The prevalence of ESRD is rapidly increasing in the adult

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1 Clinical Science Articles Estimating Pediatric Glomerular Filtration Rates in the Era of Chronic Kidney Disease Staging Andre Mattman,* Shaun Eintracht,* Thomas Mock,* Geraldine Schick, David W. Seccombe, Robert Morrison Hurley, and Colin Thomas White *Laboratory Medicine and Division of Nephrology, Department of Pediatrics, British Columbia s Children s and Women s Hospital, Canadian External Quality Assessment Laboratory, Department of Pathology and Laboratory Medicine, and Faculty of Medicine, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada With the use of information from a database of pediatric patients with concomitant nuclear GFR and serum creatinine (Cr), estimated GFR equations were derived on the basis of local laboratory methods and population. These formulas then were compared with those recommended by the National Kidney Foundation for estimating GFR in children. For this, their ability to estimate accurately an individual s true GFR and chronic kidney disease stage, identify patients whose true GFR was <60 ml/min per 1.73 m 2, and to identify correctly deterioration in an individual s GFR over time was compared. Next, two methods to estimate GFR in children without the use of height or weight were developed. The first was a height- and weightindependent formula; the second was a novel approach using the Schwartz formula and calculating a Cr cutoff based on age-based estimates of height and GFR level of interest, i.e., <60 ml/min per 1.73 m 2. Our results suggest that if local laboratory constants are derived and a height is known, then the Schwartz formula offers the most accuracy with least mathematical complexity to perform in the clinical setting. If height is not available but the local laboratory constants have been derived, then the British Columbia s Children s Hospital 2 formula is of value; however, in the setting of estimating pediatric renal function in the outpatient laboratory, where neither of these factors is commonly known, an approach whereby a Cr cutoff for a GFR of interest is developed is suggested. Provided are Cr levels that are based on a reference method of Cr measurement to facilitate this approach for the clinician. J Am Soc Nephrol 17: , doi: /ASN Received January 10, Accepted November 1, Published online ahead of print. Publication date available at A.M. and S.E. contributed equally to this work. Address correspondence to: Dr. Colin White, British Columbia s Children s Hospital, Division of Nephrology, 4480 Oak Street, ACB K4-151, Vancouver, British Columbia, Canada, V6H 3V4. Phone: ; Fax: ; cwhite@cw.bc.ca The prevalence of ESRD is rapidly increasing in the adult population, with 1 million people affected worldwide by the end of 2001 (1) and at a cost to the North American ESRD programs of $25.2 billion in 2002 (2). The National Kidney Foundation (NKF) has recognized that to further improve dialysis outcomes, it is necessary to improve the health status of those who reach ESRD... from earliest kidney damage through the various stages of progression to kidney failure (3). As a first step toward achieving this goal, the NKF developed a chronic kidney disease (CKD) classification system, the NKF Disease Outcomes Quality Initiative (NKF-DOQI) classification, to improve/standardize care of the patient at all stages of CKD (3). In the adult nephrology literature, a move toward classification and management of CKD on the basis of GFR has led to the proposal for widespread implementation of equations to calculated estimated GFR (egfr) (4). These equations are often derived from studies in patients with particular illnesses, e.g., cancer (5,6), renal dysfunction (7,8), and organ transplantation (9 11). They use some combination of easily obtained demographics (e.g., height, weight, gender, race) and serum measurements (e.g., creatinine [Cr], urea, albumin) (12) to calculate the individual s GFR or Cr clearance. Similarly, the pediatric members of the NKF CKD working group clearly stated that major emphasis is placed on the identification of children and adolescents with CKD by measuring the protein-to-cr ratio in spot urine specimens and by estimating the GFR from serum Cr using prediction equations (13). Recognizing that egfr would play a vital role in the new CKD classification, the NKF reviewed the published literature on formulas to determine which were most accurate and clinically applicable. In adults, the formulas suggested were the Modification of Diet in Renal Disease (MDRD) formulas by Levey et al. (12) or the Cockcroft-Gault formula (CG) (14). In pediatrics, they recommended using either the Schwartz (15), or the Counahan-Barratt (CB) formulas (16) for estimating GFR (13). Although recommended by the NKF, both the Schwartz and the CB formulas do have clinically important limitations. For example, a recent study that evaluated an optimized form of Copyright 2006 by the American Society of Nephrology ISSN: /

