Drug dosing and estimates of kidney function

Abstract

Serum (or plasma) creatinine, creatinine clearance (CrCl), estimated creatinine clearance (eCrCl) and estimated glomerular filtration rate (eGFR) are used to assess kidney function in order to detect and manage kidney disease and to optimize the dosing of renally excreted medicines. Despite improvements in assay performance following the introduction of isotope dilution mass spectrometry (IDMS)-traceable creatinine methods, including enzymatic methods, serum creatinine results can still vary by 13% between laboratories at levels of 85 mmol/L. In addition to methodological issues, there are other limitations to serum creatinine as a measure of kidney function. For example, serum creatinine can vary by about 10% depending upon meat intake; creatinine is secreted in the proximal tubule and at low urine flow rates can be reabsorbed; extrarenal excretion of creatinine can also occur. Creatinine is not an ideal filtration marker. CrCl is calculated using methods that do not measure the ‘true’ creatinine, but which estimate its concentration in blood and a timed urine collection. To avoid collecting a timed urine, numerous equations and nomograms have been devised to estimate CrCl from serum creatinine. In estimating CrCl, it is assumed that creatinine excretion is constant and equal to creatinine production, which itself is proportional to muscle mass and can, in turn, be estimated from an individual’s age, gender and weight. eCrCl will overestimate CrCl in obese or oedematous patients and in those with reduced creatinine production. eCrCl also assumes that serum creatinine concentration is at steady state. eCrCl is probably most commonly calculated using the Cockcroft and Gault (C&G) equation first described in 1976 using serum creatinine measured with a kinetic Jaffe assay on a Technicon Autoanalyser II. In principle, the technique used to determine the patient’s serum creatinine should be the same as the one used to derive the equation from which the eCrCl (or eGFR) are calculated: this can clearly not be the case with modern use of the C&G equation. Other equations have now been proposed including the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology (CKD-EPI) collaboration equations that estimate GFR normalized to a body surface area (BSA) of 1.73m. All equations are valid only for the population in which they were derived and some have been produced for more specific purposes, e.g. the Wright formula for cancer patients. Wright et al. recognized that such equations were also serum creatinine method dependent. The C&G equation has been and is used in pharmacokinetic studies. It is therefore included in drug dosage information despite the fact that the serum creatinine method used to derive it is no longer available and despite the fact that IDMS-traceable creatinine assays tend to give lower results and therefore a higher eCrCl than the earlier non-IDMS traceable creatinine assays. In 2005, the Department of Health recommended the use of the MDRD equation to detect chronic kidney disease (CKD) in the UK. Since then eGFR has been routinely reported and the relative merits of using eGFR and the C&G eCrCl to guide drug dosing have been debated in the literature. On occasions, articles arguing for eGFR have appeared in the same edition of the same journal as articles supporting the continued use of the C&G eCrCl. In this edition of the Annals, Chin et al. compare the performance of C&G, MDRD and CKD-EPI equations in predicting gentamicin clearance. The authors