Comparison of 99Tcm-mercaptoacetyltriglycine and 131I-orthoiodohippurate in determination of effective renal plasma flow (ERPF)

Recent studies have suggested that 99Tcm-labelled mercaptoacetyltriglycine (99Tcm-MAG3) is a potential replacement for 131I-orthoiodohippurate (131I-OIH). The two radiopharmaceuticals were studied in 19 patients with varying degrees of renal impairment, for comparison of effective renal plasma flow (ERPF). All patients were injected i.v. with 2-3 mCi 99Tcm-MAG3 and 250-300 microCi of 131I-OIH simultaneously in separate arms to avoid any chemical incompatibility. Serial digital images were acquired simultaneously for 99Tcm-MAG3 and 131I-OIH at 15 s per frame for 30 min. The renogram curve was generated and ERPF value was calculated for each kidney using both radiopharmaceuticals and applying the same computer program (Schlegel's program). In all cases, the 99Tcm-MAG3 and 131I-OIH renogram curves were quite similar. The values of ERPF of 99Tcm-MAG3 were not significantly different from those of 131I-OIH studies (paired t test, p less than 0.01). The correlation coefficient between the two methods was 0.95 (p less than 0.001) with a linear regression equation Y = -12.96 + 0.995X, where Y = ERPF determined by 131I-OIH and X = ERPF determined by 99Tcm-MAG3. This study indicates that 99Tcm-MAG3 is a useful 99Tcm replacement for 131I-OIH in the determination of ERPF and generation of renogram curves.     

99Tcm-MAG3: in vitro stability and in vivo behaviour at different times after preparation

A kit for preparing technetium-99m mercaptoacetyltriglycine (99Tcm-MAG3), a new radiopharmaceutical for gamma camera renography, is available commercially. A drawback to the use of this kit is the recommended 1h expiry for 99Tcm-MAG3. This short expiry is a consequence of the possible growth of an impurity which undergoes hepatobiliary excretion and might interfere with renal imaging. Radiochemical purity of 99Tcm-MAG3 was measured by high performance liquid chromatography at 0, 1 and 6 h after preparation and was found to be consistently greater than 95. 99Tcm-MAG3 was shown to contain five impurities, one of which increased from 0.5% to 1% over 6 h. Dilution of 99Tcm-MAG3 eliminated this effect. A two-part clinical study was undertaken. For Part I, 99Tcm-MAG3 was prepared at 400 MBq/4 ml. For Part II, 99Tcm-MAG3 was prepared at 1 GBq/4 ml then subdivided and diluted to give single doses of 175 MBq/2.5 ml. In both parts, 10 patients were injected within 1 h after preparation and 10 were injected 5-6 h after preparation. From gamma camera images of the abdomen acquired 30 min after injection, the % injected 99Tcm in gall bladder and liver were calculated. In both parts, the % injected 99Tcm in gall-bladders and livers of the 1 h group were compared with those in the 5-6 h group and not found significantly different (p greater than 0.05). In conclusion, 99Tcm-MAG3 prepared according to the methods described, can be used up to 6 h after preparation.     

A new approach in radionuclide imaging to ureteric peristalsis using 99Tcm-MAG 3 and condensed images.

A new method for the evaluation of ureteric peristalsis is described. Standard, dynamic renal scintigraphy was carried out using 99Tcm-MAG 3 in 59 patients. Time-activity curves and condensed images over the ureter area were created simultaneously. A six-grade scale (O-V) was chosen for the classification of ureteral function. The results obtained were compared with parameters of renographic curves and other clinical findings. In a group of 13 patients, two different renal radiopharmaceuticals were used: 131I-OIH and 99Tcm-DTPA. The results show that the new method is suitable for the assessment of ureteral disorders, and has some advantages compared with previously described methods. 99Tcm-MAG 3, with a better target-to-background ratio compared to 131I-OIH and 99Tcm-DTPA, is the most suitable radiopharmaceutical for this purpose.     