2 488 Journal of the American Society of Nephrology J Am Soc Nephrol 17: , 2006 the Schwartz equation against a concurrent iothalamate GFR showed that the SD of the difference of these two methods was approximately 10 ml/min per 1.73 m 2 ; in other words, the relative error of the GFR (as defined as 2 SD) estimated by the Schwartz formula approximated 20 ml/min per 1.73 m 2 (8). For a GFR of 75 ml min per 1.73 m 2, this degree of uncertainty encompasses a wide range of GFR values from 60 to 90 ml/min per 1.73 m 2, or CKD stages 1 to 3. These relative errors will be substantially higher when Cr calibration differences from laboratory to laboratory are not corrected (12). A second limitation of these egfr formulas in pediatrics is the requirement for both a height and a serum Cr measurement. Height is not readily available or verifiable in the clinical laboratories that obtain the blood sample and report the Cr results, thus discouraging the routine application of GFR estimation equations to the pediatric population. With these limitations of pediatric egfr formulas in mind, the goals of this study were to (1) derive egfr equations based on our local laboratory methods and patient population; (2) compare these formulas with those recommended by the NKF for use in estimating GFR in children as related to each formula s ability to (a) accurately estimate an individuals true GFR, (b) correctly identify the patient whose true GFR was 60 ml/min per 1.73 m 2, and (c) assess the ability of each formula to identify correctly a deterioration of an individuals GFR over time; and finally (3) develop a height- and weight-independent method for estimating GFR in children and identifying those who are at risk for having significant renal dysfunction. Materials and Methods We undertook a retrospective review of data on all patients who were referred to the British Columbia s Children s Hospital (BCCH) nephrology service over the 5-yr period from 1998 to 2003 and had both a two-point single injection of technetium-99m-diethylenetriaminepentaacetic acid ( 99m Tc-DTPA) nuclear GFR measurement (ngfr) and a serum Cr measurement (enzymatic Cr method; Vitros 950/250) within 1 d of each other. During this period, there was no change in either the laboratory or nuclear medicine equipment or protocols used. All studies were performed during the regular care or investigation of the patient, and the vast majority was done on an outpatient basis. The ngfr was considered to be the patient s true GFR. This study received approval from the University of British Columbia ethics review board. Patients The data set consisted of 267 unique patients with a total of 473 observations. Of these, 116 patients had multiple database entries, accounting for 206 of the 473 observations. Each observation included the patient s height, weight, diagnosis, Cr, age, gender, and ngfr. One infant who was younger than 1 yr was excluded from the study, leaving a total of 266 patients (472 observations). The patient demographics are summarized in Table 1, and diagnoses are summarized in Table 2. Derivation of Local Formulas To derive our local egfr formulas, we used the first available set of paired ngfr and Cr measurements for each patient (n 266) and randomly assigned them between a modeling (n 180) and a validation group (n 86). There were no statistically significant differences between the modeling and validation groups with respect to mean age, ngfr, serum Cr, height, or weight. The derivation of all formulas and constants was performed using only the modeling group s data, whereas the validation group data were used to compare each formula in terms of accuracy, ability to identify CKD staging, and ability to identify patients with a GFR 60 ml/min per 1.73 m 2. The only exception to this is in the data on the serial egfr, for which the various formulas were applied to all patients, irrespective of original group, with two or more ngfr. Two novel egfr formulas were subsequently developed using data from the modeling group. The first (BCCH1) was developed using a linear regression of the patient data (aside from diagnosis) onto ngfr (ml/min per 1.73 m 2 ). Forward stepwise regression was used to narrow down a list of candidate variables. For the BCCH1 formula, these variables included weight, height, age, presence of nephrotic syndrome, gender, inverse of Cr and inverse of Cr squared, age height, age/cr, height/cr, gender age, and gender/cr. The second formula (BCCH2) was derived using only easily available demographic variables: the inverse of Cr, age, and gender. Model selection was based on the Akaike Information Criterion (S-plus Statistical Software, Seattle, WA) (17). Akaike Information Criterion selection serves to optimize the Table 1. Patient demographics a Modeling Group Validation Group Cohort with Repeat ngfr Measurements Total patients Mean age at initial ngfr (yr range ) 10.5 (1.1 to 19.4) 10.4 (1.93 to 19.7) 11.4 (3.1 to 19.2) Median age at initial ngfr (yr) Gender male female Mean ngfr (ml/min per 1.73 m 2 SD ) 97.5 (44) 93 (38) 88 (43) % of group with GFR of 30, 30 to 59, 5, 15, 23, 56 6, 14, 33, 48 4, 21, 36, to 89, and 90 ml/min per 1.73 m 2 Mean creatinine ( mol/l SD ) 71 (43) 71 (41) 84 (57) Mean height (cm SD ) 137 (27) 136 (28) 141 (24) Mean weight (kg SD ) 38 (20) 40 (25) 42 (22) a ngfr, nuclear GFR.

