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Three consensus reports entitled "renal clearance," "ACE inhibitor renography for detecting renovascular hypertension," and "diuresis renography for investigating the dilated upper urinary tract" were published in The Journal of Nuclear Medicine in 1996. Although nuclear nephrology is useful technique to evaluate renal function, there were wide variations of technical procedure and their interpretations among different centers. Minimal standardization by these consensus reports may help to raise the level of practice of renal nuclear medicine. The introduction of 99mTc-MAG3 (MAG3) enhanced the utility of renal nuclear medicine because of the rapid clearance and suitable gamma-ray energy for imaging by gamma camera. In this chapter, the principle, procedures, and interpretations of renal nuclear medicine examinations using MAG3 regarding renal clearance measurements, ACE inhibitor renography, and diuresis renography are explained and discussed.

Our objective was to assess mean transit time (MTT) and initial uptake, both parameters derived from the renal retention function (RRF), in the study of renal function in patients with diabetic nephropathy. We studied 25 patients, 7 with type I diabetes mellitus and 18 with type II diabetes mellitus, all of whom fulfilled the criteria for diabetic nephropathy with proteinuria and/or retinopathy. We found a statistically significant correlation between initial uptake and the other biochemical and renographic parameters studied except proteinuria: serum creatinine (r = 0.66, P < 0.002), creatinine clearance (r = 0.61, P < 0.003), glomerular filtration rate (r = 0.74, P < 0.003) and effective renal plasma flow (r = 0.66, P < 0.003). The other renographic parameters studied (maximal activity of the conventional renogram and MTT of the deconvoluted renogram) did not show any correlation. Initial uptake is a semi-quantitative renographic parameter that can provide complementary information to biochemical data and it may be useful in the management of diabetic nephropathy, especially in patients with high serum creatinine or creatinine clearance.

Substitution of the oxidation-sensitive thiol function of mercaptoacetyltriglycine (MAG3) by a hydroxyl group yields a tetraligand (hydroxyacetyltriglycine or HAG3) which is almost insensitive to oxidation and has the advantage over MAG3 that it can be stored safely without protection of the alcohol function. We found that deprotected HAG3 could be directly labelled at alkaline pH (pH>/=11.5) and room temperature in high yield (>95%). Results of electrophoresis experiments suggested a comparable structure for 99mTc-HAG3 and 99mTc-MAG3, namely binding of an oxotechnetium(V)core via three deprotonated amides and a deprotonated hydroxyl group. Biodistribution studies in mice at 10 min and 30 min p.i. showed a slightly higher urinary excretion, a faster renal transit and a significantly lower hepatobiliary handling for 99mTc-HAG3 than for 99mTc-MAG3. In a baboon, the 1-h plasma clearance of 99mTc-HAG3 was clearly higher than that of 99mTc-MAG3. Its plasma protein binding was in the same order as that of Hippuran and much lower than that of 99mTc-MAG3. Evaluation in a human volunteer confirmed the favourable biological characteristics of 99mTc-HAG3, namely a rapid renal excretion, a high 1-h plasma clearance and a negligible hepatobiliary handling. The results indicate that 99mTc-HAG3 may be an easy-to-prepare and practical substitute for 99mTc-MAG3 with improved renal excretion characteristics.

Renal transit time usually refers to tubular transit time, as introduced by Taplin, but other measures of renal transit have been proposed. Here we examine the vascular transit time (VTT, following Rutland) and the standard deviation of tubular transit time (SDTT, following Britton) in a group of 30 patients having baseline and ACE-inhibitor 99Tcm-MAG3 renography prior to arteriography. A same-day, low-dose/high-dose protocol was used for renography; only the post-captopril dose was high enough to measure VTT. Pre-captopril, the Spearman rank correlation coefficient for SDTT was rho = 0.52 (n = 53 kidneys; P < 0.0002); post-captopril, rho = 0.54 (n = 49 kidneys; P < 0.0002). For VTT, the post-captopril value was rho = 0.24 (n = 30 kidneys; N.S.). For comparison, the same statistics were calculated for Taplin's original measure of transit time: the time from injection to maximum count rate (peak time). Pre-captopril, for peak time, rho was 0.47 (n = 53 kidneys; P < 0.001); post-captopril, rho was 0.39 (n = 50 kidneys, P < 0.01). These findings confirm the diagnostic value of SDTT but not of VTT. SDTT correlated better than peak time with the arteriographic findings.

99Tcm-bicisate (99Tcm-ECD), often used as a brain perfusion agent, is rapidly converted following intravenous injection to the polar monoacid (99Tcm-ECM) and diacid (99Tcm-EC) metabolites. Such polar metabolites, which are eliminated principally by renal clearance, are potential renal imaging agents. In this study, 99Tcm-ECD was compared for the first time with 99Tcm-EC, 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3) and 131I-orthoiodohippurate (OIH) as renal imaging agents in rabbits. Whole-body images and renograms were obtained for all three of the 99Tcm agents, and pharmacokinetic parameters including plasma and urinary clearance were studied for all four agents. The plasma clearance of 99Tcm-EC (37 ml min-1) was slower than that of 99Tcm-ECD (51 ml min-1), which could be accounted for by the higher liver uptake of 99Tcm-ECD. The urinary clearance of 99Tcm-ECD (35 ml min-1), 99Tcm-EC (34 ml min-1) and 99Tcm-MAG3 (39 ml min-1) was similar. The renal images obtained with 99Tcm-ECD were comparable to those for 99Tcm-MAG3 and 99Tcm-EC. However, liver uptake was more prominent with 99Tcm-ECD than with the other agents. The 99Tcm-ECD renogram curves showed a prolonged decrease in renal activity compared to both 99Tcm-EC and 99Tcm-MAG3. In potential human studies, the relatively high liver uptake of 99Tcm-ECD superimposed on right renal activity may be a limitation. Therefore, we conclude that 99Tcm-ECD is less favourable when compared to existing renal agents due to its high extrarenal uptake and renal kinetics.

