Can a Glomerular Filtration Rate Estimate Be Too High?

An accurate estimate of a patient's glomerular filtration rate (GFR) is a critical element in the safe and effective dosing of renally eliminated medications. Serum creatinine, which is an endogenous marker of glomerular filtration, is commonly used to help estimate the GFR. The GFR estimate is derived using either the Cockcroft-Gault or modification of diet in renal disease (MDRD) equation. The MDRD equation estimates the GFR directly, whereas the Cockcroft-Gault equation estimates creatinine clearance (CrCl). CrCl is the parameter most often used in clinical trials to determine dose adjustments for renally eliminated medications.

Many problems are associated with using estimation equations:

1. The use of the filtration marker creatinine, which is generated by the breakdown of creatine in muscle, limits both estimation equations.
2. Patient-to-patient variation in muscle mass and diet have a significant effect on creatinine generation and subsequent clearance estimates produced by these equations.
3. CrCl slightly overestimates the GFR due to the fact that creatinine is not only filtered by the glomerulus but also secreted by the proximal tubule.
4. In patients with acutely increasing serum creatinine, the CrCl and GFR are overestimated, whereas in patients with declining serum creatinine, the CrCl and GFR are underestimated.
5. CrCl and GFR equations are less accurate at higher levels of the estimated CrCl and GFR.

Given the aforementioned list, there are reasons that clinicians should be circumspect of extremely elevated estimates:

1. The highest CrCl value for participants in the Cockcroft and Gault study was 130 mL/min; the highest value in the MDRD study was 90 mL/min/1.73 m².The accuracy of values higher than those from which the estimating equation was derived and tested is likely to be suboptimal.
2. Patients with altered muscle mass caused by poor nutrition, paralysis, amputation, or deconditioning due to chronic illness will have decreased creatinine production. This will result in lower serum creatinine values than would be expected for a similar patient without altered muscle mass. Estimating the CrCl or GFR using these values will result in an overestimate that can be quite significant.

Due to all the potential factors that affect calculated CrCl or GFR estimates, it is important for the clinician to use judgment when using these values to adjust drug dosages. Rather than blindly following recommendations derived from calculated estimates, careful assessment of the clinical status of the patient and the desired therapeutic outcomes as well as the risks associated with subtherapeutic or supratherapeutic doses of the pharmacologic agent must always be considered. When possible, drug level monitoring will give more accurate guidance to ensure appropriate dosing.