Assessment of accuracy and precision of 99mTc-HEPIDA clearances determined by means of a simplified method

BACKGROUND: The aim of the present study was the assessment of the accuracy and precision of our own simplified method for the determination of 99mTc-HEPIDA liver clearance. MATERIAL AND METHODS: It has been assumed that archived results of plasma clearance (ClPl) and hepatic (ClHp), determined by means of multisample methods, could be legitimately used as a reference standard. The accuracy and precision of the simplified method was assessed by means of a Monte Carlo method alternatively utilizing three blood sampling times (T) of 68, 75 and 83 minutes post i.v. administration of 99mTc-HEPIDA. The corresponding alternative three urine voiding times (Y) were: 75, 80, and 95 min p.i. The analysed model was created accepting values of ClPl and ClHp, of administered activity Ap and parameters of biexponential function, describing the concentration C(t) decrease of the radiopharmaceutical (RF) in plasma during time as real values. Using the function C(t) for each individual, the plasma concentrations of RF at three sampling times, urinary clearance (ClPl - ClHp), and voided activity (AUr(Y)) were calculated. Simulated random errors were added to the assumed blood sampling times T and to voiding time Y. To the activity Ap and AUr(Y), and RF plasma concentrations random errors were added, assuming normal distribution with relative SD from 0 to 5% and then clearance values were computed. For each process there were 5000 repeated simulated determinations. The accuracy of the simplified methods was assessed by comparing mean values of simulated clearance computations with the reference. Comparison of standard deviations with mean uncertainties enabled us to gain insight into the degree of agreement of the estimator of relative uncertainty with the coefficient of variation as a measure of precision. RESULTS: There were strong correlations between the reference clearance values and the mean values of determinations by means of the simplified procedure (r > 0.93). The correlations were practically insensitive to the uncertainty of pipetting. The lines of regression differed slightly from the lines of identity, giving an indication that there was a systematic error involved; it amounted to +4 ml/min at ClPl = 60 ml/min and to -7 ml/min for ClPl of 370 ml/min. For ClPl a bias of +6 ml/min was found for a clearance value of 16 ml/min and –13 ml/min at ClPl > 300 ml/min. At uncertainty of pipetting of 2%, a precision of 6-7% was found for ClPl of 300 ml/min. For ClPl of 200 and 150 ml/min the corresponding precisions were 7–8% and 10%, respectively. For ClPl of 200, 150 and 100 ml/min the corresponding precisions were 10, 12 and 17%, respectively. These precisions are 5 percent worse than those that were obtained from determinations by means of multisampling procedures

Modification of a two blood sample method used for measurement of GFR with 99mTc-DTPA