Purpose: To evaluate an improved camera-based method for calculating the clearance of technetium-99m mercaptoacetyltriglycine (MAG3) in a multicenter trial., Materials and Methods: Tc-99m MAG3 scintigraphy was performed in 49 patients at three sites in the United States and Canada. The percentage of the injected dose of Tc-99m MAG3 in the kidney at 1-2, 1.0-2.5, and 2-3 minutes after injection was correlated with the plasma-based Tc-99m MAG3 clearances. The data were combined with the results obtained in 20 additional patients in a previously published pilot study., Results: Regression models correlating the plasma-based Tc-99m MAG3 clearance with the percentage uptake in the kidney for each time interval were developed; there was no statistically significant difference among sites in the regression equations. Correction for body surface area statistically significantly (P < .005) improved the correlation coefficient for each time interval. For the 1.0-2.5-minute interval, the body surface area-corrected correlation coefficient for the four combined sites was .87, and it improved to .93 when one outlier was omitted from the analysis. Similar results were obtained with the other time intervals. Independent processing by two observers showed no clinically important differences in the percentage dose in the kidney or in relative function., Conclusion: An improved camera-based method to calculate the clearance of Tc-99m MAG3 was validated in a multicenter trial.

Steady-state captopril renography (SSCR) is an original technique for assessing the captopril-induced increase in technetium-99m mercaptoacetyltriglycine (99mTc-MAG3) mean parenchymal transit time (MPTT) in kidneys affected with functional renal artery stenosis (RAS). The steady-state parenchymal activity achieved by constant infusion of 99mTc-MAG3 is directly linked to the MPTT of the radiopharmaceutical. This steady-state parenchymal activity was continuously monitored from 15 min before to 60 min after a single dose of captopril in order to detect possible disruption of the steady state. SSCR was performed in 11 hypertensive patients with unilateral RAS and in two with RAS of a solitary kidney before renal revascularization (RR). In four of these patients, an additional SSCR was performed after RR. Of the ten patients whose hypertension was cured or improved by RR, one presented an uninterpretable SSCR and six presented a positive SSCR on the affected side. Control SSCR performed in four of these six patients was bilaterally negative. SSCR was also bilaterally negative in the three patients who showed no blood pressure response to RR. These preliminary results tend to indicate that, in spite of the stability of pre- and post-captopril hydration and data acquisition conditions allowed by this steady-state technique, the sensitivity is lower than expected. However, the reason for the false-negative results does not seem to be inherent to SSCR.

In the presented study 99mTc-MAG3 clearance measurements were undertaken in 14 dogs during renal scintigraphic examination. Of these dogs, 10 showed no renal impairment, the other 4 exhibited clinically manifested nephropathy. It was the aim of these examinations to determine if this type of clearance measurement that is routinely used in human medicine is suitable for diagnosis of canine nephropathy. An algorithm for the calculation of the MAG3-Clearance developed for humans was modified. The clearance measurement can be performed during the renal scintigraphic procedure without any difficulties. In the group of dogs with no renal impairment the clearance values ranged between 6.4 and 8.0 ml/min/kg, whereas in the group of patients exhibiting nephropathies the values ranged between 2.0 and 2.7 ml/min/kg. The suitability of the method for its use in dogs needs to be confirmed with higher patient numbers. In addition, further studies are necessary to precisely assess the correlation between measured clearance values and effective renal plasma flow in dogs.

Measurement of 99mTc-MAG3 plasma clearance based on 1-compartment model (MPC method) were applied to 12 pediatric patients and evaluated for the factors which might affect the calculated results. Depth correction is a critical factor for the measurement of renal uptake. Three different equations for estimating renal depth were compared with the real depth measured by ultrasonography. The equation proposed by K. Itoh was suitable though the equations by T. Ito and Raynaud were insufficient. Estimation of distribution volume, which is regarded as circulating plasma volume (CPV), is also critical for the calculation of MAG3 clearance by MPC method. Precisely, hematocrit measured by venous sampling and circulating blood volume (CBV) calculated as 7.5% of body weight are used for estimation of CPV. However, assumed CPV as 5% of body weight was acceptable if the hematocrit was not severely deviated from the normal value. Simplified MPC method utilizing two factors mentioned above gave a positive correlation with Russell's one point sampling method. In conclusion, MPC method is applicable for pediatric patients.