99Tcm-MAG3: problems with radiochemical purity testing

The radiochemical purity (RCP) of 99Tcm-MAG3 was determined using solid-phase extraction (SPE), high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). The difference between the HPLC and SPE methods was highly significant (P < 0.001), yielding values for RCP of 94.4 +/- 1.4% and 86.0 +/- 5.1% [corrected] respectively (mean +/- s). Further qualitative analysis of the SPE fractions obtained, was carried out using HPLC and TLC. The unexpected presence of 99Tcm-MAG3 in one of the fractions was observed together with the appearance of hydrophilic impurities in the hydrophobic extract. This lack of specificity may be the reason for the discrepancy between the SPE and HPLC methods. Use of the SPE method leads to an underestimation of the RCP of 99Tcm-MAG3 and, indeed, had we been relied solely on this method of analysis, we would have had to reject most kits we prepared. In a separate study, we compared a TLC method with HPLC. Differences were found to be highly significant (P < 0.001), yielding values of 98.3 +/- 0.6% and 95.8 +/- 0.9% respectively. Comparison of the data points showed that TLC gave consistently higher RCP yield than HPLC. This elevated value was found to be due to the inability of the TLC method to separate 99Tcm-lipophilic impurity, seen on HPLC, from the 99Tcm-MAG3. Therefore, use of this TLC method leads to an overestimation of the RCP of 99Tcm-MAG3.     

Feasibility of fractionating MAG3 cold kit for cost reduction.

99Tcm-MAG3 is the first 99Tcm-labelled radiopharmaceutical with a renal clearance similar to that of 131I-OIH. The cost of a unit dose of 99Tcm-MAG3 is comparatively less expensive than the cost of a combined 99Tcm-DTPA and 131I-OIH study dose. However, this cost-saving is dramatically reduced when only a few doses are withdrawn from a 99Tcm-MAG3 kit. Our goal in this study was to subdivide the MAG3 kit into fractions to reduce expense. By dissolving the lyophilized ingredients of MAG3 kits with either 5 or 10 ml N2-purged normal saline, the resultant liquid was divided into 1-ml aliquot vials filled with N2. The MAG3 aliquot vials were then frozen at -70 degrees C for future use. The radiochemical purity (RCP) of each vial was evaluated using the recommended Sep-Pak C18 column chromatography at different time periods. Over the entire 28-day evaluation period, the average RCP of the 5:1 dilution MAG3 vials after reconstitution with 3.7 GBq 99Tcm was maintained at 95.6 +/- 2.7% (n = 100) for 6 h, whereas the 10:1 fractionation MAG3 kits after labelling with 740 MBq 99Tcm showed an average RCP value of 98.4 +/- 2.1% (n = 100) for 6 h. Based upon these results, it is concluded that the fractionation of MAG3 kits and frozen storage in an N2 atmosphere not only maintains the stability of MAG3 but also provides a cost-effective method for using 99Tcm-MAG3.     

Deadtime correction in measurement of fractional renal accumulation of 99Tcm-MAG3

Fractional renal accumulation of a radiotracer is often used to measure renal function with camera-based methods. We evaluated the effect of deadtime count loss on the calculation of fractional renal accumulation of 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3). In 15 patients, dynamic renal scintigraphy was performed after the injection of 250 MBq of 99Tcm-MAG3. A reference source was placed on the periphery of the field of view of the gamma camera to monitor the loss of counts in dynamic imaging. The activity in the syringe was also counted with the camera to measure the injected dose, and the deadtime count loss in the syringe was computed from the observed count rate and deadtime in imaging a point source. Fractional renal accumulation, the ratio of renal accumulation on dynamic imaging to the injected dose, was assessed with and without correction for deadtime loss. Fractional renal accumulation was over-estimated by 4.1% with no deadtime correction, when the value after correction for loss in both syringe counts and dynamic imaging was used as a standard. It was underestimated by 4.0% with correction for syringe counts only. The results suggest that correction for count loss only in measuring the injected dose does not lead to a significant improvement in the accuracy of estimating renal function with camera-based methods.     

99Tcm-mercapto acetyl triglycine in paediatric renal tract disease.

The use of 99Tcm-mercapto acetyl triglycine (99Tcm-MAG3), a new hippuran substitute, has been reported widely in adults but not in children. Our experience of its use in 100 infants and children for renography and indirect micturating cystography (IMC) is reported. The average age was 5.6 years. 65 patients completed IMC studies and nine patients had 99Tcm-dimercaptosuccinic acid (99Tcm-DMSA) scans performed on the same day. The majority of patients were referred for the investigation of urinary tract infection. 32 kidneys were found to be scarred on 99Tcm-MAG3 scans, 17 kidneys and ureters refluxed on IMC and 14 kidneys were obstructed. The results of 99Tcm-MAG3 scans were compared with those of other urinary tract investigations including ultrasound, micturating cystography (MCUG), intravenous urography (IVU) and 99Tcm-DMSA scintigraphy. No kidney which was scarred had a normal 99Tcm-MAG3 scan. All significant degrees of dilatation or obstruction on IVU or ultrasound were also detected by 99Tcm-MAG3. 99Tcm-MAG3 gave more information than any other single imaging modality and we believe it represents an ideal initial screening test in the investigation of urinary tract infection in older toilet-trained children.     

