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Simplified Iohexol-Based Method for Measurement of Glomerular Filtration Rate in Goats and Pigs.

ABSTRACT: The preclinical evaluation of novel therapies for chronic kidney disease requires a simple method for the assessment of kidney function in a uremic large animal model. An intravenous bolus of iohexol was administered to goats (13 measurements in n = 3 goats) and pigs (23 measurements in n = 5 pigs) before and after induction of kidney failure, followed by frequent blood sampling up to 1440 min. Plasma clearance (CL) was estimated by a nonlinear mixed-effects model (CL_NLME) and by a one-compartmental pharmacokinetic disposition model using iohexol plasma concentrations during the terminal elimination phase (CL_1CMT). A simple method (CL_SM) for the calculation of plasma clearance was developed based on the most appropriate relationship between CL_NLME and CL_1CMT. CL_SM and CL_NLME showed good agreement (CL_NLME/CL_SM ratio: 1.00 ± 0.07; bias: 0.03 ± 1.64 mL/min; precision CL_SM and CL_NLME: 80.9% and 80.7%, respectively; the percentage of CL_SM estimates falling within ±30% (P30) or ±10% (P10) of CL_NLME: 53% and 12%, respectively). For mGFR_NLME vs. mGFR_SM, bias was -0.25 ± 2.24 and precision was 49.2% and 53.6%, respectively, P30 and P10 for mGFR based on CL_SM were 71% and 24%, respectively. A simple method for measurement of GFR in healthy and uremic goats and pigs was successfully developed, which eliminates the need for continuous infusion of an exogenous marker, urine collection and frequent blood sampling.

SUBMITTER: van Gelder MK

PROVIDER: S-EPMC8224736 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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 .

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Simplified Iohexol-Based Method for Measurement of Glomerular Filtration Rate in Goats and Pigs.

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