The aim of this study was to assess the intra-individual reproducibility of 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3) clearance in routine clinical practice in various circumstances using a single-sample method. Three groups of 30 patients each were enrolled in the study. Investigations were repeated on the same day with two different levels of activity (group A), within 1 week (group B), or after 1 year (group C). Blood samples were taken after 20 and 25 min and clearance values were averaged to minimize incidental errors after calculation according to the formula proposed by Bubeck et al. For clearance estimation on the same day, time-dependent background correction for residual activity was carried out. The mean difference was -2.0%, +6.0% and -1.5% (S.D. = 6.3%, 15.7% and 11.7%) for groups A, B and C respectively, taking into account values > 100 ml min-1 only. We demonstrated that 99Tcm-MAG3 clearance is highly reproducible under the same conditions. However, a repeat clearance measurement on a separate day revealed large differences. Therefore, in follow-up studies for evaluation of changing kidney function (e.g. surgery or chemotherapy), differences should exceed 30% (i.e. 2 S.D. of group B) to be statistically significant.

Unlabelled: This study assessed 99mTc-mercaptoacetyltriglycine (MAG3) for determination of renal transplant prognosis for recovery in patients with early postoperative dysfunction. The postulate tested was that good tracer extraction may imply high likelihood of recovery, while poor extraction may confer a poor prognosis., Methods: A 2-min image acquired 1 min after MAG3 administration, named a cortical uptake phase (CUP) image, was visually analyzed according to standardized semiquantitative guidelines. Interpretation was expressed in tubular injury severity scores (TISS) that ranged from 1 (a normally functioning renal transplant) to 6 (a photopenic defect in place of renal transplant)., Results: The study analyzed 64 patients (35 men, 29 women, age 45.9 +/- 14 yr). All five patients with TISS of 6 or 5 lost the transplant. Only 1 of 10 patients with TISS of 4 lost the transplant. All patients with TISS of less than 4 recovered renal transplant function., Conclusion: This study suggests that MAG3 scan (the CUP image specifically) is an accurate prognosticator in patients with early postoperative renal transplant dysfunction. Reproduction of these results in a larger population and other institutions is necessary before clinical implementation of this methodology.

Simplified methods based on a single blood sample have been proposed to estimate the clearance of 131I-hippuran (HIP) and 99Tcm-mercaptoacetyltriglycine (MAG). The blood sample is usually drawn at that time which yields a minimum error between the estimated clearance and that obtained by the standard nine-sample method. In this paper, we establish the regression equations to obtain the HIP and MAG clearances using one sample withdrawn during a fixed time interval. As HIP has long been the agent of choice, we have also established regression equations to estimate the clearance of HIP using one sample after MAG administration. Our results suggest that it is possible to obtain plasma samples 30-50 min post-injection which result in an error of the estimate only slightly higher than the minimum.

We evaluated the clinical usefulness of 99Tcm-N,N-ethylenedicysteine (99Tcm-EC), a new renal tubular agent, in normal children and in children with various renal disorders and compared it with 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3). In a first group of children (Group 1), which included 15 patients and 4 normal children, both 99Tcm-EC and 99Tcm-MAG3 renal scintigraphy were performed within a period of 1-5 days. In a second group (Group 2), consisting of 12 patients, only 99Tcm-EC scintigraphy was performed. In the normal children, renograms, differential renal function (DRF) ratios and semi-quantitative parameters of the two agents were similar. For 99Tcm-EC and 99Tcm-MAG3, the mean (+/- S.D.) time to peak activity (Tmax) values were 3.2 +/- 0.5 and 3.1 +/- 0.4 min respectively, and the mean time from peak activity to 50% activity (T1/2) values were 6.3 +/- 0.5 and 6.4 +/- 0.4 min respectively. The mean parenchymal transit time index (PTTI) and mean whole-kidney transit time index (WKTTI) for 99Tcm-EC were 1.7 +/- 0.3 and 2.8 +/- 0.4 respectively, and for 99Tcm-MAG3 they were 1.8 +/- 0.2 and 3.0 +/- 0.3 min respectively. There were also no significant differences between these parameters for the two agents in children with various renal disorders, and the correlation coefficients (r) for DRF, Tmax, T1/2, PTTI and WKTTI were 0.99, 0.98, 0.94, 0.77 and 0.63 respectively. We conclude that 99Tcm-EC has excellent imaging characteristics in children, and even has some advantages over 99Tcm-MAG3. We suggest this agent can be used routinely with children.

The in vitro stability and animal pharmacokinetics of 99mTc bound to Sandoz and C110 IgG antibodies via a modified MAG3 has been compared with the hydrazino nicotinamide (SHNH) moiety as standard. For both antibodies, the stabilities of the label to challenge at up to 50:1 cysteine: IgG molar ratio were comparable, but at higher molar ratios, MAG3 showed greater instabilities. For the Sandoz antibody, size-exclusion HPLC analysis of 37 degrees C serum incubates and plasma samples from injected mice showed no clearly distinguishable differences. In the C110 case, some increased high molecular weight radioactivity was apparent with MAG3. Biodistributions in normal mice showed significant differences only in liver (Sandoz) and liver, spleen, intestines, stomach, and blood (C110), with SHNH usually providing higher levels. Thus, for two different antibodies and under the conditions of this study, the MAG3 chelator provided a 99mTc label with properties similar to that of SHNH moiety.

