Iohexol plasma clearance in children: validation of multiple formulas and single-point sampling times

Abstract

Background: The non-ionic agent iohexol is increasingly used as the marker of choice for glomerular filtration rate (GFR) measurement. Estimates of GFR in children have low accuracy and limiting the number of blood-draws in this patient population is especially relevant. We have performed a study to evaluate different formulas for calculating measured GFR based on plasma iohexol clearance with blood sampling at only one time point (GFR1p) and to determine the optimal sampling time point.

Methods: Ninety-six children with chronic kidney disease (CKD) stage 1-5 (median age 9.2 years; range 3 months to 17.5 years) were examined in a cross-sectional study using iohexol clearance and blood sampling at seven time points within 5 h (GFR7p) as the reference method. Median GFR7p was 66 (range 6-153) mL/min/1.73 m2. The performances of six different single time-point formulas (Fleming, Ham and Piepsz, Groth and Aasted, Stake, Jacobsson- and Jacobsson-modified) were validated against the reference. The two-point GFR (GFR2p) was calculated according to the Jødal and Brøchner-Mortensen formula.

Results: The GFR1p calculated according to Fleming with sampling at 3 h (GFR1p3h-Fleming) had the best overall performance, with 82% of measures within 10% of the reference value (P10). In children with a GFR ≥ 30 mL/min/1.73 m2 (n = 78), the GFR1p3h-Fleming had a P10 of 92.3%, which is not significantly different (p = 0.29) from that of GFR2p (P10 = 96.2%). Considerable differences within and between the different formulas were found for different CKD stages and different time points for blood sampling.

Conclusions: For determination of mGFR in children with CKD and an assumed GFR of ≥ 30 mL/min/1.73 m2 we recommend GFR1p3h-Fleming as the preferred single-point method as an alternative to GFR2p. For children with a GFR < 30 mL/min/1.73 m2, we recommend the slope-GFR with at least two blood samples.

Clinical trial registration: ClinicalTrials.gov , Identifier NCT01092260, https://ichgcp.net/clinical-trials-registry/NCT01092260?term=tondel&rank=2.

Keywords: Children; Chronic kidney disease; Glomerular filtration rate; Renal function.

Conflict of interest statement

Financial disclosure

The authors have no financial relationships relevant to this article to disclose.

Approval

The study was approved by the Regional Ethics Committee of Western Norway and an informed consent form was signed by all patients and/or their designees. The study was performed in accordance with the Declaration of Helsinki.

Conflict of interests

The authors declare that they have no conflict of interest.

Figures

Fig. 1

Plot of estimation error versus the estimation method for glomerular filtration rate (GFR) calculated by six single-sample formulas [12, 13, 17, 20, 22, 26], stratified by sampling time point (n = 96 children). The y-axis shows the difference between the single-point GFR and a reference GFR based on seven sampling time points. Each point corresponds to a combination of patient, estimation method and sample time. The solid horizontal line is the bias, i.e. the mean difference between the single-point GFR estimate and the reference GFR. The dashed lines are limits of agreement, i.e. bias ± two standard deviations of the differences. The figure can be used to compare different methods within each sampling time point

Fig. 2

Plot of estimation error versus time point for glomerular filtration rate (GFR) calculated at five time points, stratified by estimation method (n = 96 children). The y-axis shows the difference between the single-point GFR [12, 13, 17, 20, 22, 26] and a reference GFR based on seven sampling time points. Each point corresponds to a combination of patient, estimation method and sample time. The solid horizontal line is the bias, i.e. the mean difference between the single-point GFR and the reference GFR. The dashed lines are limits of agreement, i.e. bias ± two standard deviations of the differences. For each estimation method, the figure can be used to compare the performance of the single-point GFR estimates at different sampling time-points

Fig. 3

Plot of estimation error versus reference glomerular filtration rate (GFR) for GFR calculated by six single-sample formulas [12, 13, 17, 20, 22, 26] and at five sampling time points (n = 96 children). The y-axis shows the difference between the single-point GFR estimate and a reference GFR based on seven sampling time points. The x-axis shows the reference GFR. Each point corresponds to a combination of patient, determination method and sample time. The solid horizontal line is the bias, i.e. the mean difference between the single-point GFR and the reference GFR. The dashed lines are limits of agreement, i.e. bias ± two standard deviations of the differences. Large determination errors, i.e. errors outside the displayed range, are indicated by arrows. The figure can be used to examine patterns in how the estimation errors of the different estimation methods vary with GFR for each method and sampling time

Fig. 4

Percentage plot showing the determination accuracy of six single-sample determination methods [12, 13, 17, 20, 22, 26] at five sampling time points (n = 96 patients/children). Each symbol, labeled Px (P5, P10, P15 and P20), shows the calculated proportion of single-sample glomerular filtration rate (GFR) within x% of the reference method. The horizontal lines show the corresponding 95% confidence intervals