Original Article. Saudi Journal of Kidney Diseases and Transplantation

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1 Saudi J Kidney Dis Transpl 2014;25(5): Saudi Center for Organ Transplantation Saudi Journal of Kidney Diseases and Transplantation Original Article Comparison of the Performance of the Updated, Combined and the Grubb Glomerular Filtration Rate Equations in a General Pediatric Population Alaleh Gheissari 1,2, Peyman Roomizadeh 2,3, Roya Kelishadi 4, Amin Abedini 3, Shaghayegh Haghjooy-Javanmard 5, Seyed-Hossein Abtahi 3, Bahareh Mehdikhani 6 1 Department of Pediatric Nephrology, 2 Isfahan Kidney Diseases Research Center, 3 Medical Students Research Center, 4 Pediatrics Department, Faculty of Medicine and Child Growth and Development Research Center, 5 Applied Physiology Research Center, Department of Physiology, Isfahan University of Medical Sciences, Isfahan, 6 Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran ABSTRACT. To determine the performance of the updated, combined and Grubb glomerular filtration rate (GFR) s in a relatively large number of healthy children with no known renal disease, we studied 712 students aged between seven and 18 years from the Isfahan province of Iran by random cluster sampling between 2009 and Blood investigations included blood urea nitrogen, creatinine and cystatin C. For each participant, GFR was calculated based on the three s. We used Bland Altman plots and weighted kappa statistics to compare the performance of the study s. The mean age of the children was 12.2 ± 2.4 years. A high concordance in estimating GFR (mean difference: 0 ± 12.7 ml/min/1.73 m 2 ) and a very good agreement in defining chronic kidney disease ( ) and non- individuals (weighted kappa: 0.85; 95% confidence intervals: ) were observed between the updated and the combined s. Poor agreement was observed between the Grubb and two s in estimating GFR and defining. There was no systematic deviation between the updated and the combined s in children with normal renal function. The Grubb was highly inconsistent with both s in this population. We conclude that the updated is simpler and more accessible than the combined in daily clinical practice and screening programs. Correspondence to: Dr. Peyman Roomizadeh, Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences and Health Services, Isfahan, Iran roomizadeh@gmail.com Introduction Glomerular filtration rate (GFR) is widely accepted as the best overall indicator of renal function. 1 The reference methods for the measurement of the GFR require determination of renal clearance of exogenous substances such as inulin, Cr51-EDTA, iohexol and iothala-

2 Combined, and the Grubb glomerular filtration rate s in children 1005 mate. These methods are invasive, expensive and hard to employ in daily clinical practice; therefore, the GFR is routinely estimated by measuring serum concentration of endogenous markers of renal function. 2 Serum creatinine is the most commonly used endogenous marker for assessment of the GFR worldwide. However, in recent years, a novel marker of renal function, cystatin C, is suggested as a more sensitive marker than serum creatinine in the assessment of GFR. 3,4 The original (developed in 1976) was the most popular GFR for children below 18 years of age for the past three decades. 5 This was developed with creatinine measured by the Jaffé reaction. 5 However, during these years, the laboratory methods for the measurement of serum creatinine have been widely replaced with new enzymatic methods (isotope dilution mass spetrometry). The original is believed to overestimate GFR when creatinine is measured by the enzymatic methods. 2 Accordingly, in 2009, et al 6 proposed an updated version of their original that was developed based on the enzymatic method of creatinine measurement. In addition to their updated, they also developed a new GFR that is based on serum levels of creatinine, blood urea nitrogen (BUN) and cystatin C (named as the com - bined ). 6 Beside the s proposed by et al, there are several other cystatin C-based GFR s used in the pediatric population. Among the existing s, only the proposed by Grubb et al 7 is developed with a cystatin C measurement method similar to the method used in the 2009 et al study. 6 This methodological similarity has made the comparison between these s possible. We aimed in this study to compare the updated, the combined and the Grubb s in a relatively large number of healthy children with no known renal disease in estimating the GFR and categorizing individuals into chronic kidney disease () and non- groups in this population. Patients and Methods The data used in this study were obtained from a baseline survey of the Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable Disease (CASPIAN Study). The third phase of this nationwide school-based health survey was conducted in 5028 Iranian students aged seven to 18 years who were selected by multistage random cluster sampling from urban and rural areas of 27 provinces of Iran between 2009 and The present paper describes the findings of 712 school students from Isfahan, a large province located in the central part of the country. A detailed description about the procedure of data gathering and sample collection of the Caspian studies has been characterized elsewhere. 8 In brief, after complete explanation of the study objectives and protocol to the students and their parents, a team of trained nurses collected the demographic and the clinical data of the eligible subjects including age, sex, height, weight and blood pressure. Fasting blood samples were drawn from the participants and centrifuged for 10 min at 3000 rpm within 30 min of venipuncture in the Isfahan central provincial laboratory, where biochemical measurements were carried out. Written informed consents were obtained from the parents/caregivers besides oral assent from the students before enrollment in the study. The study was approved by the institutional review boards, and adhered to the tenets of Helsinki declaration. Serum creatinine and BUN levels were measured by the enzymatic methods on a Hitachi 917 auto-analyzer. Serum cystatin C levels were measured by the particle-enhanced immunoturbidimetric method (Dako, Glostrup, Denmark). 9 Cystatin C levels lower than 1.38 mg/l were considered normal in the general population. 10 To calculate the GFR for each subject, we applied the following s: The updated : 6 GFR (ml/min/1.73 m 2 ) = height (cm)/ serum creatinine (mg/dl) The combined : 6 GFR (ml/min/1.73 m 2 )

