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      Validation of Neutron Activation as a Novel Method to Determine Glomerular Filtration Rate

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          Background/Aims: Despite widespread interest in determining the glomerular filtration rate (GFR) of patients, current methods all have significant limitations. Therefore, a compelling need exists for new tests of GFR that are both accurate and easy to perform. We have previously reported that the technique of neutron activation (NA) accurately measures iohexol in vitro. In this study, we demonstrate that NA can be used to determine GFR by measuring the clearance of iohexol, and directly compare these results to a gold-standard method based on <sup>99m</sup>Tc-DTPA. Methods: We studied 57 patients with mild to moderate chronic kidney disease and normal volunteers. Subjects were simultaneously injected with iohexol and <sup>99m</sup>Tc-DTPA. Blood and urine samples were collected over 4 h to calculate GFR by the UV/P method. Results: The range of GFRs was 28–212 ml/min. GFRs obtained using iohexol and <sup>99m</sup>Tc-DTPA correlated closely (R = 0.95). The bias between the 2 techniques was 0.96 ml/min, and precision (defined as the standard deviation of the mean of the difference between the 2 values for each patient) was 10.6 ml/min. Accuracy was such that 98% of subjects had NA GFRs within 20% of the reference <sup>99m</sup>Tc-DTPA measurements. Conclusions: We conclude that NA is an excellent technique to measure GFR. NA has several advantages over current methods to directly measure GFR, including the ability to reassay samples, high throughput and the avoidance of patient and hospital radioactivity exposure. In the future, NA could be applied to GFR agents that do not contain iodine, such as Gd-DTPA, and to the simultaneous measurement of agents that reflect renal blood flow, such as iodohippurate. Therefore, NA holds great potential to improve the measurement of renal function in a safe, easily obtainable way.

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          Most cited references 13

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          Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate.

          Equations using serum creatinine level, age, sex, and other patient characteristics often are used to estimate glomerular filtration rate (GFR) in both clinical practice and research studies. However, the critical dependence of these equations on serum creatinine assay calibration often is overlooked, and the reproducibility of estimated GFR is rarely discussed. We address these issues in frozen samples from 212 Modification of Diet in Renal Disease (MDRD) study participants and 342 Third National Health and Nutrition Examination Survey (NHANES III) participants assayed for serum creatinine level a second time during November 2000. Variation in serum creatinine level was assessed in 1,919 NHANES III participants who had serum creatinine measured on two visits a median of 17 days apart. Linear regression was used to compare estimates. Calibration of serum creatinine varied substantially across laboratories and time. Data indicate that serum creatinine assays on the same samples were 0.23 mg/dL higher in the NHANES III than MDRD study. Data from the College of American Pathologists suggest that a difference of this magnitude across laboratories is not unusual. Conversely, serum creatinine assays an average of 2 weeks apart have better precision (SD of percentage of difference in estimated GFR, 15%; 90% of estimates within 21%). Errors in calibration make little difference in estimating severely decreased GFR (<30 mL/min/1.73 m2), but result in progressively larger differences at higher GFRs. Both clinical and research use of serum creatinine or equations to estimate GFR require knowledge of the calibration of the serum creatinine assay. Copyright 2002 by the National Kidney Foundation, Inc.
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            Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease.

            The performance of the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault (CG) equations as compared with measured (125)I-iothalamate GFR (iGFR) was analyzed in patients with chronic kidney disease (CKD) and in potential kidney donors. All outpatients (n = 1285) who underwent an iGFR between 1996 and 2003 were considered for analysis. Of these, 828 patients had CKD and 457 were potential kidney donors. Special emphasis was put on the calibration of the serum creatinine measurements. In CKD patients with GFR <60 ml/min per 1.73 m(2), the MDRD equation performed better than the CG formula with respect to bias (-0.5 versus 3.5 ml/min per 1.73 m(2), respectively) and accuracy within 30% (71 versus 60%, respectively) and 50% (89 versus 77%, respectively). Similar results are reported for 249 CKD patients with diabetes. In the kidney donor group, the MDRD equation significantly underestimated the measured GFR when compared with the CG formula, with a bias of -9.0 versus 1.9 ml/min per 1.73 m(2), respectively (P < 0.01), and both the MDRD and CG equations overestimated the strength of the association of GFR with measured serum creatinine. The present data add further validation of the MDRD equation in outpatients with moderate to advanced kidney disease as well as in those with diabetic nephropathy but suggest that its use is problematic in healthy individuals. This study also emphasizes the complexity of laboratory calibration of serum creatinine measurements, a determining factor when estimating GFR in both healthy individuals and CKD patients with preserved GFR.
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              A comparison of prediction equations for estimating glomerular filtration rate in adults without kidney disease.

              The ability of the Modification of Renal Disease (MDRD) equation to predict GFR when compared with multiple other prediction equations in healthy subjects without known kidney disease was analyzed. Between May 1995 and December 2001, a total of 117 healthy individuals underwent (125)I-iothalamate or (99m)Tc-diethylenetriamine-pentaacetic acid (DTPA) renal studies as part of a routine kidney donor evaluation at either Brigham and Women's Hospital or Boston Children's Hospital. On chart review, 100 individuals had sufficient data for analysis. The MDRD 1, MDRD 2 (simplified MDRD equation), Cockcroft-Gault (CG), Cockcroft-Gault corrected for GFR (CG-GFR), and other equations were tested. The median absolute difference in ml/min per 1.73 m(2) between calculated and measured GFR was 28.7 for MDRD 1, 18.5 for MDRD 2, 33.1 for CG, and 28.6 for CG-GFR in the (125)I-iothalamate group and was 31.1 for MDRD 1, 38.2 for MDRD 2, 22.0 for CG, and 31.1 for CG-GFR in the (99m)Tc-DTPA group. Bias was -0.5, -3.3, 25.6, and 5.0 for MDRD 1, MDRD 2, CG, and CG-GFR, respectively, in subjects who received (125)I-iothalamate and -33.2, -36.5, 6.0, and -15.0 for MDRD 1, MDRD 2, CG, and CG-GFR, respectively, in those who received (99m)Tc-DTPA studies. Precision testing, as measured by linear regression, yielded R(2) values of 0.04 for CG, 0.05 for CG-GFR, 0.15 for MDRD 1, and 0.14 for MDRD in those who underwent (125)I-iothalamate studies and 0.18 for CG, 0.21 for CG-GFR, 0.40 for MDRD 1, and 0.38 for MDRD 2 for those who underwent (99m)Tc-DTPA studies. The MDRD equations were more accurate within 30 and 50% of the measured GFR compared with the CG and CG-GFR equations. When compared with the CG equation, the MDRD equations are more precise and more accurate for predicting GFR in healthy adults. The MDRD equations, however, consistently underestimate GFR, whereas the CG equations consistently overestimate measured GFR in people with normal renal function. In potential kidney donors, prediction equations may not be sufficient for estimating GFR; radioisotope studies may be needed for a better assessment of GFR. Further studies are needed to derive and assess GFR prediction equations in people with normal or mildly impaired renal function.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                November 2007
                16 October 2007
                : 107
                : 3
                : c117-c122
                aUMassMemorial Medical Center, bBeth Israel Deaconess Medical Center, and cBioPal Inc., Boston, Mass., USA
                109820 Nephron Clin Pract 2007;107:c117–c122
                © 2007 S. Karger AG, Basel

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                Figures: 3, Tables: 1, References: 29, Pages: 1
                Original Paper


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