Technetium-99m-MAG3 is accepted as a renal tubular function agent. However, sporadic liver and gall bladder visualisation during its clinical use is clearly a disadvantage. HPLC-purified 99mTc-MAG3 samples exhibited appreciable hepatobiliary uptake (7%), and an elevated level of such uptake was observed in unpurified kit preparations, which was stated to be associated with the excretory property of the radiolabeled kit impurities. To verify this we attempted to quantitate the hepatobiliary uptake of the kit preparations with that of its radiolabeled components. The contribution of each component toward hepatobiliary uptake of the sample was calculated from their abundance in the chelate mixture and the individual biodistribution of the isolated components. However, the anticipated hepatobiliary uptake of different preparations of 99mTc-MAG3 calculated in this way was always lower than that of the experimental value determined directly. Further work is needed to explain the anomaly.

Unlabelled: The aim of the present study was to evaluate the accuracy of 99mTc-MAG3 clearance measurements using a precordial gamma camera curve calibrated by a single plasma sample., Methods: Technetium-99m-MAG3 was administered to ten young normal volunteers. A 60-min gamma camera acquisition was performed. Five different segments of the gamma camera curve were determined: 3 min to 20 min, 3 min to 30 min, 3 min to 40 min, 3 min to 50 min and 3 min to 60 min. A biexponential function was fitted on each of these five different segments, which were thereafter calibrated using eight different blood samples. These blood samples were successively used for calibration at 5, 10, 15, 20, 30, 40, 50 and 60 min. The single injection, multiple plasma sample method was used as reference., Results: Camera clearances varied markedly based on the length of the precordial curve and on the time of the calibration sample. Different regression equations were obtained for each duration of the camera curve, and for each blood sample timing. Correlation coefficients were > 0.95 in most cases recording period of at least 50 min, however, was necessary to obtain a s.e.e. better than those obtained using a single blood sample method without gamma camera curve., Conclusion: The 99mTc-MAG3 clearance determination using a gamma camera heart curve calibrated with a single blood sample does not necessarily improve the accuracy of the one blood sample method.

To answer the question for the most effective use of all usually available information, the MAG3 clearance was determined by different methods: firstly in an optimated whole-body technique for reference, further for comparison by means of a camera background-curve and a dedicated evaluating procedure, and in addition according to the compartmental principle (Sapirstein), by the latter method also simultaneously together with the hippurate clearance. Two simplified methods were applied as well, a non-invasive one and a single-sample method. The results revealed the relatively unpretentious camera technique to be nearly equivalent to more expensive procedures, but qualitatively superior to those methods, which are unnecessarily oversimplified.

Four patients with the clinical diagnosis of nephronophthisis are presented, all having a very poor renal uptake of 99mtechnetium-dimercaptosuccinic acid (99mTc-DMSA) but clearly visualized kidneys on early images with 99mtechnetium-mercaptoacetyltriglycine and a normal or almost normal renogram. There was no difference between a young patient in an early stage of the disease and the other three patients with more advanced renal disease. In contrast, a patient with tubulointerstitial nephritis with uveitis had considerably better renal uptake of 99mTc-DMSA despite impaired renal function. We suggest that the specific tubular function defect in nephronophthisis might be the cause of the poor uptake of 99mTc-DMSA. We also recommend the method to support the clinical suspicion of nephronophthisis, even in the early stages of the disease.

Unlabelled: A single-injection, single-sample procedure for measuring 99mTc-MAG3 clearance is presented that incorporates scaling for patient size and is valid for both children and adults., Methods: The procedure is based on an empirical formula in which all measurements are expressed in dimensionless combinations. The formula was obtained by fitting data collected from 122 adults and 80 children at several centers., Results: All results were scaled to standard adult surface area and are presented in units of ml/min/1.73 m2. For adult subjects, the residual standard deviation (r.s.d.) calculated from a single sample at 45 min was found to be 23, using the plasma clearance calculated from a multi-sample clearance curve as a reference. This did not differ significantly from the value of 22 obtained with our previous formula, which was valid for adults only. For pediatric subjects, an r.s.d. of 24 was calculated by the new formula from a single sample at 35 min; a comparable value of 33 was found using a pediatric formula previously published., Conclusion: The new clearance formula is recommended as a replacement for the formula we previously published, since it is based on a larger and more diverse subject population, and since it now holds for children as well, with no loss of accuracy for adult subjects.

