健康人新的GFR估算公式的建立及GFR随增龄下降危险因素分析
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摘要
背景与目的:肾脏是容易衰老的器官,肾功能随增龄逐渐减退。肾小球滤过率(GFR)是评价肾脏功能的理想指标。人群横断面和纵向随访研究显示40岁以后肌酐清除率随增龄以7.5-8ml/10年的速度下降。虽然肾小球滤过率随增龄下降已得到共识,但是既往研究对象仅排除了肾脏疾病,其中仍可能混杂有对肾脏功能具有潜在影响的未检出疾病。因此,健康人群GFR随增龄的变化及其相关因素并不完全清楚。目前虽然评价GFR的方法有多种,但没有完全适用于评估健康人GFR的方法。内生肌酐清除率:难以准确、完整收集尿液,受肾小管分泌肌酐的影响,存在系统高估GFR的风险,不推荐作为肾功能评价的指标。~(99m)Tc-DTPA肾动态显像:无需收集血、尿标本,操作简单、可反映肾脏血流量和分肾功能,临床应用方便。但影响因素较多,精确度不高。2003年K/DOQI指南建议采用肌酐基础上的MDRD公式和CG公式来估算GFR,由于两公式的研究人群都是CKD患者,因此在实际应用中并不适合于健康人群。北医改良的MDRD公式(c-a GFR)的精确度和准确性较原公式有所提高,但是在健康人中的适用性并不明确。因此,本研究以健康人群为研究对象,以双血浆法为参照标准,探寻适合健康人GFR的评估方法,分析健康人GFR随增龄变化的影响因素,为临床判断健康老年人的肾功能状态提供依据。拟从以下三方面开展研究:第一、评价目前5种GFR评估方法在健康人肾功能评价中的价值;第二、以双血浆法为参照建立新的健康人GFR估算公式;第三、纵向分析5年GFR下降的影响因素。
对象与方法:1.分别采用双血浆法和同位素肾动态显像测定144例北京地区社区健康居民GFR,同时计算Ccr,并采用CG公式、MDRD公式和改良的MDRD公式估算GFR,以双血浆GFR为参照评价5种GFR评估方法在健康人中的价值。2.新的健康人GFR估算公式的建立:以双血浆法测定144例健康人GFR为因变量,以同位素肾动态显像GFR为自变量,建立两者间的换算公式。同时以性别、年龄、血肌酐、尿素、胱抑素C、体表面积为自变量,双血浆GFR为因变量,采用多元线性回归最小二乘法,分别建立以肌酐、胱抑素C和肌酐联合胱抑素C的GFR估算公式。最后对新建公式进行初步评价。3.GFR随增龄下降的影响因素:收集研究人群2004年的基线资料和随访5年2009年的资料,分别采用CG公式、简化的MDRD公式和改良的MDRD公式以及新建方程4(血酐联合胱抑素C)计算2004年和2009年GFR,△GFR(ml/min.1.7 3m~2)=2009年GFR-2 004年GFR,如果△GFR＜0则提示GFR下降。以△GFR为因变量,基线指标为自变量,采用多元线性回归模型进一步分析GFR下降的影响因素。
结果:
1.(1)Ccr、CG GFR、T c GFR、a GFR、和c-a GFR5的偏差分别是0.11、-13.57、-6.11、-8.89和-3.64 ml/min.1.73m~2,除Ccr外CG GFR、T c GFR、a GFR、和c-a GFR5均低估GFR。(2)Ccr、CG GFR、T c GFR、a GFR、和c-aGFR5的精确度分别是24.5、26.2、17.5、12.9和11.8 ml/min.1.7 3m~2;准确性依次为24.7%、19.3%、16.7%、16.1%和14.9%;30%的相对准确性为70.1%、85.4%、81.9%、90.2%和90.2%。(3)以60 ml/min.1.7 3m~2和90 ml/min.1.7 3m~2为截点,5种方法中CG GFR的曲线下面积最大,分别是0.897和0.856。
2.以双血浆法为标准建立了同位素肾动态显像的换算公式:女性:GFR=88.287+0.4 3×肾图GFR-0.634×年龄(r=0.727,r~2=0.529);男性:GFR=103.789+0.275×肾图GFR-0.645×年龄(r=0.6 01,r~2=0.362)。分别利用肌酐、胱抑素C和肌酐联合胱抑素C的公式是:GFR=170.729-0.7 33×年龄-0.705×肌酐+14.01 6(男性)(r=0.714,r~2=0.509);GFR=146.64-0.665×年龄-28.225×胱抑素C(r=0.642,r~2=0.410)和GFR=172.5 38-0.595×年龄-0.631×肌酐-1 8.521×胱抑素C+1 2.942(男性)(r=0.728,r~2=0.5 30)。初步评价结果显示准确度、精确性较现有5种GFR评估公式提高。
3.GFR随增龄下降的影响因素:采用4种GFR评价方法分析GFR随增龄下降的影响因素所得结果并不完全相同。但是吸烟、收缩压是影响男性GFR下降的共同主要因素;而胱抑素C水平和女性GFR下降独立相关。
结论:
1.目前现有的5种GFR评价方法均不能正确评价健康人GFR。
2.新建立的4个GFR评估公式较现有公式更适合评价健康人GFR,需要临床进一步的验证。
3.影响GFR随增龄下降的因素存在性别差异,男女应区别对待。
Backgrounds and Objective:Kidneys are fragile organs subject to aging. Glomerular filtration rate(GFR)is a good indicator for evaluating renal function which declines with age.Cross-sectional studies and longitudinal study show that, for the persons over 40 years old,the creatinine clearance rate declines with age at a rate of 7.5 to 8 ml per 10 years.The decline of GFR with age has been recognized from studies which had excluded only overt kidney diseases,but not the potential undetected diseases that might still exert influence on GFR, Therefore,the variation of GFR with age of healthy individuals is not really clear yet.Currently,there are several methods for the evaluation of renal functions,but none has been proved to be perfect