CamGFR v2: A New Model for Estimating the Glomerular Filtration Rate from Standardized or Non-standardized Creatinine in Patients with Cancer.

PURPOSE: Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS-standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods. EXPERIMENTAL DESIGN: GFR measurements, biometrics, and IDMS- or non-IDMS-standardized creatinine values were collected for adult patients from three cancer centers. Using statistical modeling, an IDMS and non-IDMS creatinine-compatible eGFR model (CamGFR v2) was developed. Its performance was compared with that of the existing models Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund-Malmö revised, and CamGFR v1, using statistics for bias, precision, accuracy, and clinical robustness. RESULTS: A total of 3,083 IDMS- and 4,612 non-IDMS-standardized creatinine measurements were obtained from 7,240 patients. IDMS-standardized creatinine values were lower than non-IDMS-standardized values in within-center comparisons (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in Manchester; P < 0.0001), and more consistent between centers. CamGFR v2 was the most accurate [root-mean-squared error for IDMS, 14.97 mL/minute (95% confidence interval, 13.84-16.13) and non-IDMS, 15.74 mL/minute (14.86-16.63)], most clinically robust [proportion with >20% error of calculated carboplatin dose for IDMS, 0.12 (0.09-0.14) and non-IDMS, 0.17 (0.15-0.2)], and least biased [median residual for IDMS, 0.73 mL/minute (-0.68 to 2.2) and non-IDMS, -0.43 mL/minute (-1.48 to 0.91)] eGFR model, particularly when eGFR was larger than 60 ml/minute. CONCLUSIONS: CamGFR v2 can utilize IDMS- and non-IDMS-standardized creatinine measurements and outperforms previous models. CamGFR v2 should be examined prospectively as a practice-changing standard of care for eGFR-based carboplatin dosing.

New gender-specific formulae for estimating extracellular fluid volume from height and weight in adults.

AIMS: First, to derive gender-specific formulae for estimation of extracellular fluid volume (eECV) and second, compare eECV as a scaling metric for slope-intercept glomerular filtration rate (GFR) with estimated body surface area (eBSA), lean body mass (eLBM) and total body water (eTBW). METHODS: GFR and 'slope-only' GFR (GFR/ECV), both single compartment-corrected, were measured in a previously published multicentre database of healthy potential kidney transplant donors. Measured ECV (mECV) was obtained as ratio GFR-to-GFR/ECV. Formulae for eECV in men and women were derived from the relationship of mECV with height and weight and expressed as eECV = a.weight.height. In a population of prospective kidney transplant donors from a single centre, eECV was compared with mECV. GFR was scaled to eECV, eBSA, eLBM and eTBW, estimated from previously published formulae. RESULTS: In men and women, respectively, a was 0.0755 and 0.0399, x was 0.6185 and 0.6065 and y was 0.4982 and 0.6217. In the single centre, biases (±precisions) of eECV against mECV in men and women were 0.26 (±1.68) and 0.31 (±1.67) l. Mean GFR/eBSA was higher in men but mean GFR/eLBM and GFR/eTBW were higher in women. Mean GFR/ECV and mean GFR/eECV were very similar between the two genders. GFR/ECV and GFR/eECV showed correlations with each other that were almost identical between men and women. CONCLUSIONS: New formulae are described for estimating eECV. Scaling GFR to eECV is more physiological than scaling to eBSA and accounts for gender. eECV used for measuring GFR from a single blood sample should be gender-specific.

Evaluation of non-polynomial equations for one-compartment correction of slope-intercept GFR: theoretical prediction and experimental measurement.