Unlabelled: Our previous studies on the preparation of 186Re-MAb conjugates for clinical radioimmunotherapy (RIT) were extended with the aim to derive conjugates which have a high Re:MAb molar ratio, are stable in vitro and in vivo, have favorable biodistribution characteristics and can be used together with 99mTc-MAb conjugates as a matched pair in combined radioimmunoscintigraphy/RIT studies., Methods: Rhenium and 99mTc-conjugates of intact MAb E48 were prepared according to our previously described multistep procedure using the MAG3 chelate and analyzed by protein mass spectrometry for the number of chelate molecules coupled to the MAb. For biodistribution analysis, tumor-free nude mice were simultaneously injected with 186Re-, 99mTc/99Tc- and/or 125I-labeled E48 IgG and dissected 1-48 hr postinjection., Results: Rhenium-186-MAb conjugates with up to 20 Re-MAG3 groups per MAb molecule were prepared with an overall radiochemical yield of 40%-60%. The conjugates did not contain empty MAG3 groups and no aggregates were formed. Only conjugates with a 186Re-MAG3:MAb molar ratio higher than 12 demonstrated slightly impaired immunoreactivity to a maximum of 15% decrease at the 20:1 molar ratio. Biodistribution experiments revealed that a proportion of the conjugate became rapidly eliminated from the blood for conjugates with a Re-MAG3:MAb molar ratio higher than 8. In this case, an increased uptake of activity was observed in the liver and intestines. The 99mTc/99Tc-MAb conjugates showed a similar enhanced blood clearance when containing more than eight Tc-MAG3 groups, while dual labeling of MAbs revealed that the in vivo stability of the conjugated Re-MAG3 complex itself does not differ from the corresponding Tc-MAG3 complex., Conclusion: With the method described in this study, it is possible to prepare 186Re-MAG3-MAb conjugates that fulfil all the aforementioned criteria for use in clinical RIT. Coupling of too many metal-MAG3 groups to MAbs results in rapid blood clearance. At the same metal-MAG3:MAb molar ratio, 99mTc/99Tc-MAb conjugates show a similar pharmacokinetic behavior as 186Re-MAb conjugates and can thus be used to predict the localization of 186Re-labeled MAbs and make dosimetric predictions in individual patients.

The aim of this paper was to determine the reproducibility (precision) of technetium-99m mercaptoacetyltriglycine (MAG3) clearance and to compare it with that of chromium-51 ethylenediamine tetra-acetic acid (EDTA). Twelve young volunteers (aged between 21 and 34 years), without any history of medical problems, were enrolled in this study. The test was performed twice, at an interval of 8 days and under similar physiological conditions. After the intravenous injection of both tracers, 15 blood samples were taken between 3 and 240 min. A biexponential fit was adapted to the plasma disappearance curves (5- to 120-min samples for 99mTc-MAG3 and 10- to 240-min samples for 51Cr-EDTA); the clearances were calculated according to Sapirstein and corrected for body surface area. The mean clearance values were 110 (range 85-130) and 226 (range 109-319)ml/min/1.73 m2, respectively, for 51Cr-EDTA and 99mTc-MAG3. For 51Cr-EDTA clearance, the mean difference between the first and the second measurement was -2.1% of the mean of the two successive values (SD: 8.4%). In ten cases, the difference was less than 12%; in two cases, the differences were 15% and 18%, respectively. For 99mTc-MAG3 clearance, the mean difference between the first and the second measurement was -20% of the mean of the two successive values (SD: 25%). In six cases, the difference was less than 12%; in four cases, between 15% and 40%; and in two cases, more than 60%. Methodological factors (impurities contained in the commercial kit, variable protein binding) as well as physiological factors (pH of urine, sodium load, stress) may explain the lack of precision of the 99mTc-MAG3 clearance. It is concluded that changes in 99mTc-MAG3 plasma clearance should be interpreted with care in daily routine.

. This investigation was undertaken in order to determine whether the clearance of technetium-99m mercaptoacetyltriglycine (99mTc-MAG3) is more closely correlated to the clearance of iodine-125 orthoiodohippurate (125I-OIH) than to the clearance of chromium-51 ethylene diamine tetra-acetate (51Cr-EDTA) and whether there is a clinically significant extrarenal clearance of 99mTc-MAG3 . Fifty-one patients with a glomerular filtration rate (GFR) of 4-132ml/min were studied. After a simultaneous single injection of the three tracers, plasma clearance was measured from blood samples 0-5h post injection (p.i.) (0-24h in patients with GFR<15ml/min). Renal plasma clearance was measured 0-5h p.i. The ratio between the renal plasma clearance of 99mTc-MAG3 and 125I-OIH was 0.57. The ratio between the renal plasma clearance of 99mTc-MAG3 and 51Cr-EDTA was 2.57. The coefficient of variation (CV) of the 99mTc-MAG3/125I-OIH ratio was significantly smaller than the CV of the 99mTc-MAG3/51Cr-EDTA ratio (13.4% versus 31.2%). The corresponding plasma clearance ratios were 0.59 (CV=14.8%) and 2.48 (CV=27.0%). Plasma clearance overestimated renal plasma clearance by 7.0ml/min (5.4%) for 99mTc-MAG3 and by 4.1ml/min (8.4%) for 51Cr-EDTA. The difference in plasma and renal plasma clearance of 125I-OIH of 5.5ml/min did not reach statistical significance. Red blood cell binding of 99mTc-MAG3, 125I-OIH and 51Cr-EDTA was 2.0%, 14.6% and 0.2%, respectively. Protein binding of 99mTc-MAG3, 125I-OIH and 51Cr-EDTA was 86.3%, 61.1% and 5.9%, respectively. The volume of distribution of 99mTc-MAG3, 125I-OIH and 51Cr-EDTA was 16.3%, 27.0% and 19.4% of body weight. In conclusion, the clearances of 99mTc-MAG3 and 125I-OIH are more closely correlated than is the clearance of 99mTc-MAG3 with GFR. Extrarenal clearance of 99mTc-MAG3 is relatively smaller than extrarenal clearance of 51Cr-EDTA. Thus, plasma clearance of 99mTc-MAG3 can be used as a measure of renal tubular function.