BACKGROUND Measurements of GFR may be performed with a slope/intercept method (S/I), using only two blood samples taken in strictly defined time points. The aim of the study was to modify this method in order to extend time intervals suitable for blood sampling. Modification was based on a variation of a Russel et al. model parameter, selection of time intervals suitable for blood sampling and assessment of uncertainty of calculated results. MATERIAL AND METHODS Archived values of GFR measurements of 169 patients with different renal function, from 5.5 to 179 mL/min, calculated with a multiple blood sample method were used. Concentrations of a radiopharmaceutical in consecutive minutes, from 60th to 190th after injection, were calculated theoretically, using archived parameters of biexponential functions describing a decrease in 99mTc-DTPA concentration in blood plasma with time. These values, together with injected activities, were treated as measurements and used for S/I clearance calculations. Next, values of S/I clearance were compared with the multiple blood sample method in order to calculate suitable values of exponent present in a Russel’s model, for every combination of two blood sampling time points. A model was considered accurately fitted to measured values when SEE ≤ 3.6 mL/min. Assessments of uncertainty of obtained results were based on law of error superposition, taking into account mean square prediction error and also errors introduced by pipetting, time measurement and stochastic radioactive decay. RESULTS The accepted criteria resulted in extension of time intervals suitable for blood sampling to: between 60 and 90 minutes after injection for the first sample and between 150 and 180 minutes for the second sample. Uncertainty of results was assessed as between 4 mL/min for GFR = 5–10 mL/min and 8 mL/min for GFR = 180 mL/min. CONCLUSIONS Time intervals accepted for blood sampling fully satisfy nuclear medicine staff and ensure proper determination of GFR. Uncertainty of results is entirely acceptable and for high GFR values even comparable with uncertainty of multi-sample measurements.BACKGROUND Measurements of GFR may be performed with a slope/intercept method (S/I), using only two blood samples taken in strictly defined time points. The aim of the study was to modify this method in order to extend time intervals suitable for blood sampling. Modification was based on a variation of a Russel et al. model parameter, selection of time intervals suitable for blood sampling and assessment of uncertainty of calculated results. MATERIAL AND METHODS Archived values of GFR measurements of 169 patients with different renal function, from 5.5 to 179 mL/min, calculated with a multiple blood sample method were used. Concentrations of a radiopharmaceutical in consecutive minutes, from 60th to 190th after injection, were calculated theoretically, using archived parameters of biexponential functions describing a decrease in 99mTc-DTPA concentration in blood plasma with time. These values, together with injected activities, were treated as measurements and used for S/I clearance calculations. Next, values of S/I clearance were compared with the multiple blood sample method in order to calculate suitable values of exponent present in a Russel’s model, for every combination of two blood sampling time points. A model was considered accurately fitted to measured values when SEE ≤ 3.6 mL/min. Assessments of uncertainty of obtained results were based on law of error superposition, taking into account mean square prediction error and also errors introduced by pipetting, time measurement and stochastic radioactive decay. RESULTS The accepted criteria resulted in extension of time intervals suitable for blood sampling to: between 60 and 90 minutes after injection for the first sample and between 150 and 180 minutes for the second sample. Uncertainty of results was assessed as between 4 mL/min for GFR = 5–10 mL/min and 8 mL/min for GFR = 180 mL/min. CONCLUSIONS Time intervals accepted for blood sampling fully satisfy nuclear medicine staff and ensure proper determination of GFR. Uncertainty of results is entirely acceptable and for high GFR values even comparable with uncertainty of multi-sample measurements

Usefulness of clearance parametric images in detection of regional renal parenchyma dysfunction

BACKGROUND: The aim of the study was to examine whether parametric clearance images (PAR) enhance diagnostic potential of a dynamic renal scintigraphy with detection of local dysfunction of kidneys, on a model of kidneys after treatment with extracorporeal shock wave lithotripsy (ESWL), MATERIAL AND METHODS: Kidneys after ESWL were accepted as a proper model for the implementation of this objective because of the previously proven damaging effect of a shock wave on renal parenchyma and known region of ESWL application. Forty patients (23 males and 17 females) at the age of 37 to 70 years (mean value 54) with untreated earlier single, one-sided nephrolithiasis, currently treated with ESWL, underwent a study. A dynamic renal 99mTc-EC scintigraphy was performed three times: before ESWL, a week and a month after this therapeutic intervention. PAR images generated with use of an in-house developed software were compared with summation (SUM) of images obtained from radiopharmaceutical uptake phase and quantitative global function parameters (GFP) of each kidney, like split function, MTT — mean transit time and PTT — parenchymal transit time. RESULTS: PAR and SUM images of all 40 kidneys before ESWL were normal. PAR images revealed local or diffused defects a week and a month after therapeutic intervention in statistically significantly larger numbers of kidneys than SUM images (19 vs. 6, p = 0.002 and 16 vs. 5, p = 0.003, respectively). A week after ESWL, when defects in PAR images were observed in about a half of all renal segments (29/57 — 51%) all GFP values were significantly worse than in kidneys without defects. A month after ESWL defects in PAR images could be observed in ab. 1/3 (17/48 — 35%) of segments and were less extensive, whereas GFP values did not differ significantly from values in kidneys without clearance function impairment in the PAR images. CONCLUSIONS: PAR images enhance diagnostic potential of a dynamic renal scintigraphy with detection of local function defects. These images allow to detect more local renal function defects than SUM images

