Project description:BackgroundThe 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.MethodsNinety-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.ResultsThe 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.ConclusionsFor 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 registrationClinicalTrials.gov , Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2.

Project description:BackgroundIohexol plasma clearance-based glomerular filtration rate (GFR) determination provides an accurate method for renal function evaluation. This technique is increasingly advocated for clinical situations that dictate highly accurate renal function assessment, as an alternative to conventional serum creatinine-based methods with limited accuracy or poor feasibility. In the renal transplantation setting, this particularly applies to living renal transplant donor eligibility screening, renal transplant function monitoring and research purposes. The dependency of current iohexol GFR estimation techniques on extensive sampling, however, has limited its clinical application. We developed a population pharmacokinetic model and limited sampling schedules, implemented in the online InsightRX precision dosing platform, to facilitate pragmatic iohexol GFR assessment.MethodsIohexol concentrations (n = 587) drawn 5 min to 4 h after administration were available from 67 renal transplant recipients and 41 living renal transplant donor candidates with measured iohexol GFRs of 27-117 mL/min/1.73 m2. These were split into a model development (n = 72) cohort and an internal validation (n = 36) cohort. External validation was performed with 1040 iohexol concentrations from 268 renal transplant recipients drawn between 5 min and 4 h after administration, and extended iohexol curves up to 24 h from 11 random patients with impaired renal function. Limited sampling schedules based on one to four blood draws within 4 h after iohexol administration were evaluated in terms of bias and imprecision, using the mean relative prediction error and mean absolute relative prediction error. The total deviation index and percentage of limited sampling schedule-based GFR predictions within ± 10% of those of the full model (P10) were assessed to aid interpretation.ResultsIohexol pharmacokinetics was best described with a two-compartmental first-order elimination model, allometrically scaled to fat-free mass, with patient type as a covariate on clearance and the central distribution volume. Model validity was confirmed during the internal and external validation. Various limited sampling schedules based on three to four blood draws within 4 h showed excellent predictive performance (mean relative prediction error < ± 0.5%, mean absolute relative prediction error < 3.5%, total deviation index < 5.5%, P10 > 97%). The best limited sampling schedules based on three to four blood draws within 3 h showed reduced predictive performance (mean relative prediction error < ± 0.75%, mean absolute relative prediction error < 5.5%, total deviation index < 9.5%, P10 ≥ 85%), but may be considered for their enhanced clinical feasibility when deemed justified.ConclusionsOur online pharmacometric tool provides an accurate, pragmatic, and ready-to-use technique for measured GFR-based renal function evaluation for clinical situations where conventional methods lack accuracy or show limited feasibility. Additional adaptation and validation of our model and limited sampling schedules for renal transplant recipients with GFRs below 30 mL/min is warranted before considering this technique in these patients.

Project description:BackgroundMeasuring glomerular filtration rate (GFR) using iohexol plasma clearance has been proposed as the preferred way for GFR determination. The extended multiple-sample protocol is based on fitting the full concentration-time decay-curve, and from the obtained fit-parameters, the area under the curve (AUC) and GFR (the injected dose divided by the AUC) were calculated. The goal of the current study is to evaluate the impact of different fitting procedures on the precision of GFR-results obtained from the full concentration-time curve, and compare these results with those obtained with simplified multiple-samples and single-sample protocols.MethodsThe concentration-time curves of 8 samples at times 30, 60, 90, 120, 150, 180, 240 and 300 min after bolus injection of iohexol of 570 adults, aged 70+, from the Berlin Initiative Study (BIS), were analysed. The fit-parameters for the two-compartment model (double-exponential decay curve), and from these, the AUC and GFR were obtained with 8 different fitting procedures.ResultsThe two-compartmental non-linear least squares fitting procedure showed the best accuracy (541 out of 570 reported GFR-results were within 5% of the majority of the 8 fitting methods). The two-compartmental slope-intercept fitting procedure was not always applicable and the non-compartmental fitting procedures did not always allow to calculate the GFR. All correction formulas for the simplified late multiple-samples methods showed acceptable accuracy and precision with a preference for Ng's correction formula (Lin's CCC = 0.992, bias = 0.5 ± 2.5). Jacobsson's iterative method was the best one-sample method, with Lin's CCC = 0.983 and bias = - 0.6 ± 3.4.ConclusionThe fitting procedure has an important impact on the precision of the calculated AUC and GFR. The simplified late-sample protocols and one-sample methods did not suffer from fitting problems and showed acceptable equivalence when compared to the full compartment GFR-results.Trial registrationThe "Berlin Initiative Study" is officially registered with the German Register for Clinical Studies ("Deutschen Register Klinischer Studien"(DRKS)) under registration number DRKS00017058 , since April 12, 2019, and it is also visible on the WHO clinical trials registry platform (within the next 4 weeks after the registration date).

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Iohexol Plasma Clearance: Impact of Weighing the Syringe

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