Changes Of Serum IFGF-23, α-Klotho Protein, NLR And PLR Levels In Patients With Type 2 Diabetic Nephropathy

Objective To investigate the levels of the serum fibroblast growth factor-23(iFGF-23), a-klotho protein, neutrophil to lymphocyte ratio (NLR), platelet and lymphocyte ratio (PLR) in the patients with type 2 diabetes mellitus and with diabetic kidney disease (DKD) in different clinical stages.To study the correlation of the levels of serum iFGF-23, a-klotho, NLR and PLR and urinary albumin excretion rate (UAER) and renal function. To explore the possibility of apply the levels of serum iFGF-23, α-klotho, NLR and PLR as early predictors of diabetic kidney disease.Methods A total of 119 patients with type 2 diabetes and 29 healthy control subjects were enrolled. According to urinary albumin excretion rate and renal function,the patients with type 2 diabetes were divided into four groups:urinary albumin excretion rate in normal group (group DM1,8°UAER<20μg/min, serum creatinine was normal, n=30), microalbuminuria group (group DM2,8°UAER 20-200μg/min, serum creatinine level is normal, n=30), clinical albuminuria group (group DM3,8°UAER>200μg/min, serum creatinine level is normal,n=28), uremic hemodialysis group (DM4 group, n=31), normal control group (group N, n=29).The general data of the subjects was recorded. Fasting venous blood samples were collected for glucose, lipid, liver and kiDKDey function, blood routine tests, intact parathyroid hormone (iPTH), and serum iFGF-23 determination.8 hour urine (from 10pm to 6am) was also collected for UAER detection in DM1、DM2 and DM3groups. SPSS 22.0 software package was used for statistical analysis.Results:l.The serum iFGF-23 level of DM4 group (558.93,168.65-2333.50 pg/mL)was significantly higher than other groups (P< 0.001), but there was no significant difference between the other groups. The level of serum iFGF-23 was negatively correlated with estimated glomerular filtration rate (eGFR), and was positively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), blood glucose (GLU), phosphorus (P), serum alkaline phosphatase (ALP), iPTH. Multiple linear regression equation:YLogiFGF-23=0.848-0.005XeGFR+0.805Xp, (P<0.001, R2=0.803) 2. The level of serum a-klotho protein decreased gradually with the progression of diabetic kidney disease, the lowest was the level of the DM4 group. The level of serum a-klotho protein of the DM4 group (403.14+154.07pg/mL) was significantly lower than that of N group (757.61 ±224.0.1 pg/mL, P<0.001), DM1 group (731.21± 262.09 pg/mL,P<0.001) and DM2 group (609.65±217.88 pg/mL, P<0.001) but no significant difference compared with that of DM3 group (493.30 ±234.46 pg/mL, P=0.086), the levels of serum a-klotho protein of DM3 group was significantly lower than that of N group(P<0.001), DM1 group(P<0.001) and DM2 group (P=0.028). The a-klotho level of DM2 group significantly decreased. It was significantly lower than that of N group (P=0.012) and DM1 group (P=0.046). The level of Serum a-klotho protein was negatively correlated with age, course of disease,8 ° UAER, Scr, BUN, uric acid (UA), GLU. P, iPTH, serum ferritin (SF), iFGF-23, and were positively correlated with plasma albumin (ALB), eGFR, hemoglobin(HGB), hematocrit (HCT). Multiple linear regression equation:YLogK1.6mo=3.2+0.776XLogHCT-0.073XLog8LAER(P<0.001, R2= 0.222); The receiver operating characteristic curve (ROC) with a-klotho protein 531.95pg/mL as the cut-off point, the sensitivity of 50.9%in diagnosis of DKD, the specificity was 86.7%, the area under ROC was 0.698 (95%Cl:0.581-0.816,P<0.001) 3. The NLR level of DM4 group (3.87±1.56) was significantly higher than that of N group (2.09±0.92, P<0.001), DM1 group (2.00±0.75, P<0.001)、DM2 group (2.48±1.21, P<0.001) and DM3 group (2.90±1.78, P=0.003). The NLR level of DM3 group was significantly higher than that of N group (P=0.005), DM1 group (P±0.003). The NLR level of DM3 group was higher than that of DM2 group, but the difference was no statistically significant (P=0.169), The NLR level of DM2 group was higher than that of DM1 group, but the difference was not statistically significant (P=0.102)。There was no significant difference of the levels of NLR among N、DM1 and DM2 groups.The level of NLR was positively correlated with the levels of age,8°UAER, BUN, iPTH, and was negatively correlated with eGFR, ALB, HDL. Multiple linear regression equation:YLogNER=0.29+0.54Log8°LAER+0.004年龄(R2=0.152, P= 0.00.1). The receiver operating characteristic curve (ROC) with NLR 2.290 as the cut-off point for the diagnosis of DKD,the sensitivity is 52.6%,the specificity is 73.3%, the area under the ROC is 0.0.661 (95% Cl:0.544-0.779; P=0.014).4. The levels of PLR were increased gradually, that of DM4 group (175.7±80.67) was significantly higher than that of N group (127.95±42.33, P=0.004), DM1 group (110.41 ±45.50, P< 0.001) and DM2 group (134,68±67.81, P=0.004),,but there was no statistically significant difference with that of DM3 (143.16±53.53,P=0.074). The PLR levels of DM3 group was significantly higher than that of group DM1 (P=0.009).The PLR levels of PLR were positively correlated with age,8° UAER, BUN, iPTH and were negatively correlated with eGFR. Multiple linear regression equation:YLogPLR= 1.997+0.45Log8°LAER (R2 = 0.057, P=0.028), With PLR 124.47 as the cut-off point for the diagnosis of DKD,the sensitivity is 50.9%, the specificity is 83.8%, the area under the ROC is 0.655 (95% C1:0.539-0.771;P=0.018).Conclusion I.The level of serum iFGF-23 was significantly increased in the late stage of diabetic kidney disease, the serum level of iFGF-23 was positively correlated with the levels of P, Scr, BUN and iPTH and was negatively correlated with the level of eGFR. iFGF-23 cannot be used as a biochemical marker of early DKD, But it may become an early biochemical marker of renal insufficiency.2.The decline in serum level of a-klotho protein can be detected in the early stage of diabetic kidney disease, and the serum-klotho protein level was negatively correlated with the 8°UAER, serum α-klotho protein may be served as a new biomarker for early diagnosis of diabetic kidney disease. 3. The level of NLR was increased significantly in diabetic clinical proteinuria, and was positively correlated with 8° UAER, but the change of NLR was later than that of 8 ° UAER, the increase of NLR maybe searved as a prediction of DKD.4. The level of PLR was significantly higher in macroalbuminuria, and was positively correlated with the levels of 8°UAER. The level of PLR can be used for the prediction of DKD, but the change is later than 8°UAER.