Comparison of 99mTc-HEPIDA and 99mTc-MBrIDA from the standpoint of hepatic clearance determination - preliminary communication

BACKGROUND. In order to evaluate the functional capacity of the liver by means of clearance determination, the derivative of iminodiacetic acid (99mTc-HEPIDA) has been used in recent decades. Because of recent problems with manufacturing and delivery of 99mTc-HEPIDA, an investigation was undertaken with the aim of testing whether a more widely available 99mTc-MBrIDA could be used for clearance determination and whether hepatic clearance measured with the use of this compound provides a similarly useful test of hepatic function. MATERIAL AND METHODS. Comparative investigations were performed in 73 patients of both sexes. The state of the efficiency of liver parenchyma was determined based on seven widely used biochemical tests, i.e. levels of: bilirubin, albumin, and gamma globulin; activity of AST, ALT, GGTP, and prothrombin index. The clearances of both radiopharmaceuticals, 99mTc-HEPIDA and 99mTc-MBrIDA, were determined by means of multisample technique. The results of determination were correlated among themselves and with the results of biochemical tests. The set of results of all estimations allowed a factorial analysis to be performed to find a common factor and to compute the values of factor loadings in particular tests. RESULTS. Obvious correlation between plasma and hepatic clearances of both radiopharmaceuticals was obtained and between plasma clearance of 99mTc-MBrIDA and hepatic clearance of 99mTc-HEPIDA. Correlation coefficients of 99mTc-MBrIDA clearance and the biochemical test results attained somewhat lower values than for 99mTc-HEPIDA clearance. Similarly, values of χ2 test of independence of 99mTc-MBrIDA clearances and test results were also less close than for 99mTc-HEPIDA clearances. Factorial analysis showed that common factor loading is greatest for hepatic clearance of 99mTc-HEPIDA; the values of two loadings of 99mTc-MBrIDA clearances are very close, but somewhat lower than those for 99mTc-HEPIDA. CONCLUSIONS. From the performed investigations it is possible to conclude that 99mTc-MBrIDA clearances may be used for the evaluation of liver parenchyma performance, even if the results may not be as certain as those obtained using 99mTc-HEPIDA

Preliminary assessment of interand intraobserver reproducibility, and normative values of renal mean transit time (MTT) and parenchymal transit time (PTT) for 99mTc-etylenodicysteine

BACKGROUND: The clinical significance of MTT and PTT, determined by deconvolution of renographic curves, is arguable. Their usefulness in diagnosis of obstructive uro- and nephropathy, renovascular hypertension and monitoring of transplanted kidneys is pointed out, but susceptibility of deconvolution methods to errors resulting from “statistical noise” is also stressed. So far there are no reports on normative MTT values for 99mTc-EC, although such values were already determined for 131I-OIH, 99mTc-DTPA and 99mTc-MAG3. The aim of this study is an assessment of inter- and intraobserver reproducibility of MTT and PTT for 99mTc-EC, and determination of normative values for these parameters. MATERIALS AND METHODS: 31 patients (17 women and 14 men aged 19–75, average 44 years) referred for dynamic renal scintigraphy with: unilateral flow impairment (11), unilateral nephrolithiasis (2), control after unilateral lithotripsy (4), moderate hypertension (demographically with > 99% probability of primary hypertension) (4), suspected cirrhosis of one kidney (3), future kidney donors (3), control after abdominal injuries (3), incontinence (1). 42 functionally efficient kidneys were included in the study. Criteria for recognition of a kidney as functionally efficient were: — no earlier history of renal disease, signs of renal damage in basic blood and urine tests, or abnormalities in ultrasonography; — normal result of dynamic renal scintigraphy (in terms of sequential images and renographic curve). MTT and PTT values were determined independently by two operators, using a matrix method for deconvolution of renographic curves. RESULTS: Differences between mean MTT and PTT from two studies by one operator were insignificant and those values were closely correlated (r = 0.99 and r = 0.97, respectively). Differences of values obtained by both operators were practically insignificant for MTT (r = 0.93), and significant for PTT (r = 0.81 and p < 0.001). These differences do not disqualify that processing method. The upper limits of normative values of MTT and PTT were based on the results from first study performed by more experienced operator — 200 s and 170 s, respectively. CONCLUSIONS: The procedure of processing dynamic renal scintigraphy used in this study is reproducible. Normative values of MTT and PTT for 99mTc-EC were established as 200 s and 170 s, respectively. An attempt to optimize and standardize the technique of determining parenchymal ROI in a matrix deconvolution method, followed by an evaluation of clinical usefulness of these parameters in the diagnosis of chosen renal function impairments would be a logical continuation of this initial research

