Quantitative lymphoscintigraphy of the lower limbs for the diagnosis of phlebolymphoedema.

INTRODUCTION: Phlebolymphoedema is caused by the interaction of the venous and lymphatic systems in a state of chronic venous insufficiency in which increased microvascular filtration causes an increased rate of lymph production. Lymphatic drainage rate increases in response, but this is unsustainable and can cause lymphatic failure and oedema. We hypothesise that in phlebolymphoedema we could measure unusually high lymphatic drainage while the lymph system is still fully functional. METHOD: Patients referred for lymphoscintigraphic investigation of swollen legs between April 2021 and December 2022 were reviewed. Quantitative lymphoscintigraphy was performed following the technique of Keramida et al . (2017) and ilio-inguinal nodal uptake (IIQ%) was calculated. The presence of scintigraphic features of increased lymph production was noted for each limb. RESULTS: A total of 39 patients were reviewed (78 limbs, 29F, 10M). Seven limbs were identified with supranormal lymphatic function (IIQ > 30%) plus three borderline. Of these 10 limbs, all had at least two scintigraphic features of increased lymph production. CONCLUSION: Quantitative lymphoscintigraphy, although developed for diagnosing abnormally low lymphatic function, may also have utility at the upper end of the spectrum for identifying chronic venous insufficiency. An IIQ% upper normal limit of 30% could be used to diagnose venous insufficiency as the cause for limb swelling. This is of note for patients of large body habitus in whom venous ultrasound is difficult.

Correction of slope-intercept glomerular filtration rate measurement without scaling for body size.

AIM: The aim of this study was to evaluate a slope-intercept glomerular filtration rate (GFR) one-compartment correction method based exclusively on the rate constant (α2) of the exponential between 2 and 4 h post-injection that requires no scaling for BSA. METHODS: The correction factor is 1/([C.α2]+1). C depends on the difference between one-compartment-corrected and uncorrected GFR, so varies with different correction procedures. Patients were in four groups: group 1 (Cr-EDTA; n = 141) and group 2 (Tc-DTPA; n = 47) had sampling at 2, 3 and 4 h. Groups 3A (Tc-DTPA; n = 168) and 3B (Tc-DTPA; n = 361) gave nine samples up to 480 min. C was calculated from GFR corrected using Brochner-Mortensen (BM) without prior BSA-scaling (CBM; GFRBM), after BSA-scaling then reverse-scaling as per British Nuclear Medicine Society (BNMS) guidelines (CBNMS; GFRBNMS), and after correction using the equations containing 'f' described by Fleming (CFlem; GFRFlem) and Jodal and Brochner-Mortensen (CJBM; GFRJBM). In group 3A, C (C9) was determined from GFR measured from all nine samples (GFR9) and from seven samples (C7) up to 240 min. In 3B, GFRC, corrected using 1/([C9.α2]+1), was compared with GFRBM, GFRBNMS, GFRFlem and GFRJBM against GFR9 (gold-standard). RESULTS: C derived from these one-compartment correction formulae ranged from 25 to 32 min. In group 3, C7 and C9 were 28 ± 11 and 38 ± 14 min (P < 0.0001). Biases of GFRBM, GFRBNMS, GFRJBM, GFRFlem and GFRC against GFR9 were 2.7, 1.5, 4.2, 3.4 and 0.4 ml/min. Corresponding precisions were 9.3, 7.3, 7.0, 6.7 and 7.6 ml/min. CONCLUSION: Correction using α2 avoids BSA scaling, has a low bias against gold-standard GFR and does not over-correct at high GFR.

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

OBJECTIVES: Glomerular 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 METHODS: We 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 Tc-DTPA studies in 142 patients, mostly paediatric patients, with suspected fluid disturbances. RESULTS: CL (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. CONCLUSION: Compared 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.

The early plasma concentration of 51Cr-EDTA in patients with cirrhosis and ascites: a comparison of three models.

