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Several whole-body variables are available for indexing glomerular filtration rate (GFR), including extracellular fluid volume (ECF volume, ECV), which has the advantage that GFR based only on the terminal exponential, alpha 2, of the chromium-51 ethylene diamine tetraacetic acid (51Cr-EDTA) plasma clearance curve is a measure already indexed for ECV. This slope-only method, however, is open to the theoretical criticism of a lack of robustness not present in the more conventional slope/intercept method, which generates GFR in absolute units before indexation to body surface area (BSA). To further evaluate the slope-only method, a large database of routine three-sample GFR measurements, based on 51Cr-EDTA, was analysed with the aim of comparing GFR/BSA with GFR/ECV, identifying the main sources of error in their respective measurements and explaining why they might be discrepant. The database was subdivided into 304 patients (group A) in whom the correlation coefficient of the fit to the three data points was greater than 0.99 and 31 patients in whom it was less than 0.99 (noisy data; group B). There was modest agreement between GFR/BSA and GFR/ECV in group A (r = 0.77; mean ratio 1.01 +/- 0.21). The difference between them correlated significantly with BSA (r = 0.52; P < 0.001), as would be expected given that small individuals have a relatively high BSA. Subdividing group A into four subgroups stratified according to BSA led to a slight improvement in the correlation between GFR/BSA and GFR/ECV. Because an error in alpha 2 is balanced by an opposing error in the intercept (which leads to a change in distribution volume in the opposite direction), and therefore impacts on both GFR/BSA and GFR/ECV, whereas an error in administered dose affects only GFR/BSA, it is possible to evaluate such errors by examining the respective relationships of GFR/BSA and GFR/ECV with indexed ECV. In group A, GFR/BSA correlated positively with ECV/1.73 m2, not surprisingly as ECV/BSA is effectively the ratio GFR/BSA to GFR/ECV, while GFR/ECV correlated negatively with ECV/1.73 m2. This implies that errors other than alpha 2, probably principally in administered dose, were as important as errors in alpha 2. This conclusion was supported by disappearance of the positive correlation between GFR/BSA and ECV/BSA in group B, brought about by the greater errors in alpha 2 in this group. This study suggests that, because of the effects of errors in the slope/intercept method that do not affect alpha 2, GFR based on slope only is at least as robust as that based on slope/intercept.

The conventional way in which to scale or index a measurement of glomerular filtration rate (GFR) is to express it in relation to body surface area (BSA). However, BSA may not be appropriate for infants and children because, as individuals increase in size, their relative BSA decreases. Several other whole-body variables have been suggested as alternatives, including extracellular fluid volume (vECF). The purpose of the present study was to compare BSA and vECF as variables against which to index GFR, and in particular to look at this comparison in children versus adults. A total of 130 patients (age range 1-80 years; 40 patients <12 years) undergoing clinically indicated routine measurement of GFR using the bolus-injection single-compartment technique were included in the study. GFR was measured as the plasma clearance of [(51)Cr]EDTA as assessed from three peripheral venous blood samples taken between 2 and 4 h after injection of [(51)Cr]EDTA. Volume of distribution (V(d)) was obtained by extrapolation of the clearance curve to zero time. GFR was scaled to a BSA of 1.73 m(2). GFR and GFR/1.73 m(2) were corrected to account for the assumption of a single compartment. The rate constant of the exponential between 2 and 4 h was also corrected to give GFR/litre ECF. GFR and GFR/1.73 m(2) were both divided by GFR/litre ECF, to give vECF and vECF/1.73 m(2) respectively. Weight per unit BSA increases as a linear function of BSA. vECF is always less than V(d), on average by about 30%. vECF increased as an exponential function of BSA and as a linear function of body weight. vECF/70 kg body weight was higher in children (16. 2+/-3 litres) than adults (13.4+/-2.3 litres), but vECF/1.73 m(2) was lower in children (9.7+/-1.7 litres) compared with adults (12. 4+/-2 litres). vECV/1.73 m(2) increased as a function of both age and BSA, but vECF/kg decreased. GFR/12.5 litres vECF was higher than GFR/1.73 m(2) in children, but these values were similar in adults, with the ratio of these two forms of indexed GFR falling significantly with both age and BSA. Although this was not a normal population, but one with a wide range of renal function, GFR/vECF showed a strong inverse association with age, whereas for GFR/BSA the association was weak. In conclusion, these data provide further evidence that vECF is more valid physiologically for indexing GFR than is BSA, especially in children. Nevertheless, a GFR measurement in a child should ideally be expressed as a percentage of normal for that child's age. However, such normal values are not yet available.

The bolus injection, single-compartment technique for measuring GFR overestimates the true value. Nevertheless, assuming that for a given indicator the area under the first exponential of the plasma clearance curve is constant from subject to subject, the observed (uncorrected) value can be corrected by multiplication with a 'sliding' factor, the value of which is a nonlinear function of GFR. Several second-order polynomials, based on pre-determined relationships between simultaneously determined two-compartment and one-compartment GFR, have been described for correcting GFR (GFR correction). It is, however, theoretically more rational to use a factor which depends on the rate constant, alpha2, of the terminal exponential of the clearance curve. We have therefore determined a set of linear equations from retrospectively analysed multiple-sample inulin, 99mTc-DTPA and 51Cr-EDTA clearance curves to enable correction of GFR using alpha2. A set of linear equations is also developed to correct the volume of distribution (Vd) of the indicator (close to extracellular fluid volume for these indicators), which is also overestimated by the one-compartment technique. At low levels of GFR, alpha2-corrected GFR is similar to uncorrected GFR for all three indicators. As GFR increases, however, uncorrected GFR progressively overestimates (alpha2-corrected GFR. The overestimation is greater for inulin than for 99mTc-DTPA or 51Cr-EDTA. In the one-compartment approximation, Vd is overestimated more than GFR, and again the greatest overestimation is seen with inulin. In a prospective study of 129 patients undergoing routine measurement of GFR with 51Cr-EDTA, alpha2 correction using a factor based on retrospective EDTA data gave values of GFR which were higher than values obtained from GFR correction using a previously published polynomial (also based on EDTA clearances) by 15% in children and 12.5% in adults when uncorrected GFR was 150 ml/min/1.73 m2. Moreover, the ratio of uncorrected GFR to GFR-corrected GFR was higher in children than adults. We conclude that alpha2 is a more rational variable with which to correct two-sample or three-sample GFR than GFR itself, that the correction formulae are not interchangeable between inulin on the one hand and EDTA and DTPA on the other, and that the relative magnitudes of the corrections given by alpha2 correction versus GFR correction are different for children and adults.