Evaluation of 99Tcm mercaptoacetyltriglycine for the detection and localization of gastrointestinal bleeding in an experimental animal model

Technetium-99m mercaptoacetyltriglycine (99Tcm-MAG3) was evaluated for the detection and localization of the site of gastrointestinal bleeding in a sheep model. Radioactivity was detected in both the stomach and lower abdomen. However, 99Tcm-MAG3 is partially excreted by the liver and in the bile. The radioactivity in the bile moved to the small bowel. This movement of radioactivity in the lower abdomen can lead to a misinterpretation of the site of bleeding. Hence, 99Tcm-MAG3 may not be an effective radiopharmaceutical for the localization of the site of bleeding in the gastrointestinal tract, particularly the lower abdomen.     

Reproducibility of 99Tcm-MAG3 clearance in normal volunteers with the two-sample method: comparison with 131I-OIH

The aim of this study was to evaluate the reproducibility of 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3) clearance and to compare it with that of 131I-orthoiodohippurate (131I-OIH), which is widely used in clinical practice. Twelve young healthy volunteers with a mean age of 23.4 years (range 19-28) were enrolled in the study. The investigations were repeated at an interval of 1 month under similar physiological conditions. Each volunteer received a simultaneous injection of 99Tcm-MAG3 and 131I-OIH that was commercially available in an already labelled form. Blood samples were obtained at 44 and 104 min post-injection. Clearance values were calculated using the two-sample method. The mean (+/- S.D.) change from the first to the second measurement was -7.1 +/- 11.1% for 99Tcm-MAG3 and 1.7 +/- 13.6% for 131I-OIH. There were no significant differences between the first and the second measurements of 99Tcm-MAG3 and 131I-OIH clearance, respectively. 99Tcm-MAG3 clearance was shown to be very similar to that of 131I-OIH in healthy volunteers.     

The absent kidney in 99Tcm-MAG3 renogram: a dramatic reversible consequence of contrast nephrotoxicity superimposed on renal obstruction

99Tcm-mercaptoacetyltriglycine (MAG3) renogram is a robust imaging technique used to delineate upper urinary tract obstruction. The changes observed on the renogram are often reversible on relief of obstruction. We present two cases illustrating the extreme consequence of contrast nephrotoxicity on pre-existing obstructed kidneys. In one case, this led to severe impairment of perfusion and uptake observed on 99Tcm-MAG3 renogram and in the second case virtual non-visualization of the obstructed kidney. Subsequent treatment of obstruction, led to dramatic improvement in renal function. It is important for clinicians, nuclear medicine physicians and radiologists to be aware of the potential of contrast nephrotoxicity in obstructed kidneys.     

Replacing 99Tcm-DMSA for renal imaging?

We have tried to evaluate the usefulness of an early 99Tcm-MAG3 image, obtained during the second minute after injection of the tracer, in predicting the renal alterations seen on a 99Tcm-DMSA scintigraph, in children clinically suspected of pyelonephritis. It appears that the accuracy of the MAG3 image is population dependent: when, in most of the patients of a study group, DMSA scintigraphy is either normal or very abnormal, the MAG3 image will correctly reflect the DMSA scintigraph. However, when the DMSA alterations are less pronounced, the early MAG3 image will miss the lesions in about 50% of the cases.     

99Tcm-MAG3 for quantitation of differential renal function

We studied two different methods for the evaluation of differential renal function in a group of 100 patients with various kidney disorders whose effective renal plasma flow (ERPF) had been calculated previously by single 125I-orthoiodohippurate (OIH) injection and multiple blood sampling. Patients were divided into three groups according to their ERPF:ERPF is greater than or equal to 250 ml min-1; ERPF less than or equal to 100 ml min-1; and ERPF greater than 100 ml min-1 and less than 250 ml min-1. The two methods used to assess differential renal function were: first, relative 99Tcm-dimercaptosuccinic acid (DMSA) uptake calculated by normalized background and attenuation corrected cumulative counts in each kidney 24 h p.i.; and second, relative 99Tcm-mercaptoacetyl-triglycine (MAG3) uptake within 1 and 2 min p.i. calculated by normalized background and attenuation corrected counts on each renal area. The results obtained with each method correlated strongly with high significance (p less than 0.0001). In the right kidney, mean values obtained with 99Tcm-MAG3 tend to be higher than mean values obtained with 99Tcm-DMSA.     

A comparison of the renal handling of 99Tcm-DTPA and 99Tcm-MAG3 in hypertensive patients using an uptake technique.