3 1006 Gheissari A, Roomizadeh P, Kelishadi R, et al = 39.1 [height (m)/creatinine (mg/dl)] [1.8/cystatin C (mg/l] [30/BUN (mg/dl)] if male (1.099) [height (m)/1.4] The Grubb : 7 GFR (ml/min/1.73 m 2 ) = [cystatin C (mg/l)] if <14 years According to the estimated GFR by each, the participants were categorized as group (defined as GFR <60 ml/min/1.73 m 2 ) or non- group (defined as GFR >60 ml/min/1.73 m 2 ). Statistical Analysis Continuous values are expressed as mean ± SD and categorical variables are presented as numbers (percentage). The level of agreement in estimating GFR between s was examined using the Bland Altman analysis. 11 Based on this statistical method, the limits of agreement were determined by the mean difference ± 1.96 SD of the percentage of changes. Weighted kappa statistics were used to assess the agreement between the s in categorizing individuals as or non-. Statistical analyses were carried out using the SPSS software version 19.0 (SPSS, Chicago, IL, USA) and MedCalc version (MedCalc Software, Mariakerke, Belgium). P-value <0.05 was considered to be statistically significant. Results Of the 712 included children, 377 (52.9%) were male. The mean age was 12.2 ± 2.4 years (range: 7 18) and the mean body mass index was 18.2 ± 3.8 kg/m 2. Detailed demographic and clinical characteristics of the participants are presented in Table 1. The mean GFR was 99.7 ± 19.7 ml/min/1.73 m 2 by the combined, 99.7 ± 19.7 ml/min/1.73 m 2 by the updated and 168 ± 81.6 ml/min/1.73 m 2 by the Grubb. Figure 1 shows the distribution of the estimated GFRs by each. The Grubb resulted in a considerably wider distribution of values at both the upper and the lower levels of GFR values in comparison with the s. Such a difference in the GFR distribution was due to the larger standard deviation of the GFR values estimated by the Grubb. Figure 2 shows the Bland Altman plots for the agreement between the GFR values by each. We found a high level of agreement between the combined and the updated s (mean difference: 0 ± 12.7 ml/min/ 1.73 m 2 ). Agreements between the combined and Grubb s (mean diffe - rence: ± 68.3 ml/min/1.73 m 2 ) and between the updated and the Grubb s (mean difference: ± 76.0 ml/ Table 1. Demographic, biochemical and renal characteristics of the study participants. Mean SD Median Range Age (years) Height (cm) BMI (kg/m 2 ) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Blood urea nitrogen (mg/dl) Serum creatinine (mg/dl) Serum cystatin C (mg/l) Estimated GFR (ml/min per 1.73 m 2 ) Combined Updated Grubb BMI: body mass index; SD: standard deviation.

