diabetic nephropathy(DN).Methods From March 2019 to February 2020,129 hospitalized patients with type 2 diabetes mellitus(T2DM)were divided into three groups of DM control(n=48),DN microalbuminuria(n=43)and DN massive proteinuria(n=38)ac⁃cording to urinary microalbumin/creatinine(UACR)ratio.In the same period,39 healthy subjects receiv⁃ing physical examination were selected as normal control group.Urinary levels of RBP and microalbumin(mAlb)were measured by immunoturbidimetry;urinary levels of L-FABP and serum levels of FGF-21 and TGF by enzyme-linked immunosorbent assay(ELISA).Triglyceride(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C);serum lev⁃els of fasting blood glucose(FPG),2-hour postprandial blood glucose,mean blood glucose,24-hour uri⁃nary protein(24 h UP),glycosylated hemoglobin(HbA1c),albumin,hemoglobin(Hb),serum creatinine(Scr),urea nitrogen(BUN)and serum uric acid(SUA)were measured by an automatic biochemical de⁃tector.Glomerular filtration rate(GFR)was calculated by modified MDRD equation.Pearson’s correla⁃tion was employed for examining the relationship between urinary RBP,urinary L-FABP,blood FGF-21 and blood TGF-2 and renal function.The value of combining urinary RBP,urinary L-FABP,blood FGF21 and TGF-βin the diagnosis of DN were analyzed by receiver operator characteristic(ROC curve).Re⁃sults Urinary RBP[(56.32±6.24)mg/L,(78.86±14.22)mg/L,(103.25±16.57)mg/L vs(37.33±5.13)mg/L],urinary L-FABP[(39.56±4.51)μg/g,(89.69±11.88)μg/g,(196.38±36.21)μg/g vs(13.45±1.33)μg/g],blood FGF-21[(254.85±25.19)μg/L,(305.42±30.36)μg/L,(354.12±35.67)μg/L vs(209.36±19.32)μg/L]and TGF-β[(427.36±43.74)ng/L,(543.89±63.45)ng/L,(672.13±82.16)ng/L vs(356.24±39.15)ng/L]in DM control,DN microalbuminuria and DN macroalbuminuria groups.The levels were significantly higher than those in normal control group(P<0.05).Compared with normal control group,the levels of Scr[(62.35±18.51)μmol/L,(68.52±27.96)μmol/L,(127.94±109.60)μmol/L vs(67.89±11.54)μmol/L],BUN[(6.01±2.43)mmol/L,(6.37±2.16)mmol/L,(9.65±4.18)mmol/L vs(4.16±0.42)mmol/L],SUA[(356.69±34.51)mmol/L,(359.23±36.42)mmol/L,(364.56±41.43)mmol/L vs(288.91±25.77)mmol/L],24 h UP[(0.05±0.25)g/24h,(0.36±0.26)g/24h,(0.77±0.28)g/24h vs(0.03±0.17)g/24h],mAlb[(6.94±1.63)μg/L,(8.32±1.75)μg/L,(10.46±1.91)μg/L vs(3.54±1.02)μg/L]and eGFR[(139.65±51.24)mL·min^(-1)·(1.73m^(2))^(-1),(134.25±63.81)mL·min^(-1)·(1.73m^(2))^(-1),(86.99±56.76)mL·min^(-1)·(1.73m^(2))^(-1) vs(113.51±24.87)mL·min^(-1)·(1.73m^(2))^(-1)]were significantly higher in DM con⁃trol,DN microalbuminuria and DN macroalbuminuria groups(P<0.05).Blood glucose related param⁃eters were significantly higher in DM control,DN microalbuminuria and DN massive proteinuria groups than those in normal control group(P<0.05).The levels of TG[(1.26±0.88)mmol/L,(1.48±0.11)mmol/L,(1.71±0.09)mmol/L vs(0.93±0.97)mmol/L],TC[(4.67±0.49)mmol/L,(5.23±0.53)mmol/L,(6.81±0.61)mmol/L vs(3.41±0.33)mmol/L],HDL-C[(1.19±0.27)mmol/L,(1.26±0.33)mmol/L,(1.42±0.54)mmol/L vs(1.67±0.23)mmol/L],LDL-C[(2.41±0.66)mmol/L,(2.53±0.81)mmol/L,(3.21±1.27)mmol/L vs(2.76±0.33)mmol/L],serum albumin[(42.49±3.96)g/L,(39.64±4.45)g/L,(37.82±4.94)g/L vs(39.51±3.08)g/L]and Hb[(129.12±16.23)g/L,(126.33±19.45)g/L,(117.72±24.93)g/L vs(134.22±10.13)g/L]were significantly higher in DM control,DN microalbuminuria and DN macroalbuminuria groups than those in normal control group(P<0.05)and the levels of Hb were significantly lower than those in normal control group(P<0.05).Pearson’s correlation analysis indicated that urinary RBP,blood FGF-21 and TGF-βwere significant positively correlated with urinary L-FABP and Scr,BUN,SUA,24 h UP,mAlb and eGFR(P<0.05).ROC curve analysis revealed that AUC for urinary RBP,urinary L-FABP,blood FGF-21 and blood TGF-βdiagnosing DN alone was 0.725,0.756,0.749 and 0.715 and diagnosing DN jointly 0.901.Conclusion The levels of urinary RBP,urinary L-FABP,serum FGF-21 and TGF-βare abnormal in DN patients.The combined application of the four factors has significant diagnostic value for early DN.