3 J Am Soc Nephrol 17: , 2006 Pediatric CKD and egfr 489 Table 2. Patient diagnoses for model and validation groups a Diagnostic Category Modeling Group Validation Group Urinary tract disorders dysplasias FSGS 0 1 MCNS 18 8 Glomerular disease (other) 18 5 Tubular disease Systemic diseases 22 6 Reflux nephropathy 19 7 Hypertension 5 3 Hematuria or proteinuria 9 2 CRF 8 1 Transplant 2 3 Other Total a FSGS, focal segmental glomerulosclerosis; MCNS, minimal-change nephrotic syndrome; CRF, chronic renal failure. accuracy of the modeled equation while minimizing the number of included covariates. Comparison with Published Formulas Including our two locally derived equations, BCCH 1 and 2, we compared a total of seven previously published formulas with respect to their performance in estimating the true or measured GFR. These formulas included those suggested by the NKF, e.g., Schwartz, Counahan-Barratt, CG, as well as one of the abbreviated forms of the MDRD formulas (amdrd) (12) and the more recent pediatric-derived formula proposed by Leger et al. (18) (Table 3). Of note, the adult-derived amdrd equation has never been recommended for use in the population under 18 yr of age. We included this formula in our comparison studies only for the sake of completeness. To compare fairly the accuracy of these formulas, we empirically developed constants to correct for our local laboratory Cr method. These constants were developed by iteratively changing the constant associated with the Cr variable to minimize the mean relative error between the given egfr formula and the ngfr measurement within the model group. The constants and the optimized forms of the established egfr formulas are listed in Table 3; all references to any egfr formulas from this point on can be assumed to mean the locally optimized form of that equation and may be designated by a preceding o ; for example, osch would be read as the optimized form of the Schwartz equation. The statistical comparison of the egfr formulas consisted of evaluation of Pearson correlation coefficients, determination of the mean and SD of the relative error [100 (egfr ngfr)/average (egfr, ngfr)] and the mean absolute value of the relative error [100 (egfr ngfr) /average (egfr, ngfr)]. We also compared the respective egfr formulas with respect to the proportion of egfr results that agreed within 30% of the matched ngfr result. Overall accuracy of the formulas in terms of CKD staging was based on achieving concordance with the true CKD staging as determined by ngfr. Sensitivity and specificity of each formula in terms of correctly identifying a patient with a true GFR 60 ml/min per 1.73 m 2 also were calculated. As NKF-DOQI CKD staging in pediatrics has been recommended only for the population older than 2 yr, children who were between 1 and 2 yr of age were dropped from the validation group, leaving n 83 for these latter comparisons (13). Table 3. egfr formulas: Accuracy versus nuclear GFR a Optimized egfr Formula (ml/min per 1.73 m 2 ) Pearson Correlation Coefficient Absolute Error b (%) Mean Relative Error c (%) Mean 5th to 95th Percentile of Relative Error (%) BCCH to 39 BCCH to 55 Schwartz k height/cr (for girls and boys to yr); k p 48.6; k o 38 Schwartz k height/cr (for boys 13 yr); to 31 k p 61.9; k o 44 CB k height/cr; k p 38; k o to 32 Leger k { (56.7 weight) (0.142 (height 2 ) /Cr}; to 50 k p 1; k o 1.17 CG k { (140 age) weight /(0.814 Cr)} to 45 (1.73/BSA) 0.85 if female; k p 1; k o 0.68 amdrd k 186 (Cr/88.4) (age ) if female; k p 1; k o to 90 a egfr, estimated GFR; BCCH, British Columbia s Children s Hospital; Cr, creatinine in mol/l; BSA, body surface area expressed in units of 1.73 m 2 ; k, constant for each formula where, k p refers to the previously published value for the constant and k o refers to our laboratory-specific optimized value; CB, Counahan-Barratt; CG, Cockcroft-Gault; amdrd, abbreviated Modification of Diet in Renal Disease. Height is in cm; weight is in kg; age is in years. b Absolute value of the relative error (%); c Relative error 100 (egfr ngfr)/average (egfr, ngfr) (%).