in healthy individuals.Creatinine clearance is the most frequently employed method,but urine collecting is cumbersome and susceptible to error.24-hour urine collection is no longer recommended for routine estimatation of kidney functions as the measurement of creatinine clearance is strongly influenced by urine output.As a simple and fast method, renal dynamic visualization with 99myc DTPA does not require blood and urine samples,and simultaneously provides information on renal functions.However, the clinical application of renal dynamic visualization is limited by its uncertainties due to various influencing factors.In 2003,K/DOQI guideline suggested that MDRD and CG formulae be adopted for the assessment of GFR. Nevertheless,the two formulae were obtained based on studies on CKD,and hardly applicable to healthy individuals.The modified MDRD formula in China has been found to be more accurate and precise than the MDRD one,but whether it is suitable for healthy individuals is unclear.
In this study,the GFR assessment of healthy individuals was performed with the double plasma method as a reference.The investigations were carried out on a group of northern Chinese.The report covers the following aspects:(1)assessing the performance of five available methods for GFR assessment in healthy individuals;(2)establishment of new formulae for estimating GFR based on the double plasma method;(3)risk analysis of the GFR decrease with age based on the longitudinal study.
Methods:
1.The GFR of 144 community-dwelling healthy adults were measured with dual plasma method and renal dynamic visualization of 99m Tc DTPA.Creatinine clearance was calculated with blood and urinary creatinine.GFR was estimated with Cockcroft-Gault equation,abbreviated MDRD equation and the modified MDRD equation as well.The performance of the five methods for GFR estimate was assessed with dual plasma method.
2.Establishment of new equations for the GFR determination of healthy individuals:the GFR measured with dual plasma method was used as the dependent variable,while the independent variables included sex,age,serum creatinine,urea,cystatin C and the body surface area.Multivariable linear regression model were used to establish new equations for renal assessment.At the same time,the equation with the dual plasma method and the renal dynamic visualization was established
3.Risk analysis of the decrease of GFR with age:the baseline and follow-up data of the study population were collected.GFR in 2004 and 2009 were estimated with Cockcroft-Gauit equation,abbreviated MDRD equation,the modified MDRD equation,and the newly established equation of GFR estimate.△GFR was calculated with 2009 GFR minus the 2004 GFR,and△GFR less than zero indictes GFR decline.Multiple linear regression model was used to analyze the risk factors of GFR decline with age,and△GFR being the dependent variable,and the baseline index the independent variable.