BACKGROUND: Polynomial equations for one-compartment correction of slope-intercept glomerular filtration rate (GFR) will underestimate values at high clearance rates. Non-polynomial correction equations that are independent of patient size and renal function would be advantageous and may have cross-species use. MATERIALS AND METHODS: The study explored the theoretical basis of firstly the Jodal and Brochner-Mortensen one-compartment correction equation, replacing plasma volume with extracellular fluid volume, and secondly an equation described by Peters. One-compartment correction factors (a which is related to plasma volume and v which is related to extracellular fluid volume) which avoided the need for scaling to body size were developed. Both factors were determined from the biexponential clearance curve of the markers iohexol and (51)Cr-EDTA in humans and iohexol in cats and dogs. Relationships between a and v and filtration function and body size were then determined using data from humans, cats and dogs to assess their validity and compare this with theoretical predictions. RESULTS: In all species, v was higher than a, as theoretically predicted. Both were significantly higher in humans than cats and dogs, ruling out cross-species use. Significant relationships were present between v and measures of filtration function in humans, but were weak with respect to a. Neither a nor v showed significant relationships with filtration function in animals or with body size in any species. CONCLUSIONS: a and v (which are factors independent of body size) can be used interchangeably for correcting slope-intercept clearance. However values of both for humans are higher compared to cats and dogs. Therefore a single cross-species factor cannot be used.

Extracellular fluid volume and glomerular filtration rate: their relation and variabilities in patients with renal disease and healthy individuals.

INTRODUCTION: The slope-only technique for measuring glomerular filtration rate (GFR) relies on extracellular fluid volume (ECV) remaining within narrow limits. Although this requirement is met in healthy individuals, ECV may deviate or vary more in patients with abnormal renal function. METHODS: We examined the correlation between surface area-scaled ECV and GFR, and their coefficients of variation (CVs), measured from simultaneous, multisample clearances of 51Cr-EDTA and iohexol in 20 healthy volunteers and 60 patients with a range of renal functions. We also compared scaled GFR and ECV, and their CVs, measured from three-sample, slope-intercept clearance of 51Cr-EDTA in 921 patients routinely referred for GFR measurement. RESULTS: In the 80 participants undergoing multisample, dual-indicator clearance, there was no correlation between GFR measured with one indicator and ECV measured with the other. CVs of GFR in the 60 patients were 48.1 and 44.6% for 51Cr-EDTA and iohexol, respectively, but the CVs of ECV were only 12.3 and 15.4%. These differences were less marked in the healthy participants with corresponding CVs of 13.9 and 14.9% for GFR, and 11.7 and 12.2% for ECV. There was no correlation between scaled GFR and ECV in patients having slope-intercept clearance; CVs of GFR and ECV were 32.4 and 17.8%, respectively. CONCLUSION: In unselected patient populations, there is no correlation between GFR and ECV. The CV of ECV is slightly higher in patients than healthy individuals but, in both, is less than the CV of GFR. These data do not detract from the use of slope-only GFR.

Slope-only glomerular filtration rate and single-sample glomerular filtration rate as measurements of the ratio of glomerular filtration rate to extracellular fluid volume.

AIMS: The Jacobsson single-sample equation for measuring glomerular filtration rate (GFR) after bolus injection is based on two factors of questionable theoretical validity for correcting the single-compartment assumption. The aims were to redevelop a more transparent equation, show its fundamental similarity with 'slope-only' GFR and compare it with the original equation and with slope-only GFR. METHODOLOGY: The modified Jacobsson equation is k = (1/t).ln[V(t)/V(0)], where k is the rate constant of the terminal exponential and V(0) and V(t) are distribution volumes at times 0 and t. V(0) exceeds extracellular fluid volume (ECV): that is k' = (1/t).ln[V(t)/ECV], where k' > k. Moreover, [GFR/ECV] >k (= k + [15.4.k(2)]). The ratio k/k' was determined in 476 patients to calculate single-sample k (3 or 4 h post-injection). Slope-only and single-sample GFR/ECV were measured using Cr-51-EDTA in 105 further studies, multiplied by ECV (estimated from weight), scaled to 1.73 m(2) and compared with GFR/1.73 m(2) from the original Jacobsson equation against reference multi-sample GFR/1.73 m(2) simultaneously and independently measured with iohexol. RESULTS: The relation between k and k' was linear. k/k' was 0.827 at 3 h and 0.864 at 4 h. There was no difference in bias or precision between the original Jacobsson and modified equations. In both, precision was better than slope-only GFR/BSA. When GFR remained scaled to ECV, slope-only GFR showed marginally better precision against reference GFR/ECV. CONCLUSIONS: Single-sample and slope-only techniques give GFR as k. Although the theory of the modified Jacobsson equation is more transparent than the original equation, it gives the same result. It is, however, easier to use.

