Accurate measurement of extracellular fluid volume from the slope/intercept technique after bolus injection of a filtration marker.

Extracellular fluid volume (ECV) is studied infrequently. The zero-time distribution volume (Vd) generated in the slope-intercept technique for measuring the glomerular filtration rate (GFR) substantially overestimates ECV. The aim was to validate a new technique for measuring ECV from the slope-intercept approach. GFR and ECV were measured using Cr-51-EDTA and iohexol injected into opposite arms in 51 patients undergoing routine measurement of GFR and on 48 occasions in 20 healthy volunteers. Blood samples were obtained bilaterally 20, 40, 60, 120, 180 and 240 min post-injection and assayed for indicator injected contralaterally. Reference ECV (ECV6) was calculated from all six samples as the product of indicator transit time and multi-sample GFR. GFR/ECV was calculated as the rate constant of the exponential fitted to the last three samples (GFR/ECV3). Slope-intercept GFR was calculated from the last three samples using the slope-intercept technique (GFR3). ECV (ECV3) was calculated by dividing GFR3 by GFR/ECV3, having corrected both for their one-compartment assumptions. ECV6(EDTA) correlated closely with ECV3(EDTA) (ECV3(EDTA) = 1.01.ECV6(EDTA)-0.5 L; r = 0.97; n = 99), but less closely with Vd (Vd = 1.17.ECV6(EDTA) + 0.7 L; r = 0.86). ECV6(iohexol) correlated slightly better with ECV6 (EDTA) (ECV6(EDTA) = 0.81.ECV6(iohexol) + 3.3 L; r = 0.86) than with ECV3(EDTA) (ECV3(EDTA) = 0.83.ECV6(iohexol) + 2.9 L; r = 0.84) and had slightly narrower 95% limits of agreement (-3.82 and 2.82 L versus -3.90 to 3.43 L). In conclusion, ECV can be measured from three samples almost as accurately as ECV from multiple samples.

Comparison of GFR measurements assessed from single versus multiple samples.

BACKGROUND: Many previous studies have evaluated single-sample glomerular filtration rate (GFR) against multisample GFR, of which the single sample was a member, but none have compared single and multisample GFRs against an independent reference method. We therefore performed this comparison by using simultaneous independent multisample GFR measured with a different indicator. SETTING & PARTICIPANTS: University hospital: patients and healthy volunteers (95 studies in 60 patients and 20 healthy participants). Healthy volunteers were studied fasting and after food; 10 of them had a repeated fasting study. STUDY DESIGN: Diagnostic test study. INDEX TEST: Single-sample GFR. REFERENCE TEST: Multisample GFR with a different indicator. MEASUREMENTS: GFR was measured by using chromium-51 ((51)Cr)-EDTA and iohexol, injected into opposite arms and scaled to 1.73 m(2). Blood samples, obtained bilaterally 20, 40, 60, 120, 180, and 240 minutes after injection, were assayed for indicator injected contralaterally. Single-sample GFR (Jacobsson method) was calculated from indicator concentrations at 3 and 4 hours. Single-sample GFR from 1 indicator was compared with multisample GFR from the other and vice versa, as well as from the same indicator. Differences were expressed as limits of agreement between paired measurements in Bland-Altman plots. Precision was expressed as the SD of the mean difference between paired measurements. RESULTS: Limits of agreement between multisample GFRs measured by using (51)Cr-EDTA and iohexol (-12 to 20 mL/min) were similar to the corresponding limits for single-sample GFR at 3 (-16 to 17 mL/min) and 4 hours (-11 to 17 mL/min). The precision of single-sample GFR at 4 hours by using (51)Cr-EDTA for predicting iohexol multisample GFR (6.9 mL/min) was better than that of multisample GFR with (51)Cr-EDTA (7.9 mL/min). When analysis was limited to patients with GFR less than 60 mL/min, single-sample GFR was slightly inferior to multisample GFR. In healthy participants, single-sample GFR with (51)Cr-EDTA at 3 and 4 hours showed repeatability (SD of change, 9.4 and 9.3 mL/min) similar to multisample GFR with (51)Cr-EDTA (10.7 mL/min). Single-sample GFR at 4 hours by using (51)Cr-EDTA detected a food-induced increase in GFR (4.4 +/- 5.9 mL/min; P < 0.001) with more confidence than multisample GFR by using (51)Cr-EDTA (4.6 +/- 7.5 mL/min; P < 0.01). LIMITATIONS: No separate gold standard (eg, inulin) to facilitate interpretation of observed differences between 2 markers. CONCLUSIONS: Single-sample GFR is as reliable as multisample GFR for measuring GFR, especially when GFR is greater than 60 mL/min.