Results:
1.For Ccr,CG GFR,Tc GFR,aGFR,and c-a GFR,the bias were 0.11,13.57, -6.11,-8.89 and -3.64 ml/min.l.73m~2,respectively.All the GFR estimating methods underestimated GFR except Ccr.The precision for the five GFR estimating methods were 24.5,26.2,17.5,12.9 and 11.8 ml/min.1.73m~2, respectively.The accuracy and the 30%relative accuracy for Ccr,CG GFR,Tc GFR,a GFR and c-a GFR were 24.7%,19.3%,16.7%,16.1%and 14.9%,70.1%, 85.4%,81.9%,90.2%and 90.2%,respectively.The areas under the Receiver Operating Characteristic Curve(ROC)for CG GFR were the biggest as 0.897 and 0.856,respectively.
2.The new equation were established with renal dynamic visualization as follows:GFR=88.287+0.43×Tc GFR-0.634×age(r=0.727,r~2=0.529 )for female and GFR=103.789+0.275×Tc GFR-0.645×age(r=0.601,r~2=0.362)for male. The equations for creatinine,cystatin C,and the combination of both were GFR=170.729-0.733×age-0.705×Scr+14.016(male)(r=0.714, r~2=0.509);GFR=146.64-0.665×age-28.225×cystatin C(r=0.642, r~2=0.410)and GFR=172.538-0.595×age-0.631×Scr-18.521×cystatin C +12.942(male)(r=0.728,r~2=0.530).The performance of the newly established equations was better in the healthy individuals.
3.The associated factors for GFR decline with age:Although the associated factors were not the same for Cockcroft-Gault equation,abbreviated MDRD equation,the modified MDRD equation,and the newly established equation of GFR estimate,smoke and systolic pressure were associated with GFR decline with age in male,but cystatin C for female.
Conclusions:
1.The five GFR-estimating methods being used at present can not evaluate the GFR in healthy individuals perfectly.
2.The four newly established equations for GFR assessment were better than the GFR-estimating methods used at present,although further verification is still needed before application to clinical use.
3.The associated factors of GFR decline with age were different between the genders,which should be taken into consideration separately.
对象与方法:1.分别采用双血浆法和同位素肾动态显像测定144例北京地区社区健康居民GFR,同时计算Ccr,并采用CG公式、MDRD公式和改良的MDRD公式估算GFR,以双血浆GFR为参照评价5种GFR评估方法在健康人中的价值。2.新的健康人GFR估算公式的建立:以双血浆法测定144例健康人GFR为因变量,以同位素肾动态显像GFR为自变量,建立两者间的换算公式。同时以性别、年龄、血肌酐、尿素、胱抑素C、体表面积为自变量,双血浆GFR为因变量,采用多元线性回归最小二乘法,分别建立以肌酐、胱抑素C和肌酐联合胱抑素C的GFR估算公式。最后对新建公式进行初步评价。3.GFR随增龄下降的影响因素:收集研究人群2004年的基线资料和随访5年2009年的资料,分别采用CG公式、简化的MDRD公式和改良的MDRD公式以及新建方程4(血酐联合胱抑素C)计算2004年和2009年GFR,△GFR(ml/min.1.7 3m~2)=2009年GFR-2 004年GFR,如果△GFR＜0则提示GFR下降。以△GFR为因变量,基线指标为自变量,采用多元线性回归模型进一步分析GFR下降的影响因素。
结果:
1.(1)Ccr、CG GFR、T c GFR、a GFR、和c-a GFR5的偏差分别是0.11、-13.57、-6.11、-8.89和-3.64 ml/min.1.73m~2,除Ccr外CG GFR、T c GFR、a GFR、和c-a GFR5均低估GFR。(2)Ccr、CG GFR、T c GFR、a GFR、和c-aGFR5的精确度分别是24.5、26.2、17.5、12.9和11.8 ml/min.1.7 3m~2;准确性依次为24.7%、19.3%、16.7%、16.1%和14.9%;30%的相对准确性为70.1%、85.4%、81.9%、90.2%和90.2%。(3)以60 ml/min.1.7 3m~2和90 ml/min.1.7 3m~2为截点,5种方法中CG GFR的曲线下面积最大,分别是0.897和0.856。
2.以双血浆法为标准建立了同位素肾动态显像的换算公式:女性:GFR=88.287+0.4 3×肾图GFR-0.634×年龄(r=0.727,r~2=0.529);男性:GFR=103.789+0.275×肾图GFR-0.645×年龄(r=0.6 01,r~2=0.362)。分别利用肌酐、胱抑素C和肌酐联合胱抑素C的公式是:GFR=170.729-0.7 33×年龄-0.705×肌酐+14.01 6(男性)(r=0.714,r~2=0.509);GFR=146.64-0.665×年龄-28.225×胱抑素C(r=0.642,r~2=0.410)和GFR=172.5 38-0.595×年龄-0.631×肌酐-1 8.521×胱抑素C+1 2.942(男性)(r=0.728,r~2=0.5 30)。初步评价结果显示准确度、精确性较现有5种GFR评估公式提高。
3.GFR随增龄下降的影响因素:采用4种GFR评价方法分析GFR随增龄下降的影响因素所得结果并不完全相同。但是吸烟、收缩压是影响男性GFR下降的共同主要因素;而胱抑素C水平和女性GFR下降独立相关。
结论:
1.目前现有的5种GFR评价方法均不能正确评价健康人GFR。
2.新建立的4个GFR评估公式较现有公式更适合评价健康人GFR,需要临床进一步的验证。
3.影响GFR随增龄下降的因素存在性别差异,男女应区别对待。
