Mark C. Barnfield

Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling

UNLABELLED Aim. The aim of this study was to investigate the influence of age, gender, obesity and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects. METHODS This is a retrospective multi-centre study of 1878 healthy prospective kidney transplant donors (819 men) from 15 centres. Age and body mass index (BMI) were not significantly different between men and women. Slope-intercept GFR was measured (using Cr-51-EDTA in 14 centres; Tc-99m-DTPA in one) and scaled to body surface area (BSA) and lean body mass (LBM), both estimated from height and weight. GFR was also expressed as the slope rate constant, with one-compartment correction (GFR/ECV). ECV was measured as the ratio, GFR to GFR/ECV. RESULTS ECV was age independent but GFR declined with age, at a significantly faster rate in women than men. GFR/BSA was higher in men but GFR/ECV and GFR/LBM were higher in women. Young women (<30 years) had higher GFR than young men but the reverse was recorded in the elderly (>65 years). There was no difference in GFR between obese (BMI>30 kg/m2) and non-obese men. Obese women, however, had lower GFR than non-obese women and negative correlations were observed between GFR and both BMI and %fat. The decline in GFR with age was no faster in obese versus non-obese subjects. ECV/BSA was higher in men but ECV/LBM was higher in women. ECV/weight was almost gender independent, suggesting that fat-free mass in women contains more extracellular water. BSA is therefore a misleading scaling variable. CONCLUSION There are several significant differences in GFR and ECV between healthy men and women.

Renal function evaluated by measured GFR during follow‐up in pediatric liver transplant recipients

Abstract:  Calcineurin inhibitors form the mainstay of immunosuppression in pediatric liver transplantation, but may cause significant nephrotoxicity. We evaluated renal function in liver transplant recipients treated with a tacrolimus‐based immunosuppressive regimen. GFR was measured using 99 mTc‐DTPA in patients pretransplant and annually thereafter. GFR calculated by Schwartz formula was compared with the measured values. Sixty patients who underwent 69 transplants were followed for at least one yr post‐transplant (median three yr). In children over two yr of age at transplant GFR fell significantly from pretransplant (140 mL/min/1.73 m2) to one yr post‐transplant (112 mL/min/1.73 m2) (p = 0.01) but thereafter there was no significant decline. In younger children the picture was confounded by maturation of renal function, but again there was no significant fall to five yr post‐transplant. Although 13 (22%) patients developed renal dysfunction post‐transplant, none required renal replacement therapy. cGFR correlated poorly with measured values (r = 0.21). Use of a tacrolimus‐based immunosuppressive regimen is associated with an initial decline in GFR, though this picture is confounded in younger children by normal maturation of renal function. There is no further significant fall in GFR in the medium‐term. The Schwartz formula is inaccurate in determining GFR in this patient group.

The reliability of glomerular filtration rate measured from plasma clearance: a multi-centre study of 1,878 healthy potential renal transplant donors

PurposeThe objective of the study was to undertake a clinical audit of departmental performance in the measurement of glomerular filtration rate (GFR) using the coefficient of variation (CV) of extracellular fluid volume (ECFV) as the benchmark. ECFV is held within narrow limits in healthy subjects, narrower than GFR, and should therefore have a low CV.MethodsFifteen departments participated in this retrospective study of healthy renal transplant donors. Data were analysed separately for men (n ranged from 28 to 115 per centre; total = 819) and women (n = 28–146; 1,059). All centres used the slope-intercept method with blood sample numbers ranging from two to five. Subjects did not fast prior to GFR measurement. GFR was scaled to body surface area (BSA) and corrected for the single compartment assumption. GFR scaled to ECFV was calculated as the terminal slope rate constant and corrected for the single compartment assumption. ECFV/BSA was calculated as the ratio of GFR/BSA to GFR/ECFV.ResultsThe departmental CVs of ECFV/BSA and GFR/BSA ranged from 8.3 to 25.8% and 12.8 to 21.9%, respectively, in men, and from 9.6 to 21.1% and 14.8 to 23.7%, respectively, in women. Both CVs correlated strongly between men and women from the same centre, suggesting department-specific systematic errors. GFR/BSA was higher in men in 14 of 15 centres, whereas GFR/ECFV was higher in women in 14 of 15 centres. Both correlated strongly between men and women, suggesting regional variation in GFR.ConclusionThe CV of ECFV/BSA in normal subjects is a useful indicator of the technical robustness with which GFR is measured and, in this study, indicated a wide variation in departmental performance.