Evaluation of the Modification of Diet in Renal Disease equation (eGFR) against simultaneous, dual-marker multi-sample measurements of glomerular filtration rate.

BACKGROUND: Estimation of glomerular filtration rate (GFR) using plasma creatinine remains controversial, especially when GFR approaches normal values. The aim was to re-examine estimated GFR (eGFR) using dual-reference GFR measurements. METHODS: eGFR (simplified modified Modification of Diet in Renal Disease equation) was compared with GFR measured with iohexol for predicting GFR measured with (51)Cr-ethylenediaminetetraacetic acid (EDTA). Dual six-sample GFR (20-240 min postinjection) was measured in 60 patients and 20 normal volunteers with (51)Cr-EDTA (GFR(EDTA)) and iohexol (GFR(iohexol)) injected into separate arms and sampled contralaterally. This was repeated in the normal volunteers under fasting conditions (twice in nine). Percentage bias, imprecision (SD of bias) and disagreement (sign-less difference) between eGFR and GFR(EDTA) were compared with those between GFR(iohexol) and GFR(EDTA). RESULTS: Changes between fasting and postprandial eGFR correlated significantly with corresponding changes in GFR(iohexol) and GFR(EDTA). eGFR predicted GFR(EDTA) less precisely (SD 19.9%) than GFR(iohexol) (10.5%; P < 0.01). Although eGFR showed a poorer correlation with GFR(EDTA) when GFR(EDTA) > 80 mL/min/1.73 m(2) compared with <80 mL/min/1.73 m(2), there was no significant difference with respect to imprecision or disagreement of >20 or 30%. However, eGFR was closer than GFR(iohexol) to GFR(EDTA) in a higher fraction of studies when GFR(EDTA) > 80 mL/min/1.73 m(2) (28/60) than when it was <80 mL/min/1.73 m(2) (9/37; P < 0.05). CONCLUSION: eGFR is inferior to GFR(iohexol) for predicting GFR(EDTA). The disagreement between GFR(iohexol) and GFR(EDTA) illustrates the extent to which uncertainty in GFR(EDTA) contributes to the performance of eGFR. eGFR performs no better at lower, compared with higher levels of GFR.

Using the slope-only technique and estimated glomerular filtration rate for checking the reliability of slope-intercept measurement of glomerular filtration rate.

AIM: To develop a strategy for checking the reliability of slope intercept measurement of glomerular filtration rate (GFR). METHODS: Six blood samples, obtained bilaterally 20-240 min after the injection of Cr-ethylenediaminetetraacetic acid (EDTA) and iohexol into opposite arms, were assayed for indicator injected contralaterally. GFR6iohexol, the reference value, was measured for all six samples and GFR3EDTA (slope-intercept) for the last three samples (per 1.73 m). GFR was measured from the half-time [GFR/extracellular fluid volume (ECV)3EDTA], for the single samples at 2-4 h (Christensen-Groth; GFR1) and for creatinine [estimated GFR (eGFR)]. RESULTS: In six of the 97 studies, the correlation coefficient (r) of the fit to the last three sample points was less than 0.99. In the remaining 91 studies, GFR3EDTA disagreed with GFR/ECVEDTA by more than 15% in 19 studies (group A) and by less than 15% in 72 studies (group B). GFR3EDTA disagreed with GFR6iohexol by 12.6% in group A but only by 6.3% in group B (P<0.001). No such discrimination was displayed by eGFR. Although GFR3EDTA was within 15%of GFR6iohexol in 14 group A studies, eGFR was within 15% of GFR3EDTA in only eight studies and disagreed by more than 15% in six studies. Conversely, in the five of the 19 studies in which GFR3EDTA disagreed with GFR6iohexol by more than 15%, the agreement between eGFR and GFR3EDTA was less than 15% in two studies and more than 15% in three studies. GFR3EDTA was within 15% of GFR/ECV3EDTA in all six studies in which r was less than 0.99, and GFR3EDTA disagreed with GFR6iohexol by less than 15%. Confidence in GFR3EDTA was not improved by GFR1 or eGFR. CONCLUSION: Slope intercept GFR is reliable if within 15% of GFR/ECV3. Estimated GFR was ineffective as a second checkpoint. GFR1 did not help when the fit was poor.

