Chronic kidney disease is particularly prevalent in the aging feline population, with approximately 10% of cats aged 10 to 15 years affected.1 A primary goal in managing chronic kidney disease in cats is to identify those in the early stages of disease, when intervention may be directed at the underlying cause as well as at intrinsic and extrinsic factors contributing to its progression. This has led to an increased demand for precise methods of measuring GFR, which is generally accepted as the most sensitive index of functioning renal mass. Measurement of GFR is also useful clinically to evaluate patients with polyuria or polydipsia and patients with plasma creatinine concentrations that are at or near the upper reference limit to assess renal function prior to the use of renally excreted drugs, to predict the clearance of cancer drugs from the body,2 or to evaluate the response to therapeutic interventions aimed at improving renal function.
Glomerular filtration rate can be estimated from the plasma or urinary clearance of an endogenous or exogenously administered filtration marker. Many such markers are limited in their use in feline practice because of the need for accurately timed urine collections, urinary catheterization, or nuclear medicine facilities or because of lack of an available medical-grade injectable formulation. The nonionic radiographic contrast agent iohexol can be administered exogenously as a single bolus dose, and its plasma clearance can be used to estimate GFR. Iohexol is useful as a clearance marker because it is freely filtered by the kidneys, is not secreted into the renal tubules, has negligible protein binding, and is not metabolized within the body.3–5 Several studies6–17 have involved the use of this marker for estimation of GFR in cats.
Iohexol exhibits endoisomerism and exoisomerism.18 Analysis of iohexol concentrations in samples by use of high-performance liquid chromatography allows detection of the 2 types of isomers (EnIox and ExIox). The predominant isomer is quantitatively known to be ExIox. Previous studies12,13,16,17 have revealed a difference in the clearance of the 2 isomers in cats. Measurement of Tlox may therefore lead to inaccuracies in the estimation of clearance. To determine the doses of EnIox and ExIox that have been administered, the correct ratio of each isomer must be known. The stereoselective disposition of the isomers may change in different solutions as a result of their physicochemical properties, the solution temperature,18 or the storage duration.19 The ratio of plasma concentrations may therefore change after administration when compared with the ratio in the administered formulation.
Accurate methods of determining plasma clearance rely on the collection of blood samples at multiple points to create a plasma concentration-versus-time curve. Development of techniques that involve collection of a limited number of samples has become an important goal. It was first proposed by Brochner-Mortensen20 that the initial rate of redistribution of a marker is not only independent of GFR but is also relatively constant from subject to subject and that an estimate of GFR may, without any important loss of accuracy, be based on the second elimination exponential. Errors may nevertheless arise when calculating clearance from a limited number of samples; therefore, inclusion of both exponentials (redistribution and elimination exponentials) is recommended. Exclusion of the redistribution exponential leads to an overestimation of the GFR because the AUC is underestimated.21 The error becomes particularly important in patients with clinically normal or near-normal renal function, in which the initial rapid redistribution exponential contributes to a relatively larger proportion of the AUC, compared with patients with a low GFR.
Clearance calculated from a limited number of samples collected during the elimination phase is referred to as the slope-intercept technique. Formulae that correct for the distribution exponential when a slope-intercept method is used have been developed for human patients, the most commonly used being the Chantler22 and Brochner-Mortensen20,23 formulae. A dog-specific formula has also been developed.24 The primary purpose of the study reported here was to derive a correction formula for estimating GFR in cats by use of the slope-intercept technique. A secondary aim was to determine whether correction formulae derived in humans20,23 and dogs24 could substitute for the cat-specific formula. The final purpose was to compare the plasma clearance of EnIox, ExIox, and TIox.
Area under the curve
Glomerular filtration rate
Omnipaque300, Amersham Health, Piscataway, NJ.
Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Belgium.
Chemical Pathology Department, Epsom and St Helier University Hospital NHS trust, Epsom, England.
Phoenix WinNonlin 6.0, Pharsight, Sunnyvale, Calif.
SPSS, version 17.0, SPSS Inc, Chicago, Ill.
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