Title: Optimization of estimating glomerular filtration rate equations for the evaluation of kidney function in children, adolescents and adults
Other Titles: Optimalisatie van de formules ter inschatting van de glomerulaire filtratiesnelheid bij kinderen, adolescenten en volwassenen
Authors: Hoste, Liesbeth
Issue Date: 15-Sep-2016
Abstract: The glomerular filtration rate (GFR) is widely considered as the best overall index of kidney function in health and disease. Direct measurements of GFR are technically complicated and impractical to perform in routine clinical settings. That is why more simple methods to estimate the GFR are so successful. The calculation of the estimated (e)GFR using mathematical formulas has been encouraged as a simple, rapid and reliable way of assessing kidney function. In those formulas, serum creatinine (Scr) is most commonly used as a marker for renal function. A typical problem related to the use of creatinine-based eGFR-formulas is the existing diversity of methods to determine Scr. It has been shown that small analytical changes in Scr can create major shifts in the distributions of eGFR-results, which then cause differences in the Chronic Kidney Disease (CKD) classification of patients. So it is clear that control of laboratory analysis of Scr and worldwide standardized Scr measurements are necessary. Manufacturers already made efforts to standardize their Scr measurements to have calibration traceable to the isotope dilution mass spectrometry (IDMS) gold standard method. However calibration traceability does not address (analytical) non-specificity which remains of concern. Lately there have been recommendations to abandon the Jaffe Scr assay in favor of the enzymatic Scr assay since the enzymatic assays have been reported to have generally fewer interferences than the Jaffe methods. However the higher cost of the enzymatic assay is the main reason why some clinical labs still use Jaffe or compensated (compensation made for the mean creatinine-interference) Jaffe assays. Because of the evolution in laboratory testing of Scr to IDMS-standardized techniques, new eGFR-formulas have been developed for adults and children during the last decade but no attempts have been undertaken to develop new formulas for adolescents. Pediatric eGFR-formulas are often used in the adolescent population although these equations were not developed to be used in these patients and are not accurate for the adolescent population. Besides the use of eGFR-formulas, clinicians also often rely on 24-hour creatinine clearance (24h-CrCl) to estimate the kidney function. An advantage over the use of eGFR-formulas is that CrCl can be performed in people of all ages and in patients for whom Scr-based eGFR-formulas are not applicable (eg. pregnant women). However CrCl-determination has also its own specific problems such as the lack of accuracy of the 24h-urine collection and the huge diversity in serum and urine creatinine measurement methods which may lead to different CrCl-results.
In the first part of this PhD-project (Chapter 2) we focused on the problems that may arise when working with Scr assays. To investigate the effect of Scr assays on 24h-CrCl we have set up a study to compare the CrCl calculated from three different type of assays (Jaffe (J), compensated Jaffe (CJ) and enzymatic (E) assay). We showed that CrCl determination is extremely assay-dependent. To evaluate the reliability of 24h-CrCl for estimating the kidney function, we compared the CrCl with eGFR-values calculated with the CKD-EPI eGFR-formula. The deviation of the body surface area indexed CrCl from the CKD-EPI eGFR illustrates that the use of CrCl in clinical practice remains questionable. Two compensating errors in the CrCl-J calculation result in a closer agreement with CKD-EPI eGFR, than between CrCl-CJ or CrCl-E and CKD-EPI eGFR. We therefore recommend clinical labs that work with compensated Jaffe assays not to compensate for the protein effect when a CrCl is requested. In a second study we investigated the accuracy and precision of commonly used Scr assays (J, CJ and E) in Flanders. Our interest was to study how results can vary among laboratories using different type of Scr assays and instruments. We conclude that although most assays claim to be traceable to IDMS, large inter-assay differences still exist. The inaccuracy in the lower concentration range is of particular concern and may lead to clinical misinterpretation when the creatinine-based eGFR of the patient is used for CKD staging.
The second objective of the PhD-project (Chapter 3) was to develop and validate an equation based on IDMS-standardized Scr for estimating the GFR in adolescents. The new formula is based on the concept of population-normalized Scr. We first introduced this concept by reshaping existing eGFR-formulas for adults. Then we showed that the same concept could be used to develop a simple height-independent eGFR-formula for children. Next we extended the idea of normalized Scr to develop and validate two new eGFR-equations for adolescents and young adults. We also illustrated that the newly developed formulas have their limitations and are not applicable in patients with abnormally low Scr, such as Duchenne muscular dystrophy patients. Since separate equations for children, adolescents, adults and elderly lack continuity with aging, we also proposed a GFR estimating equation (by extending the equations for children and adolescents based on population-normalized Scr) valid for the full age spectrum.
In the third part of the PhD-project (Chapter 4) we criticize the current CKD classification system which has been developed for adults, but is also considered to be applicable for children and adolescents. We presented an alternative CKD classification system based on normalized Scr. The alternative approach has the advantage of reducing the proportion of elderly that are (falsely) classified with CKD and increases sensitivity in classifying CKD in children and young adults. We also showed that abnormal GFR for children, adolescents and young adults starts below 75mL/min/1.73m², suggesting that this would be a good alternative for the CKD cut-off of 60 mL/min/1.73m².
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Public Health and Primary Care, Campus Kulak Kortrijk
Department of Public Health miscellaneous
Faculty of Medicine, Campus Kulak Kortrijk

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