4 490 Journal of the American Society of Nephrology J Am Soc Nephrol 17: , 2006 Serial GFR We subsequently analyzed data on 116 patients with two or more paired measurements of Cr and ngfr (206 repeat measurements). We determined the change in the ngfr between the initial and the final measurements in the database and evaluated the sensitivity and the specificity of the egfr formulas in correctly identifying a 30% decrease in ngfr. The 30% decrease in ngfr was chosen arbitrarily in recognition that accuracy within this percentage was deemed acceptable by the NKF-DOQI CKD workgroup when they evaluated and recommended the various egfr formulas (19). The time interval between the first and final measurements averaged 2.2 yr (range 0.3 to 4.1 yr). Height- and Weight-Independent GFR Estimation We evaluated two separate height- and weight-independent GFR estimation methods. The first was the BCCH 2 formula as described above. The second and, we believe, novel approach was that of defining GFR-specific Cr cutoffs and was designed for use in pediatric laboratory reporting of egfr. For example, to identify patients with a GFR 60 ml/min per 1.73 m 2, we determined the Cr value, based on our locally optimized Schwartz formula, above which a child of that age and gender would have an egfr 60 ml/min per 1.73 m 2. In other words, we took the Schwartz formula (15) egfr k Ht/serum Cr, which can be rearranged as serum Cr k Ht/eGFR, derived the k value locally, used an age- and gender-based estimate for the height, and then set the egfr to the value of interest, e.g., 60 ml/min per 1.73 m 2. This approach requires an age- and gender-specific estimation of height; we chose to use the third percentile value for age/gender as defined in the current Centre for Disease Control published growth curves (using the height of a child at the 97th percentile means the Cr cutoffs as generated would represent an egfr between 72 and 74 ml/min per 1.73 m 2 depending on the age and the gender of the child). We compared the results achieved by using these newly derived cutoff values, in terms of their ability to identify correctly patients whose ngfr was 60 ml/min per 1.73 m 2, with those achieved when using the optimized Schwartz equation (15). To enable other laboratories to make use of our Cr cutoff values, we converted these Vitros Cr values into equivalent values on the basis of a reference Cr method that measures Cr via isotope dilution gas chromatography/mass spectrometry (20,21). A conversion equation was developed from data obtained through a provincial external quality assurance program for Cr clinical laboratory Cr measurements. This program has been operating for the past 3 yr and includes 38 participating laboratories with either a Vitros 250 (n 28) or a Vitros 950 (n 10) Cr method. During a 6-mo period, each laboratory measured Cr levels in six different samples ranging in concentration from 37 to 132 mol/l. Reference values for these samples were obtained by quadruplicate measurements of the same samples with the reference method (20,21). This comparison study yielded a conversion equation of the form Vitros 250/950 (Cr) ( reference value Cr) All comparative statistics were performed with the software SPSS for Windows release (SPSS, Chicago, IL). Results Derivation of Local Formulas Two novel pediatric egfr equations were developed and are described below. The first equation, BCCH1, describes a quadratic relationship between the Ln (egfr) and the inverse of the Cr measurement. Height is a prominent factor in the equation, whereas weight has a more minor but still significant effect. Age, gender, and the presence or absence of the nephrotic syndrome did not have an impact on the final equation. The second equation, BCCH2, makes use of Cr, age, and gender variables only. BCCH1: Ln(eGFR) (ml/min per 1.73 m 2 ) 1.18 ( Wt [kg]) (0.01 Ht [cm]) [(149.5/Cr) (2141/Cr 2 )] BCCH2: egfr (ml/min per 1.73 m 2 ) [5886 (1/Cr)] (4.83 age [years]) (if male) Comparison with Published Formulas Using data from the validation group, all egfr formulas were compared as outlined below. However, other than in the cohort of patients who were older than 15 yr (n 22), the adult-derived amdrd (12) formula performed significantly worse than any other formula evaluated. All egfr formulas, except the amdrd, produced values that were significantly correlated with the ngfr values (P 0.005, one tailed significance; Table 3). The Sch (15) and BCCH1 formulas had the strongest correlations (r 0.83) followed by the CB (16) (r 0.79), Leger (18) (r 0.74), CG (14) (r 0.73), BCCH2 (r 0.72), and amdrd (r 0.31). The Schwartz formula, after optimization, was the most accurate formula evaluated, with an absolute percentage error of %, followed by the BCCH1 at % and the CB at %. The BCCH2 formula, with a percentage error of % and two outliers, CG formula with % and one outlier, and the Leger formulas with an absolute percentage error of and one outlier all yielded much poorer results. The amdrd formula was by far the least accurate, with a percentage error of % (Table 3, Figure 1). As a result of the optimization process that was applied to Figure 1. Absolute value of the relative errors for estimated GFR (egfr) formulas. The y axis represents the percentage absolute value of the relative error of the egfr formulas (%). The thick central line indicates the mean absolute value of the relative error, the solid box indicates the 25th to 75th percentiles, and the error bars indicate the 2.5th to 97.5th percentiles, respectively. The outliers (E) represent values that are 1.5 times the interquartile range above the 75th percentile.