Correction of the slope-intercept method for the measurement of glomerular filtration rate

ObjectiveGlomerular filtration rate (GFR) is frequently assessed using the slope–intercept method by fitting a single exponential to plasma samples obtained 2–5 h after injection. The body surface area (BSA)-corrected one-pool clearance (CO,BSA) overestimates true GFR (CT,BSA) because it fails to sample the full plasma curve, and values of CT,BSA are usually estimated from CO,BSA using the Brøchner-Mortensen (BM) equation. An improved equation, CT,BSA=CO,BSA/(1+fBSA×CO,BSA), with fBSA a fixed constant, was proposed by Fleming, but subsequently Jødal and Brøchner-Mortensen (JBM) reported that fBSA varies with BSA. We report data for a large group of individuals who underwent GFR investigations with sampling of the full plasma curve. The aims were to validate the JBM equation with independent data and assess whether replacing the BM equation with a BSA-dependent correction based on Fleming’s equation can increase the accuracy of the slope–intercept method. MethodsPlasma data were analysed for 142 children and adults aged 0.6–56 years who underwent technetium-99m-diethylenetriaminepentaacetic acid GFR investigations with blood samples taken between 5 min and 8 h after injection. Values of CO,BSA were calculated using the 2, 3 and 4 h data. Values of CT,BSA were calculated by integrating the plasma curve between 5 min and 4 h and extrapolating the terminal exponential. Individual values of fBSA were calculated using the relationship fBSA=1/CT,BSA−1/CO,BSA. Nonlinear regression was used to fit the function fBSA=f1×BSAn and find the best-fit values for f1 and n. Scatter and Bland–Altman plots were drawn comparing the various formulae for correcting slope–intercept GFR. ResultsThe trend for fBSA to decrease with increasing BSA was highly significant (Spearman’s test: RS=−0.31; P=0.0002). When the data were fitted by nonlinear regression, the best-fit values (95% confidence interval) of the model parameters were n=−0.13 (from −0.21 to −0.04) and f1=0.00191 (from 0.00183 to 0.00200). ConclusionThe results confirm that fBSA varies with BSA and provide independent values of the parameters f1 and n. Differences from GFRs calculated using the original JBM equation were small and not clinically significant. The BM equation also performed well for CT,BSA less than 125 ml/min/1.73 m2. However, there was a small number of children with CT,BSA greater than 150 ml/min/1.73 m2 for whom the JBM formula provided more accurate estimates of true GFR than did the BM equation.

A systematic review of single-sample glomerular filtration rate measurement techniques and demonstration of equal accuracy to slope-intercept methods.

PurposeWe aimed to identify the most accurate single-sample glomerular filtration rate (SS-GFR) technique for all patient ages. Materials and methodsWe performed a systematic review of all published SS-GFR measurement techniques and compared the results from each test with a gold-standard nine-point ‘area-under-curve’ measurement of GFR as well as slope-intercept (SI-GFR) methods for 412 GFR tests. ResultsWe have shown that for patients of all ages the SS-GFR technique developed by Fleming and colleagues delivers the best accuracy and precision, with results equivalent to those calculated by SI-GFR. The median percentage difference from the gold-standard GFR for the Fleming technique is 4.8% (95% confidence interval 3.9–5.7%) and that for the three-point SI-GFR is 5.6% (95% confidence interval 4.9–6.3%). The interquartile range of the distribution of percentage difference from the gold standard is −0.23 to 11% for the Fleming method and 1.6–11% for the three-point SI-GFR. ConclusionThe Fleming technique outperforms the method currently recommended by the international guidelines, and is simpler as only one equation is required for all patients instead of separate equations for adults and children. We propose that the SS-GFR technique of Fleming replace the methods currently recommended by the international and BNMS guidelines for routine measurement of GFR for expected results greater than 30 ml/min/1.73 m2. A thorough system of measurement checks should be implemented for all methods of GFR assessment; the perceived lack of opportunity for quality control checks to be performed on the result of a single-sample measurement is addressed in the companion paper of this study.

Can oncology patients' central venous catheters be used for isotope assessment of glomerular filtration rate? An in-vitro study.

BackgroundIsotope assessment of glomerular filtration rate (GFR) is frequently performed in patients with central venous catheters (CVCs). Use of the CVCs for administration of tracer and subsequent blood sampling would be less distressing for patients (particularly paediatric) and would reduce the frequency of failed samples due to poor venous access. However, the GFR test is quantitative and could be affected by incomplete tracer delivery due to adhesion to the CVC and also by contamination of blood samples due to adhered tracer leaching back into the sampled blood as it passes through the CVC. AimThis in vitro study aimed to quantify the effects on GFR assessment of tracer adhesion and leaching, in single-lumen and dual-lumen CVCs. MethodNew and clinically used single-lumen CVCs were injected with tracer (99mTc-DTPA and 51Cr-EDTA) and then flushed repeatedly with saline. The outflows were assayed in a gamma counter and, where possible, the CVCs were imaged on a gamma camera to take snap shots of tracer movement throughout a GFR assessment. In a separate experiment, a phantom patient was used to compare blood sampling through a dual lumen CVC with peripheral sampling. Result and conclusionA CVC successfully delivers >99% of tracer. Subsequent blood samples can be taken through the other lumen of a dual-lumen CVC but not through a single-lumen as this significantly alters the GFR result due to contamination.

Accurate and precise plasma clearance measurement using four 99mTc-DTPA plasma samples over 4 h.