Estimated lean body mass is more appropriate than body surface area for scaling glomerular filtration rate and extracellular fluid volume.

BACKGROUND/AIMS: To compare body surface area (BSA) with lean body mass (LBM) for scaling extracellular fluid volume (ECV) and glomerular filtration rate (GFR). METHODS: Phase 1: Total body water (TBW), bromide space and LBM were measured with (3)H-water, (77)Br and dual X-ray absorptiometry, respectively, in 6 healthy adults. Phase 2: ECV and GFR were measured with (51)Cr-EDTA in 95 healthy adults and 56 children (0.5-13 years). ECV was calculated as GFR divided by GFR/ECV, both corrected for the one-compartment assumption. LBM was estimated (eLBM) in adults from height and weight and in children using a height/weight formula for estimating ECV and a constant derived from a separate adult population relating ECV to eLBM. RESULTS: Phase 1: LBM and BSA correlated closely with TBW and bromide space. With LBM, the regressions passed through the origin, but with BSA, the intercepts were significantly below zero. Phase 2: GFR/BSA and ECV/BSA were higher in men than women but no difference was recorded in GFR/eLBM, GFR/ECV or ECV/eLBM. ECV showed a linear relation with eLBM and a non-linear relation with BSA. GFR/BSA and ECV/BSA correlated significantly with BSA but neither GFR/eLBM nor ECV/eLBM correlated with eLBM. CONCLUSION: eLBM is preferable to BSA for scaling GFR and ECV.

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.

Effect of extracellular fluid volume on single-sample measurement of glomerular filtration rate.

UNLABELLED: Objective. The objective of our study was to evaluate the effect of extracellular fluid volume (ECV) on the accuracy of measurement of glomerular filtration rate from a single sample (GFR1). METHODS: Multi-sample GFR (GFR6) and ECV (per 1.73 m(2)) were measured with both Cr-51-EDTA and iohexol, injected into opposite arms (110 studies in 80 subjects). Six plasma samples were obtained bilaterally 20- 240 min post-injection to measure GFR6/1.73 m(2). GFR1/1.73 m(2) was calculated from 2-, 3- and 4-h samples using Jacobsson's formula for iohexol and the Christensen and Groth formula for Cr-51-EDTA. The quotient, GFR1/GFR6, was taken to indicate the accuracy of GFR1. RESULTS: When GFR6 was <60 ml/min/1.73 m(2), GFR1/ GFR6 correlated positively with ECV at all single-sample times. When GFR6 was 60-90 ml/min/1.73 m(2) or >90 ml/min/1.73 m(2), GFR1/GFR6 correlated positively with ECV at 2 h, but negatively at 4 h, indicating that at some time between 2 and 4 h, GFR1/GFR6 was transiently independent of ECV. A plot of the regression gradient of GFR1/GFR6 on ECV against sample time indicated that the time of transient independence, at which time GFR1 depends exclusively on GFR6, was 3.2-3.9 h (depending on indicator combination used) when GFR6 was 60-90 ml/min/1.73 m(2) and 2.4-2.9 h when GFR was >90 ml/min/1.73 m(2). Transient independence when GFR6 was <60 ml/min/1.73 m(2) was not reached by 4 h and estimated to be 5-7 h. CONCLUSION: The accuracy of GFR1 depends on ECV, overestimation or underestimation respectively depending on sample time and GFR. The time at which GFR1 is independent of ECV increases with decreasing GFR. If sampling time is too early, GFR1 overestimates GFR, but the reverse occurs when sampling is too late, even if GFR is abnormally low.