OBJECTIVES: The aim of the study was to determine which of three two-parameter fitting functions (exponential, linear-log, and negative-power function of time) most accurately models early chromium-51-EDTA (51Cr-EDTA) plasma concentration data prior to 120 min in patients with cirrhosis and ascites and understand how these fitting functions affect the calculation of the area under the plasma concentration curve (AUC). METHODS: A bolus, antecubital intravenous injection of 2.6 MBq of 51Cr-EDTA was given to 13 patients with cirrhosis and ascites. Up to 16 blood samples were drawn at time points ranging from 5 to 1440 min following injection. The concentration data prior to 120 min were used as reference data. Early time concentration values, estimated by fitting exponential, linear-log, and negative-power functions of time to the time samples at 120, 180, and 240 min, were then compared with reference data. The AUC was calculated for each patient using the exponential, Bröchner-Mortensen-corrected exponential, and linear-log functions, and these values were compared. RESULTS: The withheld, observed plasma concentrations were (a) most accurately estimated by linear-log functions (Wilcoxon P=0.4548), (b) significantly underestimated by exponential functions (Wilcoxon P=0.0002), and (c) significantly overestimated by negative-power functions (Wilcoxon P=0.0034). The relative errors when ranked from best to worst were those for the linear-log (12.0%, 9.0%), exponential (22.9%, 14.2%), and negative-power (31.9%, 48.4%) functions of time, respectively (median, interquartile range). For each patient, the values for AUC calculated by the exponential function differed significantly (range=3.4-15.3%, median=8.3%) from those calculated by the corrected Bröchner-Mortensen exponential, as to a lesser extent did those values calculated using linear-log functions (range=0.4-8.0%, median=3.0%). CONCLUSION: In patients with cirrhosis, linear-log functions were significantly more accurate than exponential or power functions in estimating early time plasma concentrations (<120 min). However, the improved linear-log early time plasma concentration model does not provide as much correction to the total AUC as does the corrected Bröchner-Mortensen exponential method. This is likely because of the large contribution of late time data to the AUC, and future work is suggested to explore the late time fit problem.

Validation and impact of a new technique for assessment of glomerular filtration rate in patients with liver disease.

OBJECTIVES: Previously we have proposed a technique for the measurement of plasma clearance in patients with ascites. The impact of using the technique was assessed and the results compared with those from a reference technique in 111 patients having glomerular filtration rate measurements as part of their workup for liver transplantation. METHODS: Results of calculations using the new technique were compared with plasma clearance measurements obtained using a conventional slope-intercept technique and with clearance measurements based on urine collection. Discrepancies between the results of plasma clearance and urinary clearance assessments were investigated by using an uncollimated gamma camera to measure the total retention of the tracer. RESULTS: Conventional slope-intercept calculations overestimated clearance compared with the new technique by more than 20% in 21% of the patients. Significant differences between the results of the two methods were more likely in patients with more severe ascites. Results of urine collection-based measurements of Cr-51 EDTA clearance were frequently significantly lower than measurements using the new technique, whereas measurements of urinary clearance of creatinine were higher. Gamma camera measurements suggest that discrepancies between total and urinary clearance of Cr-51 EDTA are due to incomplete urine collection. CONCLUSION: The new technique is a practical method for assessment of kidney function and should be used in patients with liver disease who have or may have ascites.

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

OBJECTIVE: Glomerular 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. METHODS: Plasma 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×BSA 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. RESULTS: The 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). CONCLUSION: The 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 m. However, there was a small number of children with CT,BSA greater than 150 ml/min/1.73 m for whom the JBM formula provided more accurate estimates of true GFR than did the BM equation.

Development of a modified sampling and calculation method for isotope plasma clearance assessment of the glomerular filtration rate in patients with cirrhosis and ascites.