Suitability of a simplified technique based on iohexol for decentralized measurement of glomerular filtration rate.

OBJECTIVE: The aim of the study was to assess a simplified method for measuring glomerular filtration rate (GFR) using iohexol that could form the basis of a decentralized service for measuring GFR by sample transportation. MATERIAL AND METHODS: Non-fasting GFR was measured with Cr-51-EDTA and iohexol injected simultaneously into opposite arms (n = 110). Cubital venous blood samples, obtained bilaterally 20, 40, 60, 120, 180 and 240 min after injection, were assayed for marker injected contralaterally, Cr-51-EDTA by well-counting and iohexol by X-ray fluorescence. Following biexponential analysis of the clearance curves, GFR was measured from all six samples and also from the last three samples and scaled to body surface area (BSA). GFR scaled to extracellular fluid volume (GFR/ECV) was calculated from six samples as the mean transit time of marker through its distribution volume and from three samples as the clearance half-time. RESULTS: Cr-51-EDTA correlated closely with iohexol for measuring GFR/BSA (r = 0.97 for three samples, 0.94 for six). The two markers agreed more closely with each other in the measurement of GFR/BSA compared with GFR/ECV. GFR/BSA values showed better agreement with corresponding GFR/ECV values when they were measured with Cr-51-EDTA compared with iohexol. Six samples offered no significant advantage compared with three. CONCLUSIONS: Iohexol is less accurate than Cr-51-EDTA and scaling to BSA is more robust than scaling to ECV. Nevertheless, iohexol has potential to measure GFR by sample transportation, without having to measure injected dose. This would allow accurate measurement of GFR in a primary care setting.

Reproducibilities and responses to food intake of GFR measured with chromium-51-EDTA and iohexol simultaneously and independently in normal subjects.

BACKGROUND: The aim was to evaluate the reproducibility of glomerular filtration rate (GFR) measured with iohexol and its response to food in a direct and independent comparison with Cr-51-ethylenediaminetetraacetic acid (EDTA), and examine the influence of two different whole body scaling parameters, body surface area (BSA) and extracellular fluid volume (ECV). METHODS: Fasting and non-fasting GFR were measured in 20 normal volunteers using Cr-51-EDTA and iohexol, simultaneously injected into opposite arms. In 10, the fasting study was repeated. Venous samples obtained bilaterally 20, 40, 60, 120, 180 and 240 min after injection were assayed for indicator injected contralaterally-Cr-51-EDTA by well-counting and iohexol by X-ray fluorescence. GFR scaled to BSA was measured from six samples (GFR/BSA6) and from the last three (GFR/BSA3). GFR scaled to ECV was calculated as the mean transit time of marker using six samples (GFR/ECV6) or the last three (GFR/ECV3). RESULTS: GFR/BSA3 was reproducible (coefficient of variations of 7.4% for Cr-51-EDTA and 7.6% for iohexol). Using Cr-51-EDTA, GFR/ECV3 (9.1%) and GFR/ECV6 (7.7%) were as reproducible as GFR/BSA3 and GFR/BSA6 (both 8.1%). However, GFR/ECV3 measured with iohexol had poorer reproducibility (16.8%). Food resulted in an increase in scaled GFR of about 5 ml/min but this was statistically significant only with respect to GFR/BSA (measured with Cr-51-EDTA or iohexol) and not GFR/ECV. CONCLUSIONS: Measured with Cr-51-EDTA, but not iohexol, GFR/ECV was as reproducible as GFR/BSA. GFR/BSA, measured with Cr-51-EDTA or iohexol, but not GFR/ECV, significantly increased after food.