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.

Quantification of disease activity in patients undergoing leucocyte scintigraphy for suspected inflammatory bowel disease.

PURPOSE: Whole-body gamma camera counting is an alternative to faecal 111In collection for quantifying disease activity in inflammatory bowel disease (IBD) but requires administration of imaging activities of 111In. The aim of this study was to explore a dedicated whole-body counter which requires 20-fold less activity than gamma camera counting. METHODS: Thirty patients with known or suspected IBD received 99mTc-granulocytes (approximately 200 MBq) and 111In-granulocytes (approximately 0.5 MBq). The 99mTc-cells were injected 45 min after the 111In-cells and immediately after a baseline 111In whole-body count. The decay-corrected count at 120 h was expressed as a fraction of baseline to give whole-body 111In retention (WBR). One patient was excluded as the injected cells were non-viable. RESULTS: Median 45-min intravascular 111In recovery was 35% in patients compared with 43% in six normal volunteers (p<0.05). WBR in normals ranged from 91% to 93% and in 11 patients with negative 99mTc imaging from 87% to 96%. Only one of 11 patients with negative imaging had WBR <90% while 11/12 patients with WBR <90% had abnormal imaging. Ten of 13 patients with Crohn's disease (CD) had abnormal imaging. The lowest WBR in these ten was 77% and six had values of >90%. There was a significant association between WBR and 99mTc image grade (Rs=0.73, p<0.002) in 16 patients without CD, but not in 13 patients with CD (Rs=0.54, p>0.05). CONCLUSION: Dedicated whole-body counting is able to quantify disease activity in IBD but may give normal values in active CD.

Radionuclide method for evaluating the performance of hemodialysis in vivo.

BACKGROUND: Specifications of dialyzer performance are generally based on in vitro measurements. There is, however, a shortage of data on dialyzer performance in vivo. The aim of this study was to use continuous measurement of technetium-99m-diethyltriaminepentaacetic acid (Tc-99m-DTPA) blood concentration as a means of continuously monitoring dialyzer function in vivo in patients undergoing routine hemodialysis. METHODS: The study population comprised 15 patients (45 to 80 years old; 13 males). Tc-99m-DTPA was administered intravenously 90 minutes before obtaining a blood sample and starting dialysis. Blood Tc-99m-DTPA activity was continuously monitored by passing the line carrying blood from the patient to the dialyzer close to a scintillation probe mounted in a shielded housing. At the end of hemodialysis, lasting 180 to 300 minutes, chromium-51-ethylenediaminetetraacetic acid (Cr-51-EDTA) was given intravenously and a blood sample taken 90 minutes later. Baseline dialyzer blood flow (Q(b)) and dialysate flow (Q(d)) were 250 to 350 mL/min and 500 mL/min, respectively. The rate constant, alpha, of the decrease in blood Tc-99m-DTPA activity was used as the measure of moment-to-moment dialyzer function. Pre- and postdialysis extracellular fluid volumes were calculated from the blood Tc-99m-DTPA and Cr-51-EDTA concentrations (V(DTPA) and V(EDTA)) before and after dialysis. Tc-99m-DTPA clearance was measured as the product of alpha and V(DTPA). Dialyzer urea clearance was calculated from pre- and postdialysis urea nitrogen concentrations and the time of dialysis. The effects of brief changes in Q(b) and Q(d) on dialyzer function were assessed from the associated changes in alpha. RESULTS: The Tc-99m-DTPA clearance profile was biexponential, becoming monoexponential about 1 hour after starting hemodialysis, with alpha remaining constant for as long as dialysis continued in five patients in whom Q(b) and Q(d) were left unaltered. Mean (SEM) plasma Tc-99m-DTPA clearance averaged over the entire period of dialysis in all 15 patients was 110 (3.1) mL/min. It correlated with urea clearance (r= 0.71) (P < 0.01) which was 225 (9.5) mL/min based on a total body water of 2.5 that of V(DTPA) and 212 (13) mL/min scaled to 40 L/1.73 m(2). Extracellular fluid volume decreased by 1.73 (0.74) l over dialysis, which was comparable to the change in weight [1.48 (0.57) kg]. The extraction fraction of Tc-99m-DTPA across the artificial kidney, directly measured from afferent and efferent blood samples under baseline Q(b) and Q(d), was 0.5 (0.013). Average extraction fraction indirectly estimated from Tc-99m-DTPA blood clearance and Q(b) was 0.54 (0.019). These two measurements of extraction fraction correlated with each other under conditions of varying Q(b) and Q(d) (r= 0.74) (N= 27) (P < 0.001). Changes in alpha resulting from changes in Q(b) and Q(d) were similar to changes predicted from computerized modeling. The ratio of mass transfer coefficients of urea and Tc-99m-DTPA with respect to the dialyzer, calculated as if they were permeability-surface area products, was 3.3, similar to the ratio, obtained from the literature, in continuous capillary endothelium. CONCLUSION: Tc-99m-DTPA is a useful agent for continuously monitoring dialyzer function in vivo and provides a platform for the use of other radio-pharmaceuticals of different molecular sizes that could be used in an analogous fashion.