AIM: The aim of this study was to identify a practical sampling regimen and calculation method that could be used to measure the glomerular filtration rate in patients with ascites using plasma sampling. PATIENTS AND METHODS: Thirteen potential liver transplant patients with cirrhosis and ascites were injected with Cr-51 ethylenediaminetetraacetic acid, and plasma samples were obtained at up to 16 time points for each patient. Reference clearance values were calculated using the area under the plasma clearance curve, which was calculated using all the available data points. Clearance calculations were then performed using three and four data points from each patient and three different calculation methods to identify a sampling regimen and calculation method that yielded good agreement with the reference values. RESULTS: The reference clearances ranged from 6 to 80 ml/min. Sampling at 2, 4, 8 and 24 h and calculation of the area under the plasma clearance curve using a log-linear trapezoidal rule with extrapolation to zero and infinity yielded a relative root mean square difference from the reference of less than 7%. CONCLUSION: This method for measuring glomerular filtration rate in patients with cirrhosis and ascites was found to be more accurate than the slope-intercept technique and is a practical alternative to urine collection.

Cystatin C in assessment of glomerular filtration rate in children and young adults suffering from cancer.

The study objective was to establish the diagnostic efficacy of cystatin C in the assessment of glomerular filtration rate (GFR) in paediatric oncology patients by investigating the relationships between serum cystatin C, serum creatinine and isotope clearance and determining whether these relationships are different from those seen in a group of patients of similar age with renal disease. This was a cohort study in which patients were divided into two groups: group A comprised renal patients and group B comprised oncology patients. All patients were referred for isotopic GFR assessment as part of routine clinical management and concurrently also had assessments made of their serum creatinine and cystatin C levels, together with height and weight measurements. Reciprocals of cystatin C correlate well with isotopic GFR; correlation coefficients from linear regression were 0.83 and 0.66 for the renal and oncology groups, respectively. However, when GFR was assessed from serum creatinine and cystatin C, levels of agreement were still very high (95% levels of agreement: -33 and 31 ml/min/1.73 m for cystatin C and -46 and 30 ml/min/1.73 m for the Counahan serum creatinine estimate). Receiver-operator characteristic curve analysis demonstrated that cystatin C has improved diagnostic utility for identifying patients with GFRs both below normal (90 ml/min/1.73 m) and below the point at which chemotherapy dose reduction may be considered (60 ml/min/1.73 m). Levels of intrapatient variability were similar for both tracers. Cystatin C was shown to be a better indicator of renal function compared with serum creatinine in oncology patients as demonstrated by receiver-operator characteristic curve and Bland-Altman analyses; however, sensitivity of the tracer to mild reductions in GFR is still low.

Validation of Tikhonov adaptively regularized gamma variate fitting with 24-h plasma clearance in cirrhotic patients with ascites.

PURPOSE: The aim was to compare late-time extrapolation of plasma clearance (CL) from Tikhonov adaptively regularized gamma variate fitting (Tk-GV) and from mono-exponential (E1) fitting. METHODS: Ten (51)Cr-ethylenediaminetetraacetic acid bolus IV studies in adults--8 with ascites--assessed for liver transplantation, with 12-16 plasma samples drawn from 5-min to 24-h, were fit with Tk-GV and E1 models and CL results were compared using Passing-Bablok fitting. RESULTS: The 24-h CL(Tk-GV) values ranged from 11.4 to 79.7 ml/min. Linear regression of 4- versus 24-h CL(Tk-GV) yielded no significant departure from a slope of 1, whereas the 4- versus 24-h CL(E1) slope, 1.56, was significantly increased. For CL(Tk-GV-24-h) versus CL(E1-24-h), there was a biased slope and intercept (0.85, 5.97 ml/min). Moreover, the quality of fitting of 24-h data was significantly better for Tk-GV than for E1, as follows. For 10 logarithm of concentration curves, higher r values were obtained for each Tk-GV fit (median 0.998) than for its corresponding E1 fit (median 0.965), with p < 0.0001 (paired t-test of z-statistics from Fisher r-z transformations). The E1 fit quality degraded with increasing V/W [volume of distribution (l) per kg body weight, p = 0.003]. However, Tk-GV fit quality versus V/W was uncorrelated (p = 0.8). CONCLUSION: CL(E1) values were dependent on sample time and the quality of fit was poor and degraded with increasing ascites, consistent with current opinion that CL(E1) is contraindicated in ascitic patients. CL(Tk-GV) was relatively more accurate and the good quality of fit was unaffected by ascites. CL(Tk-GV) was the preferred method for the accurate calculation of CL and was useful despite liver failure and ascites.