ObjectivesGlomerular filtration rate can be measured as the plasma clearance (CL) of a glomerular filtration rate marker despite body fluid disturbances using numerous, prolonged time samples. We desire a simplified technique without compromised accuracy and precision. Materials and methodsWe compared CL values derived from two plasma concentration curve area methods – (a) biexponential fitting [CL (E2)] and (b) Tikhonov adaptively regularized gamma variate fitting [CL (Tk-GV)] – for 4 versus 8 h time samplings from 412 99mTc-DTPA studies in 142 patients, mostly paediatric patients, with suspected fluid disturbances. ResultsCL (Tk-GV) from four samples/4 h and from nine samples/8 h, both accurately and precisely agreed with the standard, which was taken to be nine samples/8 h CL from (noncompartmental) numerical integration [CL (NI)]. The E2 method, four samples/4 h, and nine samples/8 h median CL values significantly overestimated the CL (NI) values by 4.9 and 3.8%, respectively. ConclusionCompared with the standard, CL (E2) from four samples/4 h and from nine samples/8 h proved to be the most inaccurate and imprecise method examined, and can be replaced by better methods for calculating CL. The CL (Tk-GV) can be used to reduce sampling time in half from 8 to 4 h and from nine to four samples for a precise and accurate, yet more easily tolerated and simplified test.

Measuring glomerular filtration rate using chromium-51 EDTA: body surface area normalization before or after Brøchner-Mortensen correction?

BackgroundGuidelines for measuring glomerular filtration rate (GFR) using 51Cr-EDTA require normalizing of GFR for body surface area (BSA) before applying the Bröchner-Mortensen (BM) correction. The guideline explicitly mentions the importance of performing BSA normalization before BM correction and that this is particularly important in children in whom the effects of BSA normalization are largest. Materials and methodsWe theoretically showed that the order of applying BM correction and BSA indexing is indeed important for patient populations having a low BSA and a high slow GFR. We then compared the exact GFR, obtained from the double-exponential concentration–time curve in Duchenne muscular dystrophy (DMD) patients, with the GFR obtained from the slow compartment method using the BM correction. ResultsThe median GFR for the 20 DMD patients obtained from the BSA-BM order deviates 5.40% from the exact GFR (P=0.0006), whereas the median GFR obtained from the BM-BSA order deviates only −0.05% (P>0.05) from the exact GFR, resulting in a median of differences of 5.50% between the two methods (P<0.0001). ConclusionThe correct order of application in this DMD population should be BM correction first, followed by BSA indexing, and not vice versa. In general, the order of applying the BM correction and BSA normalization becomes more important with increasing slow GFR and extreme low BSA. The order of application is of less importance for people with normal BSA and/or normal GFR.

Higher extracellular fluid volume in women is concealed by scaling to body surface area

Abstract Objective. The objective was to assess body surface area (BSA) for scaling extracellular fluid volume (ECV) in comparison with estimated lean body mass (LBM) and total body water (TBW) across a range of body mass indices (BMI). Methods. This was a multi-centre study from 15 centres that submitted raw data from routine measurement of GFR in potential kidney transplant donors. There were 819 men and 1059 women in total. ECV was calculated from slope-intercept and slope-only measurements of GFR. ECV was scaled using two methods: Firstly, division of ECV by the scaling variable (ratio method), and secondly the regression method of Turner and Reilly. Subjects were placed into five BMI groups: < 20, 20–24.9, 25–29.9, 30–34.9, and 35 + kg/m2. LBM and TBW were estimated from previously published, gender-specific prediction equations. Results. Ratio and regression scaling gave almost identical results. ECV scaled to BSA by either method was higher in men in all BMI groups but ECV scaled to LBM and TBW was higher in women. There was, however, little difference between men and women in respect to ECV per unit weight in any BMI group, even though women have 10% more adipose tissue. The relations between TBW and BSA and between LBM and BSA, but not between LBM and TBW, were different between men and women. Conclusion. Lean tissue in women contains more extracellular water than in men, a difference that is obscured by scaling to BSA. The likely problem with BSA is its insensitivity to body composition.

Optimized robust plasma sampling for glomerular filtration rate studies.

In the presence of abnormal fluid collection (e.g. ascites), the measurement of glomerular filtration rate (GFR) based on a small number (1–4) of plasma samples fails. This study investigated how a few samples will allow adequate characterization of plasma clearance to give a robust and accurate GFR measurement. A total of 68 nine-sample GFR tests (from 45 oncology patients) with abnormal clearance of a glomerular tracer were audited to develop a Monte Carlo model. This was used to generate 20 000 synthetic but clinically realistic clearance curves, which were sampled at the 10 time points suggested by the British Nuclear Medicine Society. All combinations comprising between four and 10 samples were then used to estimate the area under the clearance curve by nonlinear regression. The audited clinical plasma curves were all well represented pragmatically as biexponential curves. The area under the curve can be well estimated using as few as five judiciously timed samples (5, 10, 15, 90 and 180 min). Several seven-sample schedules (e.g. 5, 10, 15, 60, 90, 180 and 240 min) are tolerant to any one sample being discounted without significant loss of accuracy or precision. A research tool has been developed that can be used to estimate the accuracy and precision of any pattern of plasma sampling in the presence of ‘third-space’ kinetics. This could also be used clinically to estimate the accuracy and precision of GFR calculated from mistimed or incomplete sets of samples. It has been used to identify optimized plasma sampling schedules for GFR measurement.