Six hundred and thirty-nine clearance studies performed in children aged 7 days to 19 years utilizing technetium-99m mercaptoacetyltriglycine (MAG 3) were retrospectively analysed. Standardized conditions for the investigation included: parenteral hydration (60 ml/hxm2 body surface) in addition to normal oral fluid intake, weight-related dose of 99mTc-MAG 3 (1 MBq/kg body weight, minimum 15 MBq) and calculation of clearance according to Bubeck et al. Of the 513 children, 169 included in this analysis could be classified as "normal" with regard to their renal function. Normal kidney function was judged by the following criteria: normal GFR for age, normal tubular function (absence of proteinuria and glucosuria), normal renal parenchyma (on ultrasonography, MAG 3 scan and intravenous pyelography), absence of significant obstruction and gross reflux (>grade I), no single kidney and no difference in split renal function >20%. Results showed increasing MAG 3 clearance values for infants during the first months of life, reaching the normal range for older children and adults between 7 and 12 months.

Two strategies have been used to increase the 99Tcm binding strength of human serum albumin (HSA) and thus enhance its blood retention. In a first approach, HSA was derivatized with a varying number of hydrazino nicotinyl (Hynic) side-chains using N-hydroxysuccinimidyl hydrazino nicotinate. Labelling of this albumin derivative with 99Tcm resulted in labelling yields of 90-95%. On the other hand, a 99Tcm-MAG3-HSA conjugate was prepared using the preformed chelate approach. In this way, non-specific binding of 99Tcm to HSA could be excluded. The in vitro stability of both 99Tcm-HSA derivatives was evaluated by cysteine challenge experiments and revealed a much higher stability for 99Tcm-Hynic-HSA than for 99Tcm-MAG3-HSA. The biological behaviour of the preparations was evaluated in mice and a rabbit using 125I-HSA as an internal biological standard. The blood retention of 99Tcm-MAG3-HSA decreased more rapidly than that of 125I-HSA in both animal species, whereas 99Tcm-Hynic-HSA seemed to provide a quasi-perfect 99Tcm-labelled analogue for 125I-HSA and 99Tcm-red blood cells (99Tcm-RBCs). In addition, the blood retention of 99Tcm-Hynic-HSA appeared to be similar to that of 99Tcm-RBCs in a volunteer. These results clearly indicate the superiority of 99Tcm-Hynic-HSA over 99Tcm-MAG3-HSA as a possible blood pool agent.

In a study of gamma-camera renography, a digitized time-activity curve, or renogram, was standardized in terms of absolute renal uptake. The algorithm for standardization of the renogram was based on a gamma-camera uptake method employed by Gates and Schlegel et al. All count rates for the background-corrected renograms were converted to percent renal uptake per injected dose per minute (%RU). The maximum value for the scale on the y-axis was set at 20% RU. The renograms were generated from 66 kidneys in 35 patients (27 males, 8 females) aged 19-80 years. Using the newly developed computer program, the shape of the renograms was considered abnormal between 8/52 (15%) and 10/53 (19%) kidneys, depending on the observer, all of which were classified as normal when displayed conventionally. All the renograms for 4 patients with one poorly functioning kidney, and between 8 (28%) and 10 (32%) renograms for 31 patients with two poorly performing kidneys, exceeded the maximum g-axis value of 20% RU. Expression of the renograms based on absolute uptake is helpful in avoiding the potential problem of two poorly functioning kidneys, which may be considered near-normal in terms of count rate. The maximum value on the y-axis in 99Tcm-MAG3 renography should be fixed between 25 and 30% RU, while the actual amplitude of the standardized renogram may depend on the method used for quantification.

S-Benzyl-, S-benzamidomethyl- and S-benzoylmercaptoacetyltriglycine were synthesized and compared in exchange labelling experiments for the preparation of 99mTc-MAG3. The rate of exchange from 99mTc-tartrate to 99mTc-MAG3 starting from the respective precursors was determined in different conditions. Labelling proceeded most rapidly starting from the S-benzoyl protected precursor but efficient labelling was also accomplished using the more stable S-benzamidomethyl- and S-benzylmercaptoacetyltriglycine. 99mTc-MAG3 was also prepared by direct labelling of unprotected mercaptoacetyltriglycine at alkaline pH. Radiochemical purity in these conditions is mainly dependent on the pH during labelling.

