Abstract
Monitoring iohexol plasma clearance is considered a useful, reliable, and sensitive tool to establish glomerular filtration rate (GFR) and early stages of kidney disease in both humans and veterinary medicine. The assessment of GFR based on iohexol plasma clearance needs repeated blood sampling over hours, which is not easily attainable in a clinical setting. The study aimed to build a population pharmacokinetic (Pop PK) model to estimate iohexol plasma clearance in a population of dogs and based on this model, to indicate the best sampling times that enable a precise clearance estimation using a low number of samples. A Pop PK model was developed based on 5 iohexol plasma samples taken from 5 to 180 minutes (min) after an intravenous iohexol nominal dose of 64.7 mg/kg from 49 client-owned dogs of different breeds, sexes, ages, body weights, and clinical conditions (healthy or presenting chronic kidney disease CKD). The design of the best sampling times could contain either 1 or 2 or 3 sampling times. These were discretized with a step of 30 min between 30 and 180 min. A two-compartment Pop PK model best fitted the data; creatinine and kidney status were the covariates included in the model to explain a part of clearance variability. When 1 sample was available, 90 or 120 min were the best sampling times to assess clearance for healthy dogs with a low creatinine value. Whereas for dogs with CKD and medium creatinine value, the best sampling time was 150 or 180 min, for CKD dogs with a high creatinine value, it was 180 min. If 2 or 3 samples were available, several sampling times were possible. The method to define the best sampling times could be used with other Pop PK models as long as it is representative of the patient population and once the model is built, the use of individualized sampling times for each patient allows to precisely estimate the GFR.
Highlights
Glomerular filtration rate (GFR) is considered the most useful indicator of the overall kidney function and a sensitive biomarker to establish early stages of kidney disease in both humans and veterinary medicine (Schwartz et al, 2006; Lefebvre 2011)
The assessment of GFR based on iohexol plasma clearance has a major limitation on the requirement of repeated blood sampling over several hours, which is not feasible in a clinical setting
Dogs were of different breeds, sexes, ages, body weights, and clinical conditions, all scheduled at the University Veterinary Teaching Hospital of the University of Milan for different clinical procedures
Summary
Glomerular filtration rate (GFR) is considered the most useful indicator of the overall kidney function and a sensitive biomarker to establish early stages of kidney disease in both humans and veterinary medicine (Schwartz et al, 2006; Lefebvre 2011). GFR is generally determined by different methods monitoring plasma clearance of a marker substance, and iohexol is considered a useful and reliable plasma clearance marker (Delanaye et al, 2016b). Strategies to reduce the number of sampling have been exploited as first reported by Bröchner-Mortensen (1972) in humans All of these foresaw the addition of correction formulas to achieve more accurate GFR estimation (Gleadhill and Michell 1996; Bexfield et al, 2008; Von Hendy-Willson and Pressler 2011; Sasaki et al, 2015; Pocar et al, 2019). From veterinary practitioners there is still a demand for reliable and applicable GFR estimations methods in a clinical setting
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