Backgrounds and Objective:Kidneys are fragile organs subject to aging. Glomerular filtration rate(GFR)is a good indicator for evaluating renal function which declines with age.Cross-sectional studies and longitudinal study show that, for the persons over 40 years old,the creatinine clearance rate declines with age at a rate of 7.5 to 8 ml per 10 years.The decline of GFR with age has been recognized from studies which had excluded only overt kidney diseases,but not the potential undetected diseases that might still exert influence on GFR, Therefore,the variation of GFR with age of healthy individuals is not really clear yet.Currently,there are several methods for the evaluation of renal functions,but none has been proved to be perfect in healthy individuals.Creatinine clearance is the most frequently employed method,but urine collecting is cumbersome and susceptible to error.24-hour urine collection is no longer recommended for routine estimatation of kidney functions as the measurement of creatinine clearance is strongly influenced by urine output.As a simple and fast method, renal dynamic visualization with 99myc DTPA does not require blood and urine samples,and simultaneously provides information on renal functions.However, the clinical application of renal dynamic visualization is limited by its uncertainties due to various influencing factors.In 2003,K/DOQI guideline suggested that MDRD and CG formulae be adopted for the assessment of GFR. Nevertheless,the two formulae were obtained based on studies on CKD,and hardly applicable to healthy individuals.The modified MDRD formula in China has been found to be more accurate and precise than the MDRD one,but whether it is suitable for healthy individuals is unclear.
In this study,the GFR assessment of healthy individuals was performed with the double plasma method as a reference.The investigations were carried out on a group of northern Chinese.The report covers the following aspects:(1)assessing the performance of five available methods for GFR assessment in healthy individuals;(2)establishment of new formulae for estimating GFR based on the double plasma method;(3)risk analysis of the GFR decrease with age based on the longitudinal study.
Methods:
1.The GFR of 144 community-dwelling healthy adults were measured with dual plasma method and renal dynamic visualization of 99m Tc DTPA.Creatinine clearance was calculated with blood and urinary creatinine.GFR was estimated with Cockcroft-Gault equation,abbreviated MDRD equation and the modified MDRD equation as well.The performance of the five methods for GFR estimate was assessed with dual plasma method.
2.Establishment of new equations for the GFR determination of healthy individuals:the GFR measured with dual plasma method was used as the dependent variable,while the independent variables included sex,age,serum creatinine,urea,cystatin C and the body surface area.Multivariable linear regression model were used to establish new equations for renal assessment.At the same time,the equation with the dual plasma method and the renal dynamic visualization was established
3.Risk analysis of the decrease of GFR with age:the baseline and follow-up data of the study population were collected.GFR in 2004 and 2009 were estimated with Cockcroft-Gauit equation,abbreviated MDRD equation,the modified MDRD equation,and the newly established equation of GFR estimate.△GFR was calculated with 2009 GFR minus the 2004 GFR,and△GFR less than zero indictes GFR decline.Multiple linear regression model was used to analyze the risk factors of GFR decline with age,and△GFR being the dependent variable,and the baseline index the independent variable.
