Abstract
Renal drug elimination is a function of the combined processes of glomerular filtration, tubular secretion and reabsorption. Traditionally the dosing of renally excreted drugs has been modified according to estimates of glomerular filtration rates (eGFR) using equations based on serum creatinine(1, 2). The assumptions inherent in this process are that all components of kidney function decline at the same rate and in direct relationship with eGFR(3-6) and that eGFR is a reasonable estimate of measured GFR (mGFR). However, many drugs are eliminated by tubular anionic and cationic transport where a decline in eGFR may not necessarily reflect parallel changes in tubular function. This study investigates the relationship between GFR and renal tubular function with reference to drug handling using an established drug “cocktail” method(7-9). Measured GFR (mGFR; Cr51 EDTA clearance) is compared to tubular anionic transport (urate clearance), tubular reabsorption (fluconazole clearance) and cationic transport (S-pindolol clearance). In addition, the influence of comorbid pathology (primarily hypertension) over and above that of aging alone is investigated by recruiting subjects with a range of ages, coexistent disease and renal function and comparing four groups. The groups investigated were “young” controls with normal serum creatinine, two groups above the age of 65 years with normal creatinine both with and without mild co-morbid pathology known to affect renal function such as hypertension, diabetes and heart disease and those with established chronic kidney disease. To complete the study mGFR is compared to several of the commonly utilised estimating formulae for GFR (eGFR).
The major findings demonstrate a moderate positive correlation between mGFR and proximal tubular anion transport and reabsorption (R2=0.41 and 0.44, p<0.05). In contrast, cationic secretion correlated poorly with mGFR (R2=0.11, p<0.05). In the study population with normal renal function the estimating equations significantly underestimated measured GFR (-26-38 mL/min/1.73m2) with the Chronic Kidney Disease Epidemiology (CKD-EPI) formula the most accurate overall. The tubular processes investigated displayed declining clearances with age and GFR. However, in the elderly with normal creatinine, mild pathology unexpectedly increased clearances relative to those without disease.
In clinical practice the elderly, both with and without comorbid disease, form a significant proportion of any caseload where adjustments of drug dosing for renal function are extremely important to avoid significant side effects. However given that drug-dosing schedules utilise eGFR values as the basis for modifying drug dosing, these results suggest that a global recommendation of dose reduction according to eGFR alone should be treated with some caution. This is due to the significant underestimation in GFR by the estimating equations in those without chronic kidney disease (CKD) and the lack of parallel decline of tubular function to GFR. This is most significant where cationic tubular handling of the drug is the major component of elimination where reliance on eGFR may lead to under-dosing of these medications.