5 J Am Soc Nephrol 17: , 2006 Pediatric CKD and egfr 491 Figure 2. Bland-Altmann plots for nuclear medicine GFR versus British Columbia s Children s Hospital 1 (BCCH1) (a), BCCH2 (b), osch (c), and ocb (d) egfr formulas, respectively. The solid line indicates the mean and the dashed lines indicate 2 SD for the relative difference between nuclear GFR (ngfr) and the respective egfr formulas. each equation, all egfr formulas had a mean relative error that was close to and evenly distributed around zero; however, the confidence limits for the relative error for all formulas tested were broad (Table 3), with the minimal 90% confidence limits for any formula tested being 30 to 39% for the BCCH1 egfr formula (Table 3). Figure 2 demonstrates distribution of the relative error according to the GFR for the BCCH1, BCCH2, optimized Schwartz, and CB formulas. In terms of the percentage of optimized egfr results within 30% of the ngfr, this value ranged from as low as 35% for the amdrd formula to 83% for the BCCH1 formulas (Figure 3). Concordance with CKD Stage Table 4 outlines the concordance rates, both exact stage and within one stage, for the egfr formulas. The BCCH 1 and 2, osch, and ocb formulas all performed similarly with a same stage concordance ranging from 67 to 71% and within one stage concordance of 100%. Identification of a Patient with GFR 60 ml/min per 1.73 m 2 The relative sensitivity and specificity of the egfr formulas for identifying an ngfr 60 ml/min per 1.73 m 2 are summarized in Table 4. Aside from the BCCH2 and the amdrd, all other formulas achieved a sensitivity of 86%. All formulas, aside from that of Leger (88%) and the amdrd (75%), achieved a specificity of 96%. Serial Changes in GFR Altogether, 206 follow-up measurements were performed on the 116 patients who were older than 5 yr. Figure 4 illustrates the relative change in the osch GFR (Sch final Sch initial )/ Sch initial versus the relative change in the ngfr (ngfr final ngfr initial )/ngfr initial. A decrease of 30% or more in the osch egfr had a sensitivity of 63%, specificity of 96%, a positive predictive value (PPV) of 56%, and a negative predictive value (NPV) of 97% in detecting a clinically significant 30% deterioration in the ngfr. These results are compared with the performance of the other egfr formulas in Table 5. Figure 3. Agreement between egfr values and the ngfr values for patients in the validation group. Height- and Weight-Independent GFR Estimation As current pediatric egfr formulas all require height or weight data, they are not adapted easily for use in an outpatient laboratory setting, where obtaining these values would be almost impossible. Therefore, we derived a novel formula that was dependent only on age, gender, and Cr level (BCCH2) and

6 492 Journal of the American Society of Nephrology J Am Soc Nephrol 17: , 2006 Table 4. Accuracy of egfr formulas in classifying CKD stages Optimized egfr Formula Overall Accuracy b (n 83) Detection of ngfr 60 ml/min per 1.73 m 2 Exact Match Within One K/DOQI Stage Sensitivity c Specificity c BCCH1 59/83 (71%) 83/83 (100%) 12/14 (86%) 68/69 (99%) BCCH2 57/83 (70%) 82/83 (99%) 11/14 (79%) 68/69 (99%) oschwartz 58/83 (70%) 83/83 (100%) 12/14 (86%) 67/69 (97%) ocb 56/83 (67%) 83/83 (100%) 12/14 (86%) 66/69 (96%) oleger 51/83 (61%) 82/83 (99%) 12/14 (86%) 61/69 (88%) ocg 50/83 (60%) 83/83 (100%) 12/14 (86%) 66/69 (96%) oamdrd 33/83 (41%) 74/83 (89%) 11/14 (79%) 52/69 (75%) Cr cutoff N/A N/A 12/14 (86%) 64/69 (93%) a CKD, chronic kidney disease; NKF-DOQI, National Kidney Foundation Disease Outcomes Quality Initiative. b Overall accuracy refers to the ability of egfr formulas to identify correctly the NKF-DOQI stage as determined by ngfr; c Sensitivity and specificity refer to the ability of egfr formulas to identify an ngfr value 60 ml/min per 1.73 m 2 (NKF- DOQI stages 3 through 5). Cr cutoff values as listed in Table 6. See text for details. o refers to the BCCH optimized version of the formula. Figure 4. Relative change in values of the optimized Schwartz equation as a function of relative change in ngfr. The dotted lines represent the 30% thresholds for designating a clinically significant decrease in GFR over time. These reference lines designate four quadrants that correspond to true-positive (TP), false-negative (FN), true-negative (TN), and false-positive (FP) results. fared well in comparison with the other formulas as tested (Table 3, Figure 1). Our second method for determining a height- and weightindependent GFR estimate was to use the optimized Schwartz equation to identify age- and gender-specific Cr cutoffs that would identify children with ngfr values 60 ml/min per 1.73 m 2. The resulting Cr cutoff values are listed in Table 6 in two forms: the Vitros values obtained in this study and their equivalent