Evaluation of a 3-hour indium-111 leukocyte image as a surrogate for a technetium-99m nanocolloid marrow scan in the diagnosis of orthopedic infection.

OBJECTIVES: This is a retrospective study to evaluate a 3-hour In-111-labeled leukocyte image as a surrogate for a Tc-99m nanocolloid marrow scan in the investigation of suspected orthopedic infection using In-111 leukocyte scintigraphy. METHODS: Images from 51 patients who had received contemporaneous In-111-labeled leukocyte scintigraphy and Tc-99m nanocolloid marrow scintigraphy were reviewed. Initially, the 3-hour and 22-hour In-111-labeled leukocyte images were compared. Sites of abnormal uptake on the 22-hour image were correlated with the 3-hour image and were graded according to the level of concordance or discordance. One week later, the Tc-99m nanocolloid images and 22-hour In-111-labeled leukocyte images of the same patients were compared and graded for concordance or discordance. When discrepancies in grading arose between the observers, a consensus opinion was achieved after additional review of the images a week later. RESULTS: On inspection of the 22-hour In-111 leukocyte images, 93 sites of focal, potentially abnormal leukocyte accumulation were identified. When the grading system was reduced to simply "concordant" or "discordant," there was good agreement between the observers in the majority of cases, with kappa statistics 0.77 for Tc-99m nanocolloid versus 22-hour In-111-labeled leukocyte images and 0.78 for 3-hour versus 22-hour In-111-labeled leukocyte images. Using the comparison of the Tc-99m nanocolloid marrow scan and the 22-hour In-111-labeled leukocyte images to identify concordance or discordance as the "gold standard" for scintigraphic evaluation of suspected orthopedic infection, comparison of the 3-hour In-111-labeled leukocyte images with the 3-hour In-111-labeled leukocyte images gave a sensitivity of 77%, a specificity of 77%, and an accuracy of 77%. CONCLUSIONS: A 3-hour image is helpful using In-111-labeled leukocyte scintigraphy.

Time to complete mixing for the measurement of glomerular filtration rate from single bolus plasma 51Cr-EDTA clearance.