Results:
1.For Ccr,CG GFR,Tc GFR,aGFR,and c-a GFR,the bias were 0.11,13.57, -6.11,-8.89 and -3.64 ml/min.l.73m~2,respectively.All the GFR estimating methods underestimated GFR except Ccr.The precision for the five GFR estimating methods were 24.5,26.2,17.5,12.9 and 11.8 ml/min.1.73m~2, respectively.The accuracy and the 30%relative accuracy for Ccr,CG GFR,Tc GFR,a GFR and c-a GFR were 24.7%,19.3%,16.7%,16.1%and 14.9%,70.1%, 85.4%,81.9%,90.2%and 90.2%,respectively.The areas under the Receiver Operating Characteristic Curve(ROC)for CG GFR were the biggest as 0.897 and 0.856,respectively.
2.The new equation were established with renal dynamic visualization as follows:GFR=88.287+0.43×Tc GFR-0.634×age(r=0.727,r~2=0.529 )for female and GFR=103.789+0.275×Tc GFR-0.645×age(r=0.601,r~2=0.362)for male. The equations for creatinine,cystatin C,and the combination of both were GFR=170.729-0.733×age-0.705×Scr+14.016(male)(r=0.714, r~2=0.509);GFR=146.64-0.665×age-28.225×cystatin C(r=0.642, r~2=0.410)and GFR=172.538-0.595×age-0.631×Scr-18.521×cystatin C +12.942(male)(r=0.728,r~2=0.530).The performance of the newly established equations was better in the healthy individuals.
3.The associated factors for GFR decline with age:Although the associated factors were not the same for Cockcroft-Gault equation,abbreviated MDRD equation,the modified MDRD equation,and the newly established equation of GFR estimate,smoke and systolic pressure were associated with GFR decline with age in male,but cystatin C for female.
Conclusions:
1.The five GFR-estimating methods being used at present can not evaluate the GFR in healthy individuals perfectly.
2.The four newly established equations for GFR assessment were better than the GFR-estimating methods used at present,although further verification is still needed before application to clinical use.
3.The associated factors of GFR decline with age were different between the genders,which should be taken into consideration separately.
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1.Grubb A,Simonsen O,Sturfelt G et al.Serum concentration of cystatin C,factor D and beta 2-microglobulin as a measure of glomerular filtration rate.Acta Med Scand.1985,218(5):499-503.
2.Simonsen O,Grubb A,Thysell H.The blood serum concentration of cystatin C(gamma-trace)as a measure of the glomerular filtration rate.Scand J Clin Lab Invest.1985,45(2):97-101.
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8.Gates GF.Glomerular filtration rate:estimation from fractional renal accumulation of 99mTc-DTPA(stannous).AJR Am J Roentgenol.1982,138(3):565-570.
9.Frennby B,Almen T,Lilja B,et al.Determination of the relative glomerular filtration rate of each kidney in man.Comparison between iohexol CT and 99mTc-DTPA scintigraphy.Acta Radiol.1995,36(4):410-417.
10.Jensen G.Renovascular hypertension.New diagnostic and therapeutic procedures.Scand J Urol Nephrol Suppl.1995,170:1-78.
11.Sobh M,Neamatallah A,Sheashaa H,et al.Gad H.Sobh formula:a new formula for estimation of creatinine clearance in healthy subjects and patients with chronic renal disease.Int Urol Nephrol.2005,37(2):403-408.
12.Itoh K,Tsushima S,Tsukamoto S,et al.Comparison of methods for determination of glomerular filtration rate:99mTc-DTPA renography,predicted creatinine clearance method and plasma sample method.Ann Nucl Med.2003,7:561-565.
13.Levey AS,Greene T,Kusek J,et al.Group MS.A simplified equation to predict glomerular filtration rate from serum creatinine.J Am Soc Nephrol.2000,11:A0828(abstract).
14.Ma YC,Zuo L,Zhang CL,et al.Comparison of 99mTc-DTPA renal dynamic imaging with modified MDRD equation for glomerular filtration rate estimation in Chinese patients in different stages of chronic kidney disease.Nephrol Dial Transplant.2007,22(2):417-423.
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