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Using a three-compartment model improves the estimation of iohexol clearance to assess glomerular filtration rate.

ABSTRACT: Plasma clearance of iohexol is a key tool to precisely determine glomerular filtration rate (GFR) in clinical research and clinical practice. Despite evidence that iohexol pharmacokinetics are described best by three-compartment models, two-compartment approaches (Schwartz approach) are customary, which might result in avoidable bias and imprecision. We aimed to provide a population pharmacokinetic (popPK) model of iohexol by re-evaluating data from the Berlin Initiative Study (BIS) to compare respective clearance estimates to the Schwartz approach and to assess the impact of revised clearance estimates on the BIS equations. A popPK model was developed based on iohexol plasma samples (8-10 per subject, iohexol dose 3235?mg) from 570 elderly patients. A three-compartment model appropriately described the pharmacokinetics of iohexol (clearance 57.4?mL/min, CV 33%). Compared to the three-compartment model, clearance values were overestimated by the Schwartz approach (bias 6.5?mL/min), resulting in limited effects on regression coefficients of the BIS equations (e.g., proportionality factor of BIS2 changed from 767 to 720). Predictions based on the BIS2 equation were biased (5.4?mL/min/1.73?m²) and the sensitivity to detect a GFR?

SUBMITTER: Taubert M

PROVIDER: S-EPMC6286374 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Using a three-compartment model improves the estimation of iohexol clearance to assess glomerular filtration rate.

Taubert Max M Ebert Natalie N Martus Peter P van der Giet Markus M Fuhr Uwe U Schaeffner Elke E

Scientific reports 20181207 1

Plasma clearance of iohexol is a key tool to precisely determine glomerular filtration rate (GFR) in clinical research and clinical practice. Despite evidence that iohexol pharmacokinetics are described best by three-compartment models, two-compartment approaches (Schwartz approach) are customary, which might result in avoidable bias and imprecision. We aimed to provide a population pharmacokinetic (popPK) model of iohexol by re-evaluating data from the Berlin Initiative Study (BIS) to compare r ...[more]

PMID: 30531802

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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).

Project description:BackgroundAccurate evaluation of glomerular filtration rates (GFRs) is of critical importance in clinical practice. A previous study showed that models based on artificial neural networks (ANNs) could achieve a better performance than traditional equations. However, large-sample cross-sectional surveys have not resolved questions about ANN performance.MethodsA total of 1,180 patients that had chronic kidney disease (CKD) were enrolled in the development data set, the internal validation data set and the external validation data set. Additional 222 patients that were admitted to two independent institutions were externally validated. Several ANNs were constructed and finally a Back Propagation network optimized by a genetic algorithm (GABP network) was chosen as a superior model, which included six input variables; i.e., serum creatinine, serum urea nitrogen, age, height, weight and gender, and estimated GFR as the one output variable. Performance was then compared with the Cockcroft-Gault equation, the MDRD equations and the CKD-EPI equation.ResultsIn the external validation data set, Bland-Altman analysis demonstrated that the precision of the six-variable GABP network was the highest among all of the estimation models; i.e., 46.7 ml/min/1.73 m(2) vs. a range from 71.3 to 101.7 ml/min/1.73 m(2), allowing improvement in accuracy (15% accuracy, 49.0%; 30% accuracy, 75.1%; 50% accuracy, 90.5% [P<0.001 for all]) and CKD stage classification (misclassification rate of CKD stage, 32.4% vs. a range from 47.3% to 53.3% [P<0.001 for all]). Furthermore, in the additional external validation data set, precision and accuracy were improved by the six-variable GABP network.ConclusionsA new ANN model (the six-variable GABP network) for CKD patients was developed that could provide a simple, more accurate and reliable means for the estimation of GFR and stage of CKD than traditional equations. Further validations are needed to assess the ability of the ANN model in diverse populations.

Project description:IntroductionThere is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m(2)).MethodsWe randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined.ResultsMean PC was 76.7 ± 28.5 mL/min/1.73 m(2) (SBI), and 78.9 ± 28.6 mL/min/1.73 m(2) (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p < 0.0001). Bias was 2.2 mL/min/1.73 m(2) (limits of agreement -8.2 to 12.6 mL/min/1.73 m(2)) for CILDI. PC overestimated RC by 7.1 ± 7.3 mL/min/1.73 m(2). Mean intra-individual variation in GFR (CILDI) was 10.3% (p < 0.003). Mean ± SD Css was 172 ± 185 min.ConclusionWe hypothesise that changes in GFR >10.3% depict evolving AKI. If this were applicable to AKI, this is less than the 50% change in serum creatinine currently required to define AKI. CILDI is now ready for testing in patients with AKI.Trial registrationThis trial was registered with the European Union Clinical Trials Register ( https://www.clinicaltrialsregister.eu/ ), registration number: 2010-019933-89 .

Dataset Information

Using a three-compartment model improves the estimation of iohexol clearance to assess glomerular filtration rate.

Publications

Using a three-compartment model improves the estimation of iohexol clearance to assess glomerular filtration rate.

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