Methods for determination of renal impairment – a critical review with special focus on Cockcroft-Gault

Oral presentation

The glomerular filtration rate (GFR) is traditionally used as measure to characterise renal function in health and disease. In clinical practice most clinicians estimate the GFR by calculation of creatinine clearance (Cl_Cr) from serum creatinine concentration using the Cockcroft-Gault formula [1]. The FDA Guidance for Industry "Pharmacokinetics in patients with impaired renal function" [2] explicitly suggests a wording for the labeling which includes that dosage adjustment, if necessary, may be dependent on creatinine clearance derived from a spot serum creatinine using the Cockroft-Gault formula. The frequent use of the Cockcroft-Gault formula in clinical practice justifies to question how the formula was generated and how useful it is in the assessment of renal function.

Cockroft and Gault reviewed the hospital records of 249 male patients with at least two 24-hour Cl_Cr measurements which did not vary by more than 20 %. S_Cr was estimated in a fasting blood sample. They plotted the mean 24-h creatinine excretion / kg body weight (CrUV24/kg) for 7 different age groups (overall age between 18 and 92) against the mean age of the respective groups. Linear regression was applied to the mean values leading to the following regression equation: CrUV24/kg / kg [mg/kg] = 28 – (0.2 x age in years)

Transforming this equation led to the urinary 24 h creatinine excretion. This term was inserted into a clearance equation and transformed into the widely used Cockroft-Gault formula (see Table 1).

However, the methodology of Cockcroft and Gault can be criticized: Applying linear regression to mean values without taking into account the different number of subjects within the age groups overemphasizes the influence of small age groups. Only the data of male subjects were used to derive the equation. The use of a factor of 0.85 to obtain estimates in women is based on expert opinion only. Details about the method of creatinine in serum and urine are missing.

Recently, data obtained in the MDRD Study (Modification of Diet in Renal Disease Study) were used by Levey et al. [3] to develop a new prediction equation. "True" GFR was measured as ¹²⁵I-iothalamate clearance. Stepwise multiple regression was used to determine a set of variables that predicted GFR. The equation which accounted for the highest percentage of the variability in GFR (R² = 91.2) included demographic (age, sex, race) and laboratory variables (serum creatinine and urea nitrogen, urine urea nitrogen). Recently, an abbreviated equation with only four variables was introduced [4], see Table 1.

Other (direct an indirect) methods of GFR estimation

Table 2 summarizes and comments methods which are currently used in the assessment of GFR.

Conclusion

Dosing adjustment in renal impairment should be based on a method, which easily can be applied by clinicians. This only applies for methods by which GFR is estimated from serum creatinine. All other clearance methods mentioned above require equipment which is not routinely available in clinical practice. Although the Cockcroft-Gault formula can be criticized, it is still widely used. The equations derived from the MDRD study are based on "modern" statistic methods. However, they still require validation, e.g. in a European population. Nevertheless these formula lead to a more accurate prediction of GRF from serum creatinine than the Cockcroft-Gault formula.

References

1. Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine.

   Nephron 1976, 16:31-41. PubMed Abstract

2. US Department of Health and Human Services, Food and Drug Administration: Guidance for Industry. Pharmacokinetics in Patients with impaired renal function – study design, data analysis, and impact on dosing and labeling. May 1999
3. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation.

   Ann Intern Med 1999, 130:461-470. PubMed Abstract | Publisher Full Text

4. Levey AS, Greene T, Kusek JW, Beck GJ: A simplified equation to predict glomerular filtration rate from serum creatinine.

   J Am Soc Nephrol 2000, 11:A0828.

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