4 Combined, and the Grubb glomerular filtration rate s in children 1007 Figure 1. The Box-and-Whisker plots of the distribution of the estimated GFR with the use of different s. The Box-and-Whisker plots display the 25 th, 50 th and 75 th percentile by the lines at the bottom, middle and top of the box. The brackets show the 95% range. min/1.73 m 2 ) were poor. The frequency of was 7%, 1.7% and 1.3%, based on the Grubb, the combined and the updated s, respectively. Table 2 shows the overlaps of individuals categorized as and non- based on each and also the corresponding weighted kappa coefficients quantifying the inter- and intra-rater reliability assessments. The weighted kappa statistics revealed a very good agreement between both s in categorizing individuals in the and non- groups (к = 0.85; 95% CI: ). On the other hand, the Grubb showed a fair agreement with both s in categorizing individuals as and non- (Table 2). Discussion In this study, we found that both 2009 s were in high concordance in estimating GFR and defining individuals as or non-, while there was a limited agreement between the s and the Grubb formula. These findings suggest that there is no systematic deviation between the s and that they can be used interchangeably in daily clinical practice. The updated only requires the values of serum creatinine and height and, therefore, is simpler than the combined. The updated can be considered more accessible and cost-beneficial in daily pediatric practice and also in large screening programs. In our study, the Grubb appeared to be highly inconsistent with the two s. A similar observation was found by Fadrowski et al, 12 who compared the performance of a number of GFR s in a large sample of American adolescents aged years. In their study, the median GFR estimated by the updated, combined and Grubb s were 96.6, 96.6 and ml/min/1.73 m 2, respectively. In our study, the Grubb yielded a higher prevalence of in comparison with the s. Such apparent discrepancies between the and the Grubb s are probably due to the differences in the characteristics of the sampled populations of the et al 6 and the Grubb et al 7 studies. It is well established that the demographic and the clinical status of the population significantly affect the accuracy of the obtained for estimation of the GFR. 13,14

5 1008 Gheissari A, Roomizadeh P, Kelishadi R, et al Figure 2. Bland Altman plots of comparison between s in estimating GFR. (A) Comparison between combined and updated s. (B) Comparison between combined and Grubb s. (C) Comparison between updated and Grubb s. The continuous line shows the mean difference between the two s and the dashed lines show the limits of agreement, defined as mean ± 1.96 SD.

6 Combined, and the Grubb glomerular filtration rate s in children 1009 Table 2. Overlaps of or non- individuals based on the study s and weighted kappa coefficients quantifying inter- and intra-rater reliability assessment (n = 712). Combined Updated Combined Grubb Updated Grubb Non- Non- Non- Non- 700 (98.3%) 0 Non- 660 (92.7%) 40 (5.6%) 10 (1.4%) Non- 660 (92.7%) 43 (6%) 7 (1%) 3 (0.4%) 9 (1.3%) 2 (0.3%) 2 (0.3%) Weighted Kappa statistics Equations Kappa 95%CI Combined vs updated Combined vs Grubb Updated vs Grubb Note: The bold numbers (percents) show overlaps between s in categorizing in and non- groups. was defined as GFR<60 ml/min per 1.73 m 2. Weighted kappa, <0.20 poor agreement; fair; moderate; good; very good. : Chronic kidney disease, CI: Confidence interval. During the past decade, several other creatinine- and/or cystatin C-based GFR s have been proposed for children (e.g., Zappitelli et al, 15 Bouvet et al, 16 Filler et al 17 and Leger et al 18 ). However, all such s originated from specific patients with various types of kidney diseases and, therefore, their extrapolation to the general pediatric population is a matter of debate. 2,19 Furthermore, the differences in the cystatin C assay methods used in these studies rendered the comparison between the existing s difficult. It is important to note that the s by et al 6 and Grubb et al 7 are developed using particle-enhanced turbidimetric immunoassay (PETIA) for cystatin C measurement. On the other hand, the majority of the other exiting cystatin C-based s used the particle-enhanced nephelometric immunoassay (PENIA) method Because we aimed to investigate the performance of the combined, we used PETIA for cystatin C measurement in our study. With respect to the lack of a uniform reference standard for the calibration of PETIA and PENIA at the present time, 12 we were able to include only the Grubb from several existing s for comparison in this study. The updated is validated in children with normal renal function. 20 The United States National Kidney Disease Education Program (NKDEP) has suggested this as the best creatinine based-gfr for all children. 21 Nevertheless, at the present time, a global consensus on an ideal GFR in children does not exist. In 2002, the National Kidney Foundation (KDOQI) recommended the use of the original in all children. 22 However, due to dramatic changes in the laboratory assay methods and considering several new GFR s introduced during the past decade, there is an essential need to update the KDOQI guidelines for an all-purpose GFR for children. Further studies with a reference GFR are warranted to investigate the accuracy of the existing s in healthy children with normal renal function. The main limitation of our study was the lack of a gold standard measurement of GFR for the study subjects. Given this, we were not able to determine the most accurate in our population. It should be considered that it was difficult to obtain reference GFR in our study as the ethical considerations may preclude the exposure of healthy children with no known renal disease to radioactive radiations that are required for determination of reference GFR. In conclusion, in this study, we demonstrated