The renal uptake and outflow of 99Tcm-DTPA and 99Tcm-MAG3 were compared by analysing renal studies performed in two different departments, but with analysis techniques and computer programs using algorithms that were almost identical. Comparison was performed by a retrospective review of results from patients who were referred for renal investigations because of hypertension but who had apparently normal kidneys. The analysis of tracer outflow rates in the form of whole-kidney transit times and renal cortical transit times showed no significant difference between the two tracers. The fractional uptake rate of tracer for each patient (both kidneys) indicated that MAG3 was extracted from the blood 3.3 times faster than DTPA in patients aged 20-69 years, with a lower ratio above the age of 70. When used to measure relative renal function, there was no overall difference between the two tracers. The fractional uptake rates were also converted to flow rates, producing values of 95.8 +/- 28.0 ml.min(-1).1.73 m-2 for DTPA and 320 +/- 75 ml.min(-1).1.73 m-2 for MAG3, in hypertensive patients aged 20-40 years. These values showed a good correlation with other published GFR and MAG3 clearance rates (obtained using blood sampling methods) in normal patients of similar ages.     

NORA: a simple and reliable parameter for estimating renal output with or without frusemide challenge

The aim of this study was to evaluate a simple parameter describing renal output, namely NORA (normalized residual activity). We first compared, in a simulated model, different parameters of transit to an ideal standard; we then compared, in a clinical study, NORA and output efficiency. 123I-hippurate, 99Tcm-DTPA and 99Tcm-MAG3 plasma curves, each with two levels of renal clearance, were convoluted by means of different types of simulated retention functions, with different mean transit times. On the reconstructed renograms, several parameters reflecting renal transit were determined and compared with mean transit time. In a second step, in 33 patients, we compared output efficiency and NORA (i.e. the residual renal activity), normalized by the renal activity at 2 min. These two parameters were calculated at the end of the renogram, at the end of the frusemide test and after the micturition phase. In the simulated model, both output efficiency and NORA were only slightly influenced by the level of overall renal function. In the clinical study, a good correlation was found between output efficiency and NORA, whatever part of the study considered (renogram, frusemide test, post-voiding image). NORA is a simple and reliable parameter that allows quantification of renal output; it is almost independent of the level of renal function and can be used whatever the timing of the frusemide injection.     

99Tcm-MAG3-isoDGR-2C分子探针的制备与体内分布的实验研究

目的 摸索99Tcm-MAG₃-isoDGR-2C分子探针的标记条件并研究其在正常昆明小鼠体内的生物学分布。 方法 利用葡庚糖酸盐（GH）转换络合法进行标记,即首先用99Tcm标记GH形成99TcmO-GH中间体,再进行99Tcm-MAG₃-isoDGR-2C的标记;考察pH值和温度等因素对标记率的影响,采用高效液相色谱法鉴定标记物的放射化学纯度;取30只昆明小鼠随机分成6组,分别于注射99Tcm-MAG₃-isoDGR-2C 15、30、60、120、240和360 min后测定其在小鼠体内的分布情况。 结果 pH值为4.6、反应温度为100℃时的标记率最高（94.2%）。体内分布研究显示该标记物能够较快地从血液中清除,且心、肺、脾、胃、骨等组织的放射性摄取均很少。 结论 99Tcm-MAG₃-isoDGR-2C标记率高、血液清除快,具备一定的成为SPECT显像剂的条件。     

Administered activity of 99Tcm-MAG3 for gamma camera renography in children.

A method of calculating the activity of 99Tcm-MAG3 to be administered to children of different ages has been developed and evaluated. The suggested administered activity schedule is only valid for estimation of split renal function. The activity required to obtain the same count rate over the kidneys for all ages was calculated as a fraction of the activity administered to an adult by using a biokinetic model and taking attenuation effects into account. The activity schedule is based on the age of the child and was tested using renograms from patients of different ages. Statistical noise was added to the smoothed renograms simulating an injected activity corresponding to 45 MBq for an adult. The precision in the determination of split renal function calculated with four different methods was determined for 500 simulated renograms. The precision was approximately the same for all ages, but varied with the method used. The activity to be administered to a very small child is 90% of the adult activity, decreases to less than 50% between 2 and 5 years of age, and then slowly increases to 100% as the child grows to adulthood.     

Comparative study of the kinetics of the renal tracers 99Tcm-MAG3 and 131I-hippuran.

