Development And Validation Of New Glomerular Filtration Rate Predicting Equations By Combining Multiple Endogenous Biomarkers

Objective:To establish more accurate equations for estimating the glomerular filtration rate based on two or more endogenous biomarkers including serum creatinine?Scr?,serum cystatin C?CysC?and serum?2-microglobulin??2MG?in Chinese patients with chronic kidney disease by using GFR measured by the exogenous biomarker Iohexol?Iohexol-GFR?as the gold standard.Methods:In the first part of the study,single-plasma Iohexol-GFR?Jacobsson-GFR and Bubeck-GFR?and renal dynamic imaging method ^99mTc-GFR were compared to the dual-plasma Iohexol-GFR in order to choose the gold standard method in the study.The second part of the study involves development and validation of the new equations:501enrolled Chinese patients with chronic kidney disease were randomly divided into two groups?equation-development group and equation-validation group?.Dual-plasma Iohexol-GFR,Scr,CysC and?2MG were determined for all patients.GFR measured by renal dynamic imaging method ^99mTc-DTPA(^99mTc-GFR)was used for 38 patients.GFR1⁷ were developed in the equation-development group by using a linear regression method.Estimated GFRs?eGFRs?were calculated by Chronic Kidney Disease Epidemiology Collaboration?CKD-EPI?equations(including CKD-EPI_Scr,CKD-EPI_Scr-CysC,CKD-EPI_CysC)and the newly developed equations eGFR1⁷.All the comparison between the equations was carried out in the equation-validation group.Results:After comparison of the methods used for the 38 patients,dual-plasma Iohexol-GFR was chosen as the gold standard in the study.In the validation group,significant correlation was observed between each new eGFRs and the mGFR?P<0.05?and good consistency between new eGFRs and the mGFR was revealed by the Passing-bablok and Bland-Altman analysis.Equations developed by two or more endogenous biomarkers performed better than those developed by single endogenous biomarker.New equations eGFR2⁴ based on Scr and combining two or three endogenous biomarkers showed less bias?median:0.26 ml/min/1.73m²,0.58ml/min/1.73m²,-0.28 ml/min/1.73m²;absolute median:7.24 ml/min/1.73m²,7.87ml/min/1.73m²,7.35 ml/min/1.73m²?,higher precision?14.73 ml/min/1.73m²,16.01ml/min/1.73m²,16.20 ml/min/1.73m²?and better accuracy(P₃₀:82.7%,83.5%,85.8%)than the CKD-EPI equations,in which the eGFR4_{Scr-CysC-?2MG} combining three endogenous biomarkers showed the best performance overall and was significantly different from the CKD-EPI equations in terms of bias,precision and accuracy?P<0.05?.As to the agreement of CKD stage between mGFR and eGFRs,eGFR4 _{Scr-CysC-?2MG}cr-CysC-?2MG outperformed all other equations?Kappa:0.639,correct rate:72.4%?and revealed significant difference from the CKD-EPI_CysC equations?P<0.05?.As for the screenimg ability for CKD,eGFR2⁴ performed better than the CKD-EPI equations in specificity.eGFR5⁷ based on?2MG and CysC didn't show better performance overall than the eGFR1⁴ based on Scr.Conclusion:1)Single-plasma Iohexol-GFR and ^99mTc-GFR were less precise and repeatable than the dual-plasma Ioheoxl-GFR,wherein Jacobsson-GFR showed higher accuracy than the other two equations.2)The newly developed equations outperformed the CKD-EPI equations in Chinese CKD patients,in which the eGFR4 _{Scr-CysC-?2MG} showed the best performance and is recommended in the use of diagnosis,staging and evaluation of CKD in Chinese CKD patients.