7 1010 Gheissari A, Roomizadeh P, Kelishadi R, et al a high concordance and agreement between the two 2009 s in estimating GFR and defining individuals in the general pediatric population. The updated is more easily implemented in daily clinical practice. More studies with reference GFR are needed to evaluate the accuracy of the existing GFR s in children with normal renal function. Conflict of Interest The authors declare that they have no conflict of interest. References 1. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function-measured and estimated glomerular filtration rate. N Engl J Med 2006;354: GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 2009;4: Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: A meta-analysis. Am J Kidney Dis 2002;40: Roos JF, Doust J, Tett SE, Kirkpatrick CM. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children-a meta-analysis. Clin Biochem 2007;40: GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976; 58: GJ, Muñoz A, Schneider MF, et al. New s to estimate GFR in children with. J Am Soc Nephrol 2009;20: Grubb A, Nyman U, Björk J, et al. Simple cystatin C-based prediction s for glomerular filtration rate compared with the modification of diet in renal disease prediction for adults and the and the Counahan-Barratt prediction s for children. Clin Chem 2005;51: Kelishadi R, Motlagh ME, Roomizadeh P, et al. First report on path analysis for cardio-metabolic components in a nationally representative sample of pediatric population in the Middle East and North Africa (MENA): the CASPIAN-III Study. Ann Nutr Metab 2013;62 (3): Kyhse-Andersen J, Schmidt C, Nordin G, et al. Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate. Clin Chem 1994;40: Bökenkamp A, Domanetzki M, Zinck R, Schumann G, Brodehl J. Reference values for cystatin C serum concentrations in children. Pediatr Nephrol 1998;12: Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1: Fadrowski JJ, Neu AM, GJ, Furth SL. Pediatric GFR estimating s applied to adolescents in the general population. Clin J Am Soc Nephrol 2011;6: Sharma AP, Yasin A, Garg AX, Filler G. Diagnostic accuracy of cystatin C-based egfr s at different GFR levels in children. Clin J Am Soc Nephrol 2011;6: Filler G, Foster J, Acker A, Lepage N, Akbari A, Ehrich JH. The Cockcroft-Gault formula should not be used in children. Kidney Int 2005;67: Zappitelli M, Parvex P, Joseph L, et al. Derivation and validation of cystatin C-based prediction s for GFR in children. Am J Kidney Dis 2006; 48: Bouvet Y, Bouissou F, Coulais Y, et al. GFR is better estimated by considering both serum cystatin C and creatinine levels. Pediatr Nephrol 2006;21: Filler G, Lepage N. Should the formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 2003;18: Léger F, Bouissou F, Coulais Y, Tafani M, Chatelut E. Estimation of glomerular filtration rate in children. Pediatr Nephrol 2002;17: Bacchetta J, Cochat P, Rognant N, Ranchin B, Hadj- Aissa A, Dubourg L. Which creatinine and cystatin C s can be reliably used in children? Clin J Am Soc Nephrol 2011;6: Staples A, LeBlond R, Watkins S, Wong C, Brandt J. Validation of the revised estimating in a predominantly non- population. Pediatr Nephrol 2010;25: National Kidney Disease Education Program (NKDEP); GFR Calculator for Children: Bedside IDMS-traceable GFR Calculator for Children. April 25, Available from: children-conventional-unit.asp [Last accessed on 2012 May 19]. 22. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1): S1-266.