Unlabelled: Technetium-99m-ethylenedicysteine has recently been developed for renal function studies. The pharmacokinetics of 99mTc-EC were studied by constant infusion technique and compared with 99mTc-MAG3 and 131I-OIH in 11 patients with various renal disorders., Methods: After giving a 7.4 MBq 131I-OIH and 90-110 MBq 99mTc-EC or 99mTc-MAG3 bolus, a constant infusion (1MBq/ml 99mTc-agent and 0.07 MBq/m 131I-OIH was started. Sixteen blood and five urine samples were obtained over three hr., Results: The renal clearance of 99mTc-EC was higher than that of 99mTc-MAG3. The 99mTc-EC/OIH and 99mTc-MAG3/OIH ratios were 0.75 +/- 0.05 and 0.55 +/- 0.10 (p = 0.00087), respectively. The distribution volume of 99mTc-EC was also higher than that of 99mTc-MAG3 (15722 +/- 4644 and 9509 +/- 2788 ml/1.73m2, respectively; p = 0.072). The 99mTc-EC/OIH and 99mTc-MAG3/OIH distribution volume ratios were 1.03 +/- 0.14 and 0.55 +/- 0.10, respectively (p = 0.0003). The 60-min excretion values of 99mTc-EC and 99mTc-MAG3 were compared to that of OIH. The 99mTc-EC/OIH and 99mTc-MAG3/OIH excretion ratios were 0.96 +/- 0.06 and 1.07 +/- 0.10, respectively (p = 0.162). The protein binding of 99mTc-EC and OIH were found to be 34% +/- 4 and 66% +/- 5, respectively (p < 0.0001). The red cell binding of 99mTc-EC was negligible (3% +/- 1.2) in comparison to OIH (27% +/- 3; p < 0.0001)., Conclusion: This limited study demonstrates the pharmacokinetic and renal clearance properties of 99mTc-EC. This agent has good potential for renal function evaluation.

We present a method for estimating 99mTc-MAG3 clearance from both a single injection and two blood samples that is valid for both adults and children. It was obtained by fitting a scaled two-compartment model (having only two adjustable parameters) to adult and pediatric data from multiple centers.

An invasive comparative study of some pharmacokinetic aspects of 99mTc-mercaptoacetyltriglycine (MAG3), 131I-orthoiodohippurate (OIH), and 125I-iothalamate (iothalamate) was performed in six pigs 0-150 min after a simultaneous single injection (SI) and during a subsequent 90 min of continuous infusion (CI). The total plasma clearance and the renal clearance of MAG3 were about 75% that of OIH. The renal clearance of MAG3 was about 2 1/2 times the glomerular filtration rate. The distribution volume of MAG3 was 71% that of iothalamate and only 47% that of OIH. There was a significant hepatic plasma clearance of MAG3 of 5.9 ml min-1 and 3.9% of the injected dose was excreted in the bile. HPLC analysis revealed that technetium was excreted in urine and bile mainly labelled to MAG3. The average red blood cell (RBC) binding after single injection/during continuous infusion was 1.0%/2.3% for MAG3, 13.5%/9.0% for OIH, and 3.1%/5.3% for iothalamate. The binding of OIH to RBC in arterial blood increased from 8% at 1 min post-injection to 21% at 150 min post-injection. The RBC binding was higher in the renal vein, indicating incomplete back diffusion from RBC to plasma. The protein binding was 90% for MAG3, 49% for OIH and 16% for iothalamate. The renal plasma extraction of MAG3 was constant but significantly smaller after SI (0.54) than during CI (0.62). Following SI, the renal plasma extraction of OIH decreased continuously from 0.85 to 0.52, 3-150 min post-injection. On the average there was no significant difference in renal plasma extraction after SI and during CI of either OIH (0.72 versus 0.77) or iothalamate (0.26 versus 0.27). It is concluded that MAG3 is preferential to OIH as a tracer for renal function studies using a single injection technique mainly due to the constant renal extraction of MAG3.

This study provides values of transit times obtained by 99Tcm- mercaptoacetyl triglycine (99Tcm-MAG3) renogram deconvolution for both normal subjects and kidney graft recipients. The analysis included 50 healthy kidney units from 25 volunteers and 28 normal functioning kidney grafts. The parameters calculated for the whole kidney (WK) and for the renal parenchyma (P) were: mean transit time (MTT) and times at 20% (T20) and 80% (T80) of renal retention function initial height. For healthy kidneys the WK MTT was 174 +/- 27 s and P MTT 148 +/- 22 s. The WK T20 values were 230 +/- 33 s and P T20 231 +/- 34 s. The WK T80 was 108 +/- 19 s and P T80 106 +/- 12 s. Whole kidney and parenchymal values of transit times for normal functioning kidney grafts do not present significant differences with respect to healthy kidneys.

From a database of 133 patients (98 children and 35 adults) who underwent multiple blood sampling for 99Tcm-mercaptoacetyltriglycine (MAG3) clearance, we determined simplified algorithms allowing the estimation of clearance. A one-compartment model with two blood samples was applied. The best choices for the adult population were the 12 and 90 min blood samples, giving a standard error of the estimate (S.E.E.) of less than 10 ml min-1 1.73 m-2; for the children, the 10 and 80 min blood samples gave a S.E.E. of 20 ml min-1 1.73 m-2; for both the adults and the children, the 10 and 70 min blood samples gave the best results with, however, a S.E.E. of 19 ml min-1 1.73 m-2. The use of such a combined algorithm will therefore result in a degradation of the results in adults, suggesting that a separate algorithm for each group is preferable. We compared the accuracy of the two blood sample method to the one blood sample method based on previously published algorithms for children and adults, respectively. The S.E.E. was significantly lower, in adults as well as in children, using the empirical two blood sample method. This two blood sample method seems potentially useful for routine practice in adult patients. The advantages of using such a method in children is balanced by the practical problems inherent in the need to take a second blood sample during the first 10 min, at a time when the plasma activity is rapidly decreasing.