Extracellular fluid volume in patients with cancer.

AIMS: Cancer patients may have extracellular fluid volume (ECV) abnormalities that potentially invalidate glomerular filtration rate (GFR) measured using the slope-intercept technique. The aim was to test this concern by measuring ECV in cancer patients in comparison with noncancer patients and healthy kidney donors. METHODS: GFR was measured with Cr-EDTA and the slope-intercept technique in patients from two hospitals, the first using three samples (540 adults, including 382 with cancer, and 124 children, including 40 with cancer) and the second using four samples (256 adults, including 132 with cancer and 75 donors), scaled to body surface area (BSA) of 1.73 m and corrected using Brochner-Mortensen's equations (GFR/BSA). GFR/ECV was measured from the exponential rate constant with an appropriate one-compartment correction. ECV/BSA was calculated as the quotient, GFR/BSA:GFR/ECV. ECV was also expressed in adults in relation to lean body mass and in children as a fraction of ECV estimated from height and weight (eECV). RESULTS: In men from both centres, neither ECV/BSA nor ECV/lean body mass showed an increase in cancer patients. In women from both centres, however, they were both significantly higher in cancer patients than in noncancer patients and, in centre 2, than in donors. In children from centre 1, ECV/BSA, but not ECV/eECV, was significantly higher in cancer patients. CONCLUSION: ECV is expanded in female cancer patients but not male cancer patients. ECV may be expanded in children with cancer but the recorded difference in ECV/BSA is probably related to differences in patient size and a nonproportionate relationship between ECV and BSA.

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

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 m(2)) to one yr post-transplant (112 mL/min/1.73 m(2)) (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.

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

BACKGROUND: Isotope 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. AIM: This in vitro study aimed to quantify the effects on GFR assessment of tracer adhesion and leaching, in single-lumen and dual-lumen CVCs. METHOD: New 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 CONCLUSION: A 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.

Tissue perfusion in non-donor and donor forearm/hand after radial artery harvest: 1- and 5-year follow-up.

Radio-labeled red cell perfusion scan of the non-donor/donor forearm/hand was undertaken, 1- and 5-years post operation, in 12 patients who had received a radial artery graft during myocardial revascularisation. Results were analysed using a Wilcoxon Signed Rank test (P-value <0.05 was taken as statistically significant). Mean tissue perfusion (in milliliters/100 ml tissue/min) declined in the non-donor (-10.06%, P=0.07) and donor (-6.65%, P=0.15) forearm, respectively, compared to 1 year post radial artery harvest. The statistically significant observed difference in tissue perfusion between the non-donor (21.9+/-5.1) and donor (17.5+/-3.7) forearm (P=0.0007) at 1 year was maintained at 5 years, non-donor and donor, 19.5+/-3.7 and 16.2+/-3.4 (P=0.001), respectively. The same pattern in tissue perfusion was observed in the non-donor/donor hand. This study demonstrates that, over time, there is little recovery in perfusion in the donor forearm/hand from ulnar artery collateral circulation. There is a significant and persistent difference in tissue perfusion between the non-donor/donor forearm/hand at 5 years post radial artery harvest. Although no functional deficit or overt ischaemic events were recorded, these findings may influence the choice of conduit and the information given when obtaining consent in patients undergoing myocardial revascularisation.