values in terms of a reference method (21,22). Using this approach, we were able to identify correctly 87% of patients in the validation group with an egfr 60 ml/min per 1.73 m 2 while maintaining a specificity of 93% (Table 4), very similar to the best results obtained from the use of optimized egfr equations when height is available. Discussion GFR, a summation of the filtration rate of each functional nephron, provides an estimate of the functional renal mass (22). Accurate knowledge of GFR is often vital for provision of appropriate medical care, including the appropriate dosing of many drugs. As well, diagnosis of a reduced GFR, i.e., CKD, often heralds other comorbidities (23), and early identification may lead to earlier interventions and minimization of morbidity and mortality. The routine chemistry measurement of Cr is a well-established marker of GFR. This has led to efforts to encourage laboratories reflexively to report egfr values whenever a Cr test is ordered. These egfr values are derived from formulas that combine serum Cr with demographic variables that are related to Cr production rates. However, a number of pitfalls are inherent in the development and the use of such a formula, the first being the intrinsic biologic variability in the GFR itself, which has substantial within-day (24) and between-day variability (25). The physiologic variability in the production and in the extraglomerular elimination of Cr will also contribute to variability in Cr-based egfr measurements; if one then factors in interlaboratory variation in terms of measurement of Cr (26), then it is clear that even a perfect egfr estimate may differ substantially from a nuclear GFR estimate. This variability is reflected in the guidelines proposed by the NKF-DOQI CKD workgroup, who chose to define the accuracy of the various GFR estimation equations as clinically acceptable if the estimated GFR value is within 30% of the true measured GFR (23). As well, because most of these formulas were derived from patients in an outpatient setting, there is a presumption that the patient will be in a steady state before and during any measurements or testing. Many patients in whom GFR estimations would be of greatest use, e.g., patients with cancer or rapidly deteriorating renal function or those who are receiving multiple nephrotoxins, will not meet that presumption. In our study we set out to derive our own local egfr for-

7 J Am Soc Nephrol 17: , 2006 Pediatric CKD and egfr 493 Table 5. Ability of serial egfr measurements to accurately identify a minimum 30% relative decrease in ngfr a BCCH1 BCCH2 Schwartz CB Leger CG amdrd Data Sensitivity (%) PPV (%) Specificity (%) NPV (%) a Only eight of 116 patients showed a 30% decline in ngfr over the 5-yr period of the study. PPV, positive predictive value; NPV, negative predictive value. Table 6. Gender- and age-dependent creatinine cutoff values a Age (yr) Creatinine ( mol/l) Cutoff Corresponding to a GFR 60 ml/min per 1.73 m 2 Vitros Boys Reference Method Vitros Girls Reference Method a Based on the third percentile for the distribution of height, given age and gender, using the optimized Schwartz formula; values presented correspond to either the Vitros 250/950 creatinine method or a reference creatinine method. mulas and compare them against the currently recommended NKF-DOQI egfr formulas as well as that of Leger et al. (18) and one of the amdrd formulas (12). To do so fairly, we derived laboratory-specific constants for the Cr term in each of the previously published equations. By all measures of accuracy, the amdrd formula as tested fared much worse than any of the other formulas in our pediatric population. This finding could be predicted as the amdrd formula was derived from an adult cohort in whom the relationship between GFR and age is much different than in the pediatric population. Similarly, the other adult formula suggested by the NKF-DOQI group, CG, has an age term that adversely affects its accuracy when used in a pediatric population. This can be explained in part by realizing that in adults, muscle bulk and, therefore, Cr production rates decline with age; i.e., the youngest adults have the highest serum Cr values for a given body surface area normalized GFR. In contrast, the situation is reversed in pediatrics, in which the youngest children are expected to have the lowest serum Cr for a given body surface area normalized GFR. Although our locally derived formula, BCCH1, performed as well as any formula tested in estimating an individual GFR, its mathematical complexity could not be justified for use in a day-to-day clinic setting by any significant improvement in accuracy over either the optimized Schwartz (15) or CB formula (16). When optimized for our local laboratory method, the Schwartz formula