慢性肾病患者基于血清胱抑素C与肌酐的肾小球滤过率估算方程的建立和评价

Establishment and evaluation of estimated glomerular filtration rate by serum cystatin C alone and in combination with serum creatinine in patients with chronic kidney disease

目的建立基于血清胱抑素C（CysC）和肌酐（Cr）浓度计算中国成人慢性肾病（CKD）患者肾小球滤过率（GFR）估计方程，并对其适用性进行评价。方法由国内不同地域6家综合医院（四川省绵阳市中心医院、北京协和医院、郑州大学第一附属医院、吉林医科大学附属第一医院、四川省成都市核工业部416医院和四川省内江市第一人民医院）组成多中心非随机试验研究小组，按照K／DOQI指南及预先设定的排除标准，选取2010年10月至2011年12月门诊或住院肾病科就诊的成人CKD患者788例（男421例，女367例，年龄19～87岁），兼顾性别和疾病分期进行分层随机抽样，将受试者分成方程开发组（687例）和验证组（101例）。以双血浆法检测99m。Tc—DTPA肾脏清除率，作为参考GFR（rGFR），同时测定所有受试者CysC和Cr浓度。采用非线性回归拟合开发组之GFR估计方程，然后用验证组资料评估所开发方程、Cockcroft—Gault方程（eGFRl）、简化MDRD方程（eGFR2）、2个MDRD／CKD—EPICysC方程（eGFR3、eGFR4）和2个中国eGFR协作组CysC方程（eGFR5、eGFR6）共8个GFR估算等式对中国CKD患者的适用性，并对其与rGFR的一致性进行相互比较。结果开发组rGFR、CysC和Cr浓度分别是44．19（3．51～166．00）ml／（min·1．73m2）、1．88（0．59—8．62）mg／L和1．73（0．40～19．77）mgJdl，验证组分别为47．85（10．49～148．12）ml／（min·1．73m2）、1．79（0．66～7．22）mg／L和1．56（0．48～23．34）mg／dl，用非线性回归拟合得到2个最佳GFR估算方程：eGFR7：173．9×CysC-0.725×Cr-0.148X年龄-0.193。（女性×0．89）（R2=0．734，P=0．000）和eGFR8=78．64×CysC-0 .964（R2=0．764，P=0．000）；8个eGFR方程估算结果与rGFR分别经Bland—Ahman一致性检验、Passing＆Bablok回归分析和Mountain一致性比较发现，仅eGFR7和eGFR8的一致性界限未超过事先规定的专业界值[〈60ml／（rain·1．73m。=2）]，且与rGFR之间没有明显的比例误差（斜率b的95％CI包含B=1）和恒定误差（截距a的95％CI包含A=0），其Mountain偏差分布曲线几乎重合，估算GFR的效果基本一致，而eGFRl、eGFR2、eGFR5和eGFR6估计GFR的偏差较eGFR7和eGFR8大，eGFR3和eGFR4整体低估了GFR。结论用血清肌酐和（或）胱抑素C来估算GFR可得到相同精度的结果。选择文献方程估算GFR时，应首先考虑其标记物的检测方法，当检测方法与文献不一致时，不应用来估算CKD患者GFR，否则可能导致eGFR与实际水平相差较大o（中华检验医学杂志．2013，36：352-359、

Objective To establish equations for estimating glomerular filtration rate （GFR） based on serum Cystatin C （CysC） and creatinine （Cr） concentration in Chinese adult patients with chronic kidney disease （CKD）, and evaluate their applicability. Methods Six tertiary hospitals located in different geographic regions of China formed a muhicenter nonrandom test research, composed of the Mianyang Central Hospital, the Peking Union Medical College Hospital, the First Affiliated Hospital of Zhengzhou University, the First Bethune Hospital of Jilin University, the Nuclear Industrial 416 Hospital, and the First people＇s Hospital of Neijiang. According to K/DOQI guidelines and pre-set exclusion criteria, 788 adult patients with CKD were enrolled, from October 2010 to December 2011 （421 males, 367 females, age from 19-year-old to 87-year-old） , and randomly divided into development group （n = 687） and validation group （n = 101 ） with a stratified sampling take into account both gender and disease stages. Two-sample 99mTc-DTPA plasma clearance was determined as the reference GFR （rGFR）, meanwhile serum CysC and Cr were also detected. The data of development group was used to fit GFR-estimating equation using nonlinear regression, and the data of validation group to evaluate the applicability of eight equations, including two developed equations, Cockcroft-Gault equation （ eGFR1 ）, MDRD equation （ eGFR2 ）, two MDRD/CKD-EPI equations （eGFR3, eGFR4） and two Chinese eGFR Investigation Collaboration equations （eGFR5, eGFR6）, and compared each other in the consistency with rGFR. Results The mean rGFR, CysC and Cr of development group were 44. 19 （3.51-166.00） ml/（ min ·1.73 m2 ）, 1.88 （0. 59-8.62） mg/L and 1.73 （O. 40-19.77 ） mg/dl, respectively. The mean rGFR, CysC and Cr of validation group were 47.85 （ 10.49-148. 12 ） ml/ （min ~ 1.73 m2） , 1.79（0. 66-7.22） mg/L and 1.56（0. 48-23.34） mg/dl, respectively. Two best-fit GFR estimation equations were established using nonlinear regression： eGFR7 = 173.9 × CysC-0. 725 x Cr-0.184 x Age -0.193 （ if female x 0. 89 ） （ R2 = 0. 734, P = O. 000 ）, and eGFR8 = 78.64 x CysC -0. 964 （ R2 = 0. 764, P = O. 000）. With Bland-Airman plot, Passing ＆ Bablok regression, and Mountain plot analysis, only the 95% agreement limits of eGFR7 and eGFR8, did not exceed the prior acceptable tolerances [ 〈 60 mL/（ rain ·1.73 m2 ） ] , and they did not show significant differences in proportional differences （ the 95% CI of slopes included B = 1 ） and constant differences （the 95% CI of intercepts included A = 0） comparied with rGFR, and their Mountain plots almost overlapped each other that indicated their basical agreement in GFR estimating effect. As compared with rGFR, the deviation of eGFR1, eGFR2, eGFR5 or eGFR6 was larger than of eGFR7 or eGFR8, especially eGFR3 and eGFR4 underestimated GFR overall. Conclusions It can provide an equal precision to estimate GFR using serum CysC alone or in combination with serum Cr. The agreement of GFR marker＇s measured method must be considered adequately before a literature eGFR equation was chosen. Otherwise, the eGFR value would have a large error, which may lead to misdiagnosis and mistreatment. （Chin J Lab Med,2013,36：352-359 ）