BACKGROUND AND METHOD: In the measurement of glomerular filtration rate from the plasma clearance of 51Cr ethylenediamine tetraacetic acid by using the slope-intercept method, the first sample is conventionally taken at 2 h, the time by which it is generally assumed that the clearance curve has reached a single exponential. We examined this assumption by comparing the slopes, alpha 12 and alpha 23, based, respectively, on samples at 2 and 3 h, and at 3 and 4 h. RESULTS: In 421 patient studies in whom the first sample was taken between 110 and 130 min after injection, the mean ratio, alpha 12/alpha 23, was 1.101 (SEM 0.011) which is significantly higher than unity (P<<0.001). The relationship between alpha 12/alpha 23 and the slope, alpha 13 (which is a measure of filtration function already indexed for body size) based on all three samples was negative. By modelling the relationship between mixing time and alpha 13 it was shown that this relationship suggests delayed mixing of the indicator throughout its distribution volume and is inconsistent with irreversible binding of indicator to plasma protein. A significant positive association was observed between alpha 12/alpha 23 and age, but this is largely explained by a generally poorer filtration function in the older age group since low levels of alpha 13 theoretically predict a longer mixing time. In 188 patient studies in whom the first sample was taken more than 130 min after injection, the mean ratio, alpha 12/alpha 23, was 1.055 (SEM 0.017) which is still significantly higher than unity (P<<0.005) but significantly less than the ratio based on studies in which the first sample was taken at 110-130 min (P<0.02). The ratio alpha 12/alpha 23 still showed a significant relation (positive) with age but not with filtration function. CONCLUSION: This error in the estimation of glomerular filtration rate to which delayed mixing leads will make its greatest impact when using the simplified slope-only technique, but can be minimized by delaying the first blood sample.

Indexing glomerular filtration rate to suit children.

UNLABELLED: In order to be able to compare individuals of differing size, glomerular filtration rate (GFR) is conventionally indexed to body surface area (BSA). This does not, however, suit children because they naturally have a relatively high BSA simply because of their small size. The aim of the study was to identify an appropriate simple whole-body variable based on height and weight suitable for indexing GFR that would be simultaneously appropriate for both children and adults. METHODS: A database of 532 routine clinical GFR measurements, each based on 3 venous blood samples obtained between 2 and 4 h after injection of (51)Cr-ethylenediaminetetraacetic acid, was analyzed to give GFR and, using only the half-time of the slope of the clearance curve, the quotient GFR to extracellular fluid volume (ECV). BSA was obtained from the Haycock formula, which is based on height and weight raised to indices to give units of area. Both GFR and GFR/ECV were corrected for the 1-compartment assumption using previously published empiric correction formulas. ECV was obtained by dividing GFR by GFR/ECV. An equation analogous to Haycock's was derived in which the indices of height and weight were varied to give an iterative best fit to ECV instead of BSA. RESULTS: GFR, ECV, and BSA increase as functions of age until about age 13 y, corresponding to a BSA of about 1.35 m(2), which was taken as the cutoff point between children and adults. As humans grow, their ratio of height to effective radius changes as a nonlinear function of surface area. Humans must therefore change shape as they grow. Moreover, the ECV-to-weight ratio decreases as a function of body size, suggesting that humans also change body composition as they grow. The new equation, giving an iterative best fit to ECV, was ECV = weight(0.6469) x height(0.7236) x 0.02154. ECV, either measured or estimated from the new equation, corresponding to a BSA of 1.73 m(2), was 12.9 L. Expressed as values normalized to the corresponding average adult values, the new equation and the second-order polynomial fit to ECV were superimposed as they increased as functions of BSA or weight. In contrast, normalized BSA and normalized weight were respectively larger and smaller than normalized ECV in children. GFR indexed to the new equation correlated more closely with GFR indexed to ECV than did GFR indexed to BSA and, along with GFR/ECV, showed a greater fall as a function of age than did GFR/BSA. CONCLUSION: When required in absolute units rather than as a rate of turnover of ECV, GFR is appropriately indexed to indices of height and weight as defined by this new equation, which avoids disadvantages to children from indexing to BSA. This unmasks higher values of filtration function in children than have hitherto been recognized.