fared much better than the nonoptimized form, with an improvement in accuracy of between 20 and 25% (Figure 3), comparable to other published studies (8,27 29). The Schwartz formula and the CB formula have simpler mathematical forms that facilitate day-to-day use in a clinic or office setting. Hogg et al. (13) clearly outlined the importance of early identification of a child with a persistent moderate to severe decrease in GFR, i.e., 60 ml/min per 1.73 m 2 (NKF-DOQI stage 3) for 3 mo, as at this level of dysfunction, children are more likely to have associated complications and hence benefit from early identification (30). In our validation group, the optimized Schwartz formula (15) had a PPV of 86% and a NPV of 97% in identifying individuals with an ngfr value of 59 ml/min per 1.73 m 2 or less. We believe that these figures are robust enough for clinicians to use this optimized equation to justify further, more definitive investigations, such as a nuclear GFR, when a child s egfr result suggests that he or she has significant renal impairment. In terms of the utility of serial egfr measurements for monitoring patients, the results achieved with the optimized Schwartz formula are equally encouraging. Overall, 108 (93%) of the 116 paired ngfr measurements did not show a decrease of 30% over time. The optimized Schwartz egfr formula correctly classified 96% of those 108 patients. Of the small number of patients who did demonstrate progressive renal insufficiency, five (63%) of eight were identified correctly for a PPV of 56% and a NPV of 97%. We believe that these results are sufficiently high to guide initial clinical decision making and justify further definitive testing as indicated. Although the pediatric egfr formulas have merit for clinicians who need to identify and monitor patients with CKD, pediatric egfr formulas present unique challenges for the

8 494 Journal of the American Society of Nephrology J Am Soc Nephrol 17: , 2006 clinical laboratories. The first problem is that all published pediatric egfr formulas use patient height. As laboratories generally do not measure patient height at the time of blood collection, pediatric egfr results cannot be reported easily. The second problem is that pediatric egfr formulas make use of constants that are specific to a particular method for Cr measurement. As illustrated in Figure 3, a clinical laboratory must derive a laboratory-specific constant to optimize the accuracy of the egfr equations. These two problems essentially have ruled out the use of a pediatric egfr formula in an outpatient laboratory setting up until now. To address the problems that are inherent with reporting egfr in children from the laboratory viewpoint, we took two approaches: (1) Derivation of a non height-, non weight-based egfr formula and (2) derivation of optimized Schwartz formula based Cr values that would identify children who have a GFR 60 ml/min per 1.73 m 2 (NKF- DOQI stage 3). Our height- and weight-independent formula, BCCH2, performed comparably to other egfr equations; its performance was only slightly below that of the optimized Schwartz on most measures (Figures 1 through 3, Tables 3 through 5). Hence, this formula does allow a reasonable estimate of GFR even in the absence of a known height or weight. There are two significant drawbacks to its routine use on a clinical basis: (1) The need for each center to derive local laboratory constants for the formula and (2) that similar to other non height-containing formulas, e.g., CG and amdrd, occasional estimates of GFR are grossly inaccurate (Figures 1 and 2). Our second approach to identifying patients with a GFR 60 ml/min per 1.73 m 2 was to use the optimized Schwartz formula to derive Cr cutoffs that are specific to a child s age and gender. These values were obtained by making the assumption that a child of a given age was at the third percentile for age- and gender-appropriate height. The third percentile was chosen to maximize the sensitivity of the Cr cutoffs. This produced a level of accuracy near that obtained by using our best egfr formulas (Table 4). Aside from eliminating the need for clinical laboratories to obtain height information on pediatric patients, this Cr cutoff approach also frees clinical laboratories from the obligation to obtain a laboratory-specific constant for the Schwartz or an alternate pediatric egfr formula. We have presented Cr cutoffs (Table 6) in terms of the Vitros Cr method that is used in our laboratory and also in terms of a reference Cr method (by definition, a nonbiased method). In British Columbia, all clinical laboratories subscribe to an external quality control service for Cr measurement that tracks the bias between the clinical laboratory result and a reference method. Thus, all laboratories in British Columbia