Accuracy and Limitations of Equations for Predicting the Glomerular Filtration Rate during Follow-up of Patients with Non-diabetic Nephropathies

Guy Rostoker; Pierre Andrivet; Isabelle Pham; Mireille Griuncelli; Serge Adnot


BMC Nephrology 

In This Article


In 126 adults with non-diabetic chronic renal disease (mainly glomerular diseases), we estimated the time course of the glomerular filtration rate with the gold-standard method (inulin clearance). In patients with deteriorating renal function, the original Cockcroft and Gault formula, the BSA-modified Cockcroft and Gault formula, the abbreviated MDRD equation and the Mayo Quadratic equation all gave reliable estimates of the GFR slope, with an acceptable bias. In contrast in the patients with improving renal function, the original Cockcroft and Gault formula, the BSA-modified Cockcroft and Gault formula, the abbreviated MDRD equation and the Mayo Quadratic equation underestimated the gain in GFR, although this may have less important clinical consequences. In the subgroup of patients with improving renal function, the underestimation of the slope was smaller with the abbreviated MDRD equation than with the other three equations.

To date, GFR equations have been developed and validated almost exclusively with cross-sectional data sets. The Cockcroft and Gault formula is an estimate of creatinine clearance originally developed in a population of 236 Canadian patients, 209 of whom were male.[2] The Cockcroft and Gault formula was further shown to be a reliable estimate of GFR in twelve studies comparing the results of the estimate with methods giving true GFR values (inulin; 2 studies with 196 patients) or more accurate GFR values (10 studies with 1218 patients; 3 studies with 99m-Tc-DPTA; 4 studies with 51Cr-EDTA; 2 with iothalamate, 1 with hippuran (reviewed in [3,4]). Three studies, one published in 1984[16] using iothalamate, an isotope with significant tubular secretion,[17] the second in 1992, in a small cohort of 20 patients with type I diabetes[18] and the third comparing inulin clearance in a cohort of 269 European patients with chronic nephropathies,[4] have shown that correction for body surface area (BSA) improves the accuracy of the original Cockcroft and Gault equation.

The MDRD formulas were developed as an estimate of 125I-Iothalamate clearance-based GFR in a population of 1628 patients with a diagnosis of CKD.[5] The MDRD equations yielded smaller median absolute errors (3.8 mL/min/1.73 m2) than the Cockcroft and Gault equation (6.8 mL/min/1.73 m2) in the princes study.[11] In recent studies conducted in France with 51Cr-EDTA, the MDRD equation was more accurate for the diagnosis and stratification of renal failure in diabetic type II patients.[19,20] Finally, despite the fact that the MDRD equations were developed in patients with heavily impaired renal function (CKD stages 3 and 4),[5] the abbreviated MDRD formula has been shown to properly categorize patients with CKD stage 2, and has fairly good accuracy in these patients.[4,21,22]

The Mayo clinic quadratic equation is a new equation based on the results of iothalamate clearance in both 320 patients with chronic kidney diseases and 580 healthy subjects evaluated for kidney donation.[6] Elderly subjects and African-Americans were underrepresented in this sample.[6] The Mayo quadratic equation was further shown to have similar diagnostic performance to the MRDD equation in diabetic patients; in contrast to MDRD equation, the Mayo quadratic equation does not underestimate normal GFR in diabetic subjects;[23]

As previously discussed, five studies, all restricted to patients with type I and II diabetes, have shown the poor accuracy of prediction equations for monitoring kidney function, unless frank renal impairment has occurred.[8–12]

One study in lung transplant patients compared longitudinal follow-up based on creatinine-based formulas (Cockcroft and Gault equation and MDRD equation 7) with the Iothalamate GFR for at least 24 months, and concluded that the creatinine-based slopes correlated with Iothalamate slopes in this setting but consistently underestimated the rate of GFR decline.[24] Similar conclusions were recently drawn in study of kidney transplant patients.[25] A post-hoc analysis of the African American Study of Kidney Disease and Hypertension (AASK) has recently shown that outcomes based on the AASK creatinine formula and the MDRD equations were similar to those obtained with 125I-Iothalamate GFR and similarly identified most risk factors for progression of renal failure.[26] Conversely, in a cohort of 234 patients with autosomal dominant polycystic kidney disease and a baseline creatinine clearance > 70 ml/min followed for 4 years, although Iothalamate clearance, the abbreviated MDRD equation and the Cockcroft-Gault formula gave similar slopes, predictor associations for renal function decline were strongest with iothalamate clearance, because non-GFR factors (e.g. creatinine production and tubular secretion) conservatively biased associations with GFR estimates.[27] Moreover, in a retrospective cohort study of 542 subjects who had been included in the MDRD study and followed for a median of 2.6 years, the estimated GFR slope tended to underestimate measured decrements in 125I-Iothalamate GFR.[28] The main methodological limitations of these latter studies was the use of 125I-Iothalamate for GFR measurement indeed, Odlind and coworkers have shown that this isotope is subject to significant tubular secretion in chicken, rats and humans.[17] The tubular secretion of iothalamate becomes even marked in case of renal failure and can overestimate GFR by up to 34%; these authors stated that iothalamate is not an ideal reference substance for GFR determinations in clinical studies, with an accuracy comparable to that of creatinine.[17]

The main limitation of our study lies in the day-to-day variations that are known to occur in inulin clearance (11%–16%), and in serum creatinine (15.5%–19.6%).[5] Furthermore, we did not pay special attention to the calibration of serum creatinine measurements, which has been shown to be of critical importance in individuals with normal or near-normal serum creatinine values, and to influence the accuracy of MDRD equations.[29–31] In clinical trials, accurate determination of the glomerular filtration rate and correct evaluation of changes in renal function are mandatory and require direct GFR measurement with inulin, isotopes or radiocontrast media.[32] In contrast, clinicians require a less expensive and less time-consuming test than direct GFR measurement, and although the results should be accurate, they do not need to be as precise as in clinical trials. The accuracy of the creatinine-based formula for follow-up of chronic nephropathies could be improved by calibrating serum creatinine measurements (see discussion above)[29–31] and by using cimetidine combined with an enzymatic plasma creatinine assay which has been shown in a longitudinal study of type II diabetic nephropathy to abolish the discrepancies between the iothalamate slope and the original Cockcroft and Gault equation.[33] Finally, for patients at an early phase of reduction of GFR reduction (CKD stage 1 and 2) and those whose GFR is improving, because of its higher diagnostic accuracy in patients with mildly to moderately impaired kidney function, cystatin C may provide useful additional information relative to the Cockcroft and Gault formulas and MDRD equations.[34,35] Indeed, an equation combining both serum creatinine and cystatin levels with demographic and morphologic data was recently shown in children to have better accurancy than the Schwartz equation when compared to EDTA clearance.[36] Similarly, in Chinese patients with near-normal renal function, a GFR estimate combining serum creatinine and cystatin C matched DTPA-clearance more closely than MDRD equations.[37] Preliminary data strongly suggest that a combination of cystatin C and serum creatinine also improves the monitoring of kidney function in patients with diabetes mellitus.[38] Finally, in a pooled analysis of 3418 subjects with CKD of various stages living in the USA and France and evaluated for GFR by isotope clearance (iothalamate and EDTA), an equation including serum cystatin in combination with serum creatinine, age, sex and race provided a more accurate estimate of GFR than cystatin or creatinine alone.[39]


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