Height: the missing link in estimating glomerular filtration rate in children and adolescents.

Glomerular filtration rate (GFR) is the most useful indicator of kidney function and kidney disease progression. Measurement of GFR is laborious to perform clinically, as it is time-consuming and costly, with turn-around time for results being too slow for many clinical situations encountered in the hospital and outpatient setting. Thus, there is great interest in developing GFR estimating formulas derived from endogenous biomarkers. This applies also to children in whom performance of GFR studies is likely to be more difficult. There is nearly universal acceptance and application of adult eGFR formulas derived from serum creatinine (Scr) [1, 2], and these formulas incorporate, in addition to Scr, sex, race and age to optimize accuracy. However, such an application is not as useful in children because of the maturational increase in Scr in the setting of normal renal function. As has been shown previously [3–5], Scr increases in pediatrics with growth and development, and after puberty shows a gender-dependent divergence. Thus, the development of GFR-estimating formulas in children has focused on additional parameters to better estimate kidney function. Previously, we showed that the parameter ‘height/Scr’ could explain more than 70% of the variability of GFR in children (Figure 1a) [6]. Whereas other parameters have been investigated, height/Scr has retained its key place in building GFR estimating equations [6–8]. The proportionality relationship between GFR and height/Scr is subsumed in the coefficient k, which was originally found to be 0.55 mg/min per cm per 1.73 m [6]. Subsequent studies showed a higher k value for adolescent boys [7, 9] probably due to the higher muscle mass per kg body weight in this group. These relationships were generated during the era when the colorimetric Jaffe reaction was adapted to an automated chemical analyzer; by incorporating a dialysis step and interposing blanks between samples, there was reduced interference and improved accuracy compared with the rapid kinetic assays [7, 10]. However, with the development of the more accurate enzymatic serum creatinine assay and international isotope dilution mass spectroscopy (IDMS) reference standards [1, 11], the proportionality-constant k was reduced by some 25% to 0.41 in the NIH-supported CKiD study of children with chronic kidney disease and GFRs ranging from 15 to 75 mL/ min per 1.73 m [8]. In this population of children with moderate CKD, growth was limited (median was the 23rd percentile) and nearly 80% of the population was immature as staged by Tanner I to III [8]. Height/Scr still explained 65% of the variability in GFR in CKD (Figure 1b) [8]. In this publication, we indicated the need to validate this formula in children and adolescents with higher GFRs and with normal or higher height percentiles. There has been a major effort to improve on these creatinine-based eGFR formulas in children. Indeed, Pottel’s group and others [12–14] have utilized medical center-based adjustments in the proportionalityconstant k, and confirmed the need for age adjustment in k for males older than 13 years [13, 15]. Recently, this group developed a very simple eGFR equation: eGFR = 107.3/(Scr/Q) [16]. Q was derived from Scr values depending on age and gender or height; databases of Belgian children and adolescents provided anthropometric and Scr data, and regressions were generated to provide these median values. Such Q values from these databases could be accessed in laboratory computers and utilized for an output to the patient’s electronic medical record. However, some of their analyses have shown that heightindependent simple eGFR equations did not perform as well as those incorporating height [16, 17]. The fact that height, and possibly race, are not always available to clinical laboratory databases limits the application of superior height-based GFRestimating formulas and suggests the need for alternative estimates, new approaches to information technology or increased interaction of laboratory databases with the electronic medical record. The paper by Hoste et al. [17] in this issue of NDT proposes a new simple equation to estimate GFR in children, adolescents and young adults. The equation is also based on the concept of a population-normalized serum creatinine (Scr) value Q, but is extended beyond the average healthy child to the adolescent and young adult. Q values specific to age and height were modeled as fourth-degree polynomials from median values of a large database of healthy children and IN F O C U S