Comparison between slope-intercept and slope-only techniques for measuring glomerular filtration rate: use of two independent markers and an independent arbiter.

PURPOSE: Exclusive use of the half-time of clearance of a filtration marker in the bolus injection, single compartment technique for measuring glomerular filtration rate (GFR) is a convenient approach that gives GFR (GFR(SO)) already scaled for extracellular fluid volume (ECV). It has been criticized as less accurate than the conventional, slope-intercept technique (GFR(SI)). The aim of the study was to compare the respective levels of agreement of GFR(SI) and GFR(SO) with GFR based on plasma creatinine (eGFR) used as an independent arbiter. METHODS: GFR was measured with both 51Cr-EDTA and iohexol, simultaneously injected into opposite arms. Plasma obtained bilaterally 20, 40, 60, 120, 180 and 240 min after injection was assayed for marker injected contra-laterally, 51Cr-EDTA by well-counting and iohexol by X-ray fluorescence. ECV and GFR, scaled to body surface area (BSA), were formally measured from six samples and GFR(SI) (scaled to BSA) and GFR(SO) from the last three. RESULTS: Disagreement between GFR(SO) measured with 51Cr-EDTA and eGFR was not significantly higher than the corresponding disagreement between eGFR and GFR(SI). Disagreement between GFR(SO) measured with iohexol and eGFR was significantly higher than between eGFR and GFR(SI). GFR(SI) and GFR(SO) correlated more closely when measured with 51Cr-EDTA than with iohexol. Individual differences between GFR(SI) and GFR(SO) using one marker correlated significantly with ECV measured with the other. CONCLUSIONS: GFR(SO) is critically dependent on the accuracy of half-time measurement and, measured with iohexol, appeared less reliable than GFR(SI). GFR(SI) and GFR(SO) measured with 51Cr-EDTA, however, have similar levels of reliability.

Extracellular distribution volumes of hydrophilic solutes used to measure the glomerular filtration rate: comparison between chromium-51-EDTA and iohexol.

Extracellular fluid volume (ECV) is larger when measured with Tc-99m-DTPA ( approximately 500 Da) than inulin (6 kDa). As part of an assessment of the suitability of the non-radioactive marker, iohexol, against the gold standard tracer, Cr-51-EDTA, for measurement of the glomerular filtration rate (GFR) based on a postal service, we took the opportunity to determine if this volume dependence is present for diffusible markers less disparate in size than inulin and Tc-99m-DTPA. Cr-51-EDTA ( approximately 400 Da) and iohexol ( approximately 900 Da) were administered into the opposite arms of 20 normal volunteers (fasting and non-fasting) and 60 patients (non-fasting), including 36 diabetics, 10 cancer patients and 13 dermatology patients. Blood was obtained from both arms 20, 40, 60, 120, 180 and 240 min after injection and assayed for a marker injected contra-laterally. The glomerular filtration rate (GFR) and mean indicator transit time, T, were measured from the bi-exponential clearance curves. ECV, the product of GFR and T, was subdivided into V(1) (administered indicator divided by the sum of zero-time intercepts of the two exponentials) and V(2) (the difference between V(1) and ECV). Variables were scaled to 1.73 m(2). For all 100 studies, the mean GFR from Cr-51-EDTA was 3 ml min(-1) higher than iohexol (p < 0.01). ECV was 0.41 L higher (p < 0.02) and V(1) 0.65 L higher (p < 0.001) from Cr-51-EDTA but V(2) was 0.33 L lower (p < 0.02). V(1)/ECV was 0.031 higher from Cr-51-EDTA (p < 0.01). ECV and V(2) from Cr-51-EDTA were both higher in diabetics (15.1 [1.7] and 5.0 [0.095] L, respectively) compared with normal non-fasting subjects (13.7 [1.5] and 4.3 [1.0]; p < 0.01). ECV and the volumes of its sub-compartments are different between markers that are less than an order of magnitude different in size.