Application of normalized values of kidney clearance function in the diagnosis of bilateral obstructive nephropathy — a preliminary report

BACKGROUND: Dynamic renal scintigraphy provides effective diagnosis of obstructive uropathy and nephropathy. However, in case of a bilateral outflow impairment, relative differential renal function (DRF), which is a primary quantitative criterion for diagnosis of unilateral obstructive nephropathy (when its value is below 45%, according to EANM guidelines from 2011), becomes unreliable. In case of bilateral nephropathy with similar severity, this parameter may even be within the normal range (45–55%) for both kidneys. The aim of this study was therefore to assess diagnostic usefulness of the original, normalized, absolute parameter proportional to the value of renal clearance function (K) in the evaluation of obstructive nephropathy in a group of patients with bilateral uropathy. MATERIAL AND METHODS: 16 healthy volunteers (32 kidneys) without history of kidney diseases were examined to determine normative value of K index. Then, 8 patients (16 kidneys) with bilateral obstructive uropathy found in standard dynamic renal scintigraphy performed using 111 MBq of 99mTc-EC (cumulative renographic curve that continued rising or dropped by less than 50% after i.v. administration of Furosemide) were examined. For each of the subjects 60 sequential 20s images were obtained, which were then assessed using an original method of post-processing scintigraphic data. It included normalization of renographic curves to the area under the heart curve. Subsequently, these normalized values from the uptake phase (between 2nd and 3rd minute) were inserted into the linear regression equation, from which K index was obtained. RESULTS: In healthy volunteers the average value of K index was 0.23 ± 0.05. The value of 0.13 (mean –2 SD) was taken as the lower limit of the norm. Values below that limit suggest obstructive nephropathy. In patients with bilateral obstructive uropathy, 5 kidneys met the conventional criteria of nephropathy (DRF < 45%), while 11 kidneys had DRF within normal range. K index was below the norm in 9 kidneys (including 4 kidneys with low and 5 with normal DRF), while its value was normal in 7, including one kidney with reduced DRF (37%). K index changed the diagnosis in 6 kidneys out of 16 (38%). CONCLUSIONS: Preliminary results indicate usefulness of K index in diagnosis of obstructive nephropathy in patients with bilateral obstructive uropathy. For further evaluation of clinical value of this method, it is planned to examine a larger group of patients with varying degrees of renal parenchymal function impairments

Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast

Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes, including yeast, and has been assigned multiple functions in addition to acting as building block of the lipid bilayer. Here, by isolating S. cerevisiae suppressor mutants that exhibit robust growth in the absence of PC, we show that PC essentiality is subject to cellular evolvability in yeast. The requirement for PC is suppressed by monosomy of chromosome XV or by a point mutation in the ACC1 gene encoding acetyl-CoA carboxylase. Although these two genetic adaptations rewire lipid biosynthesis in different ways, both decrease Acc1 activity, thereby reducing average acyl chain length. Consistently, soraphen A, a specific inhibitor of Acc1, rescues a yeast mutant with deficient PC synthesis. In the aneuploid suppressor, feedback inhibition of Acc1 through acyl-CoA produced by fatty acid synthase (FAS) results from upregulation of lipid synthesis. The results show that budding yeast regulates acyl chain length by fine-tuning the activities of Acc1 and FAS and indicate that PC evolved by benefitting the maintenance of membrane fluidity

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Verification of 99mTc-Ethylenedicysteine (99mTc-EC) distribution model in the organism

Background: The aim of the present study was an attempt to verify the systemic distribution of 99mTC-ethylenedicysteine by means of the open two-compartment model. Methods: In order to accomplish this, 99mTc-EC clearance was determined in 21 patients as: two-compartmental model-based plasma clearance, and a urinary clearance, i.e. utilising the 99mTc-EC activity excreted with urine during a finite time interval. Results: There is a close correlation (r = 0.97) between the clearance values determined according to these two methods, and the rectilinear orthogonal correlation equation assumes a C1ECu = 1.03656C1ECp - 18.064 form. The slope of the line does not differ significantly from unity. The shift of the correlation line along the X-axis indicates a minor excretion of the radiopharmaceutical also by routes different from the urinary tract, e.g. with the bile. Conlusions: The performed comparison of the clearance values has proved that distribution of 99mTc-EC in the organism is consistent with the open two-compartment model

Pharmacokinetic characteristics of 99mTc-Ethylene-l-dicysteine (99mTc-EC)

Background: Ethylenedicysteine-99mTc (99mTc-EC) has been more and more commonly applied in dynamic studies as well as for clearance determinations. However, it was necessary to investigate in detail the pharmacokinetic characteristics of the radiopharmaceutical which may be important for its applicability in assessment of renal function. Results: Kidney images obtained from renoscintigraphy are characterised by excellent quality without visualisation of the organs adjacent to kidneys (liver, spleen). Renoscintigraphic curves demonstrate typical shapes with TMAX and T1/2 values not differing from the corresponding values obtained for other radiopharmaceuticals (99mTc-MAG3, 131I-OIH). In plasma, 99mTc-EC binds with proteins to a considerably lesser degree (c. 1/3) than 131I-OIH (c. 2/3), or 99mTc-MAG3 (> 9/10). No binding of 99mTc-EC with erythrocytes has been demonstrated, whereas 131I-OIH attaches to or penetrates the red blood cells (10-12%). 99mTc-EC is quickly excreted from the organism: 40 min after i.v. injection up to 70% of the administered radiopharmaceutical is found in urine, and at 1 and 1.5 h after the administration 80% and 95%, respectively. The distribution of 99mTc-EC in the organism can be described in a fully satisfactory way by means of an open two-compartment model, which allows this model to be used for clearance determinations. Comparison of the values of renal plasma clearance without collection of urine with the values determined by means of measurement of activity excreted with urine and mean blood concentration over a finite time interval leads to the conclusion that extrarenal plasma clearance of this compound (via the liver?) is negligible and amounts to c. 17 ml/min (5-6% of the total). The obtained correlation between clearance values for 99mTc-EC and 131I-OIH supports the contention that extrarenal excretion rate of 99mTc-EC (through the liver and bile ducts) is lower than the corresponding rates of either 131I-OIH or 99mTc-MAG3. A very close correlation between clearance values for 99mTc-EC and ERPF (131I-OIH clearance) and between their extraction constants (r = 0.91 and 0.92, respectively), allows for the introduction of 99mTc-EC to the assessment of renal function instead of 131I-OIH. Effective dose to the patient from unit activity of 99mTc-EC is comparable with that resulting from administration of other radiopharmaceuticals labelled with 99mTc