This study describes methods of measuring simultaneously the renal excretion of two radiopharmaceuticals and of evaluating their different kinetics. For quantification of the dynamic contributions of scattered radiation in a double-radionuclide study a high-resolution pure germanium detector was used. The geometry of the arrangement was a semi-shielded whole-body counter according to E. Oberhausen. An intra-individual comparison of the renal elimination of 99mTc-MAG3 and 131I-Hippuran shows a systemic difference between both tracers depending on the time after injection, its average being around 11% between the 10th and 20th min. The inter-individual comparison shows deviations from the mean between -29 and +20%.

Objective: Methotrexate (MTX) treatment at high doses may cause renal failure. The effects of treatment with low MTX doses on kidney function are, however, unknown. The objective of our study was to investigate the effect of low MTX doses on kidney function., Methods: The glomerular filtration rate was measured as the plasma clearance of 51Cr-EDTA and the clearance of 99mTc-dimercaptoacetyl-triglycine (correction of triglycerine) (99mTc-MAG3), a new renal tubular function agent, was used to measure tubular effects of MTX., Results: Significant decrease of both 51Cr-EDTA clearance from 92 +/- 7 to 83 +/- 5 ml/min x 1.73 m2 (mean +/- SEM) and of the 99mTc-MAG3 clearance from 360 +/- 18 to 309 +/- 15 ml/min x 1.73 m2 (p < 0.05) was observed., Conclusion: Our results indicate that low dose MTX treatment (15 mg weekly) may significantly impair kidney function which has to be considered particularly in situations with combined treatment with other potentially nephrotoxic substances.

A multicentre European study was undertaken in order to determine a reasonable algorithm allowing the determination of overall technetium-99m mercaptoacetyltriglycine clearance using a single blood sample. Employing multiple blood sample clearance as a reference method, it was shown that an acceptable estimation of the MAG3 renal clearance could be obtained using a blood sample taken at any time between 30 and 40 min after tracer injection. After correction for body surface area, comparison of clearance determined using (a) the single blood sample and (b) the multiple blood samples provided a coefficient of correlation of 0.949 and an SEE of 27 ml/min. This algorithm is valid for clearance values higher than 100 ml/min/1.73 m2 and for children older than 1 year of age.

Measurements were made of the fraction of injected radioactivity which was secreted in breast milk following 99Tcm-MAG3 dynamic renal scans of two nursing mothers. The activity concentration in the milk expressed at different times after injection was found to decrease monoexponentially, with effective half-lives of 3.2 and 4.0 h. Two models were applied to each set of data and predicted an overall mean infant effective dose equivalent per unit administered activity of 2.9 muSv MBq-1 and maximum of 4.5 muSv MBq-1. The results demonstrated that it was not essential to interrupt breast feeding following administration of 100 MBq 99Tcm-MAG3 for a dynamic renal scan. If a renal perfusion scan is performed using greater activities of 99Tcm-MAG3, the mother should interrupt feeding and not resume until measurements on her expressed milk samples indicate that the effective dose equivalent to the infant will be less than 1 mSv. However, it was noted that a considerably lower radiation dose to the infant could be achieved by using 99Tcm-DTPA. Therefore, it was concluded that whenever clinically appropriate 99Tcm-DTPA should be used for both types of renal investigations of breast-feeding mothers.

The radiopharmaceuticals (RF) EHIDA, DTPA and MAG-3 (labeled by 99mTc), commonly used in dynamic liver/kidney scintigraphy, are distributed in intravascular (i.v.) and extravascular (e.v.) spaces, as they are simultaneously cleared from the blood passing through their target organ (liver/kidney). The drop in concentration of these RF in blood is therefore determined by distribution as well as by clearance up to the time of equilibrium. From that time only the rate of decrease of RF in blood expresses the "true" (liver/kidney) clearance and this clearance parameter is a clinically reliable index of the function of the target organ. (A) The method of analysis of the clearance curve obtained from the heart region has been reported; the method is based on a physiological approach with respect to the distribution processes of the RF in the organism. Apart from the main important parameter, T (clear) (half-time of the "pure" clearance of the resp. RF from its distribution space), two further parameters are obtained: T (distr.) (half-time of the e.v. distribution of the RF) and END (distr.) (end of this distribution). (B) The results of 218 patients examined using 99mTc-EHIDA, 192 using DTPA and 65 using MAG-3 have been statistically processed. The mutual correlation of all parameters [T (distr.), END (distr.), T (clear)] within each group of patients as well as the differences of corresponding parameters between the groups of patients are studied. The main purpose of the work was to obtain the reliable clearance parameters of the RF with extravascular distribution for routine clinical practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Because of significant difficulties encountered in the manipulation of data from 99Tcm-DTPA and 99Tcm-mercaptoacetyltriglycine (MAG3) renogram studies, it was decided to try to improve the percentage dose of radioisotope injected and thus the number of counts obtained by using a minimum dose volume of 1 ml for all injections. This resulted in an improvement in the percentage dose injected. However, difficulties were still encountered in the younger children. 18.7% of children aged less than 3 months, received less than 50% of the injected dose, showing little or no improvement using the newer method. The difficulty of injecting small babies seems the most obvious reason. During the interpretation of the findings in paediatric radioisotope studies, it is important to remember that not all children may have received an adequate percentage dose to constitute a reliably diagnostic study.