immediately can adjust and adopt our Cr cutoff values to aid in the identification of children who are at high risk for CKD. It is likewise a simple matter for other clinical laboratories to determine the bias of their Cr methods as compared with a reference method and similarly use our values as presented. There are a number of limitations to our study and potentially the broad applicability of its results. First is that all estimates of accuracy, etc., for the formulas and results are based on a pediatric nephrology referral population with a high likelihood of renal dysfunction. The PPV and NPV would differ substantially in a healthy cohort with a lower prevalence of disease. In addition, one would expect that the specificity of identifying a GFR 60 ml/min per 1.73 m 2 would be lower in a healthy cohort in which the relationship between serum Cr and GFR may be substantially different (31). A second limitation is the issue of basing our true GFR values on a plasma disappearance method on the basis of 99 Tc-DTPA sampling. Although inulin clearance is classically held to be the gold standard for measuring GFR (32), it is cumbersome to perform and is not available in North America (33). 99 Tc-DTPA is cleared primarily by glomerular filtration (34) and has a clearance that approximates that of inulin (35); the main concern with its use is that it can dissociate from DTPA during a clearance study, thereby adversely affecting the results (36). However, the two-sample 99 Tc-DTPA method used in our center has been proposed as a valid method for measuring GFR in children by the Pediatric Committee of the European Association of Nuclear Medicine for routine use in children when measuring GFR on a clinical basis, so we believe that it is a valid clinical standard with which to compare our egfr results (37). One additional limitation of our study is that the Cr cutoff values presented in Table 6 cannot be considered definitive for several reasons. First, the cutoffs were developed as part of a retrospective review. Second, the Cr measurements were performed on a Vitros analyzer, which differs significantly from other Cr methods. Although we have presented Cr cutoff values in terms of the Vitros assay and in terms of reference method for Cr, these latter values were obtained indirectly. Thus, these Cr cutoffs need to be validated in a prospective study using a reference method. Conclusion Although there are some advantages in terms of accuracy to be gained by use of our locally derived egfr formula, BCCH1, its mathematical complexity leads us to concur with the NKF- DOQI workgroup and suggests that for ease of calculation and to maintain the highest accuracy across the pediatric age group in estimating GFR, clinicians should use either the Schwartz (15) or the CB (16) formula for children who are younger than 18 yr, presuming that an appropriate constant for the local laboratory method has been validated. The optimized Schwartz formula in particular is very robust and may also be used to identify and follow GFR in pediatric patients with CKD. In situations in which height is not available but local laboratory-specific constants are developed for our non height- or weight-containing formula, BCCH2, we believe that it provides a useful tool for the clinician who wishes to estimate a child s renal function with the view to proceeding to further testing in the case in which they are estimated to have a GFR 60 ml/min per 1.73 m 2. In situations in which neither height nor local constants for the various egfr formula are available, we suggest laboratory conversion of current NKF-DOQI CKD stages to new cutoff values of Cr as outlined above, specifically targeting the stage 2/3 transition at the level of 60 ml/min per 1.73 m 2. This

9 J Am Soc Nephrol 17: , 2006 Pediatric CKD and egfr 495 method is simpler to apply to an outpatient setting than the derivation of local constants or egfr formula and can identify reliably children who are at risk for a low GFR and then may go on to benefit from timely investigations, referral, and, potentially, therapy. Finally, we remind the reader that presently the best accuracy of any of the published egfr formulas in adults or pediatrics rarely reaches the level of 80% of values closer than 30% to the true GFR. Therefore, caution should be exercised in simply applying any formula to an individual patient for whom the need for accuracy in estimating the GFR is vital to produce a high stakes decision, e.g., decisions regarding dosing of nephrotoxic or chemotherapeutic drugs (5,6). In these scenarios, obtaining a more invasive but accurate measurement of the GFR can be justified on the basis of its importance in directing potentially harmful therapy for the individual. 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