Serial measurements of plasma activity, plasma protein binding and urine excretion were obtained in order to study 99Tcm-MAG3 (MAG) and 131I-Hippuran (OIH) kinetics after simultaneous injection of both tracers in 21 patients with various renal diseases. Results were compared on the basis of a compartmental model, calculating the rate constants as well as the clearance and volume of distribution. Protein binding was calculated in 10 patients (mean: MAG = 54.7%, OIH = 33.8%). The dependence of time, tracer and patient factors was shown by ANOVA. Time was independent, with tracer and patient factors and their interaction being significant. The mean value of the renal excretion constant was equal for the two tracers (k12 = 0.052 min-1). The clearance values were found to be highly correlated (r = 0.982) with a ratio of 0.57 between them. The volumes of distribution in litres were 4.1 (MAG) and 7.0 (OIH). One-hour urine excretion was nearly the same for both tracers (MAG: 64%, OIH: 63% of the injected dose).     

Two routes for 99mTc-DMSA uptake into the renal cortical tubular cell

Critical factors determining the renal handling of 99mTc-dimercaptosuccinic acid (DMSA) are protein binding in plasma and the renal 99mTc-DMSA extraction efficiency. Comparison of the count rate over soft tissue with that over the cardiac blood pool about 1 h after injection demonstrated that 99mTc-DMSA is not exclusively an intravascular label. 99mTc-DMSA was 76% protein bound in plasma as demonstrated by HPLC and gel filtration. Assuming that the 24% that is not protein bound is filtered at the glomerulus, the renal extraction efficiency of 99mTc-DMSA by glomerular filtration is about 5%. Since the total renal extraction efficiency was also found to be about 5%, the majority of the activity that becomes fixed in the renal cortex arrives there as a result of filtration followed by tubular reabsorption rather than by direct extraction from peritubular blood. However, discordant changes in DMSA and DTPA uptake induced by captopril in renovascular hypertension (RVH) suggested that a minority of uptake was by direct peritubular extraction. This kinetic model was supported by indirect measurement of protein binding and extraction efficiency based on the kinetics of 99mTc-DMSA disappearance from plasma and kinetics of uptake in the kidneys. Furthermore, differential functional studies based on 99mTc-DMSA and 99mTc-DTPA before and after captopril in patients with RVH due to unilateral renal artery stenosis confirmed filtration followed by tubular reabsorption as the predominant route for DMSA uptake by the kidney.     

99mTc-MAG3: dynamic studies in patients with renal disease

Animal studies have suggested that 99mTc-mercapto-acetylglycyl-glycyl-glycine (99mTc-MAG3) might be suitable for the determination of the renal plasma flow (RPF) because of its high renal clearance. In this study 131I-orthoiodohippurate (131I-OIH) and 99mTc-MAG3 (labeling always greater than 95%) were administered simultaneously in 11 patients (creatinine clearance ranging from 14 to 130 ml/min per 1.73 m2) to measure effective RPF(ERPF) using the standard technique (UV/P). Glomerular filtration rate (GFR; clearance of 125I-thalamate, 125I-OT) was also measured. The mean ratio of 99mTc-MAG3 clearance to 131I-IOH clearance was 0.55 +/- 0.02 (SEM), P less than 0.01, n = 16, and was independent of GFR and ERPF. To study this difference in renal handling of the radiopharmaceuticals, renal extractions by the right kidney were determined in another six patients after a single shot of the agents. Renal extraction of 99mTc-MAG3 was 0.60 +/- 0.03 after 5 min, and 0.41 +/- 0.08 after 30 min. Renal extraction of 131I-OIH amounted to 0.86 +/- 0.04 and 0.77 +/- 0.03, respectively. Using renal extractions of 0.41 and 0.77, respectively, it appeared that calculated renal plasma flows measured simultaneously with 99mTc-MAG3 and 131I-OIH were similar. Protein binding 30 min after the priming dose was 66% for 99mTc-MAG3 and 47% for 123I-OIH. We conclude that in spite of a high renal clearance (ratio to 125I-OT clearance 2.69 +/- 0.27), 99mTc-MAG3 seems unsuitable for an accurate determination of the RPF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diuresis renography. A simultaneous comparison between 131I-hippuran and 99Tcm-MAG3

In 20 patients investigated for unilateral upper urinary tract obstruction diuresis renography was performed simultaneously with 131I-hippuran and 99Tcm-MAG3 using a gamma camera with dual isotope facilities. Furosemide was administered routinely 20 min after radionuclide injection. No significant differences were found in fractional share between the two kidneys, time to maximal activity, residual activity at 20 and 30 min, or rate of emptying after furosemide administration. The MAG3 curves showed, however, better counting statistics and on scintigrams with MAG3 more anatomic details (extent of dilation and site of obstruction) could be seen. It is concluded, that MAG3 is superior to hippuran in the evaluation of patients with possible unilateral upper urinary tract obstruction by diuresis renography.