Weighing the Evidence: The Challenge of Developing Evidence-Based Renal Dosing Strategies:

Evaluating drug dosing to account for patient renal function is one of the primary review functions of a hospital pharmacist. Available estimates of renal function have known limitations, but laboratory and medical advances have improved the detection and classification of kidney disease. How do new, more accurate methods of classifying renal disease apply to the interpretation of drug dose recommendations derived by other, less accurate methods? The application of these new strategies to medication dose evaluation lacks clarity. The Cockcroft-Gault estimation of creatinine clearance (CrCl) was introduced in 1976 and has been a standard consideration for drug dose evaluation in adult patients with renal impairment. Although it has been routinely used, this method has recognized limitations. For example, the standard modification to account for female gender in the Cockcroft-Gault equation is theoretical; the original study population did not include female patients. The Modification of Diet in Renal Disease (MDRD) estimation of glomerular filtration rate (GFR) was introduced in 1999 and generally provides a more accurate assessment of renal function than traditional estimates in adult patients. Because the MDRD equation was not available or generally accepted as a method for classifying kidney function during the development of most marketed drugs, clinicians may be unsure about how to apply estimated GFR to drug dose evaluation. Both Cockcroft-Gault and MDRD estimates are based on studies in patients with stable renal function. In contrast, hospitalized patients often demonstrate dynamic renal function due to changing clinical status and comorbidities. National Kidney Disease Education Program (NKDEP) guidance on drug dosing recognizes this limitation and acknowledges that available estimates do not account for all factors that affect serum creatinine concentrations. Available estimates lack accuracy for patients with body size or muscle mass extremes. Some clinicians using the Cockcroft-Gault equation round the low serum creatinine values in elderly patients to another value, such as 1 mg/dL, or utilize ideal body weight to overcome these limitations. However, these approaches are not evidence-based, and researchers have demonstrated that these modifications are less accurate. 2-5 A standardized technique to calibrate serum creatinine assays introduced several years ago is now expected to be fully implemented nationally. Standardization minimizes variation of serum creatinine assay results between clinical laboratories and should lead to more consistent dosing for drugs eliminated renally. Changes to serum creatinine reference ranges would have been expected at most facilities upon implementation. Standardization has generally resulted in higher CrCl values as estimated by the CockcroftGault equation. According to the NKDEP, because the original study samples are no longer available and the creatinine assay method used to derive the CockcroftGault equation is no longer utilized, the equation cannot be re-expressed to the new standardized creatinine values. In contrast, standardized calibration of serum creatinine assays increases the accuracy of estimating GFR by the MDRD method. Current US Food and Drug Administration (FDA) guidance for the industry on pharmacokinetics published in 1998 acknowledges measured serum creatinine concentrations or estimated CrCl as recognized methods to classify kidney function for drug dosing. Draft guidance posted for review in 2010 reflects the significant changes in the body of knowledge in classifying renal disease and incorporates MDRD as well as Cockcroft-Gault estimates of kidney function. According to the NKDEP, clinicians should use either the MDRD equation or the Cockcroft-Gault equation to estimate kidney function for drug dosing.