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Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of 99mTc-mercaptoacetyltriglycine (99mTc--MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq 177Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by 99mTc-MAG3-clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy., Competing Interests: CONFLICTS OF INTERESTS RAW has received the “YING” research grant from Novartis Pharma, Nürnberg, Germany. AW has received the “YING” research grant from Novartis Pharma, Nürnberg, Germany. All other authors declare no conflict of interests.

Several single sample methods for determination of (99m)Tc-mercaptoacetyltriglycine (MAG3) clearance are being used clinically. Kabasakal et al. proposed a similar formula for (99m)Tc-ethylenedicysteine (EC). This study was performed to compare his method with Bubeck et al. formula for (99m)Tc-MAG3 already in use. Twenty-eight subjects divided in two groups were registered which included 22 patients with various renal diseases (group-I) and six normal volunteers (group II). All subjects were studied twice using both the radiopharmaceuticals. The images and renogram parameters, that is TMAX and T1/2 of both the agents, were similar in all the subjects. The clearance of the (99m)Tc-EC was however considerably higher than (99m)Tc-MAG3 in both the groups (mean ± SEM =279 ± 14 ml min(-1)/1.73 m(2) versus 177 ± 15 ml min(-1)/1.73 m(2) in group-I and 377 ± 11.90 ml min(-1)/1.73 m(2) versus 238 ± 8.23 ml min(-1)/1.73 m(2) in group II). This difference was more pronounced in cases with reduced renal functions. Among the Effective Renal Plasma Flow (ERPF) values determined from EC and MAG3 clearances in six normal volunteers, four cases only in MAG3 had ERPF below the lower limit. This study has demonstrated superiority of single sample method for (99 m)Tc-EC clearance over its analogous method for (99m)Tc-MAG3., (© 2013 The Authors Clinical Physiology and Functional Imaging © 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Aim: Renal function is usually determined by means of creatinine-clearance, and of serum Cystatin C, the latter with increasing frequency. The present study analyses, whether the diagnostic accuracy of (99m)Tc-MAG(3) clearance is comparable to that of these modern serologic methods., Patients, Methods: 71 consecutive adult Caucasian patients (42 female, 29 male; age 50 +/- 16 yrs., range 20-83) who were referred to a nuclear medicine department for determination of bilateral renal function with (99m)Tc-MAG(3) were included. Following sufficient hydration, 10 ml of blood were taken for determination of Cystatin C and creatinine in serum prior to i.v. injection of the radiotracer. According to the recommendations of the National Kidney Foundation, glomerular filtration rate (GFR) was calculated from serum creatinine using either Cockcroft & Gault and Modification of Diet in Renal Disease (MDRD) study equation. These estimates of GFR served as reference. Cystatin C is a low molecular protein produced by all nuclear cells and is eliminated to 85 % by glomerular filtration. Analysis of (99m)Tc-MAG(3) clearance was performed by means of Bubeck's formula., Results: Linear regression analysis produced Pearson's correlation coefficients of r = 0.68 and r = -0.69 for the comparison of either Cystatin C and (99m)Tc-MAG(3) clearance with the Cockcroft & Gault equation. The comparison of Cystatin C and (99m)Tc-MAG(3) clearance with MDRD study equation resulted in correlation coefficients of r = 0.755 and r = -0.77. None of these differences were significant. The exclusion of renal impairment or the detection of an at least moderate renal impairment revealed again no significant differences between Cystatin C and (99m)Tc-MAG(3) clearance., Conclusions: Cystatin C and (99m)Tc-MAG(3) clearance are equally suited to exclude renal impairment or to detect a relevant renal impairment. Differences between both procedures are more likely a result of the applied reference method.

Objective: To estimate the dynamic rates of arterial delivery and renal drainage in renograms with the Homsy sign, using optimized computed compartmental modelling., Methods: Eleven F-15 renograms and one F+15 renogram (using 99mTc-mercaptoacetyltriglycine) with the Homsy sign were studied, with 26 controls. Compartmental models were constructed for each renogram using components (blood, renal, bladder) linked by variables (arterial rate, drainage rate). Each model was optimized using the Marquadt least-squares method to numerical data from the time-activity curves (TACs). The model renal component at sample points along the TAC was minimized and the corresponding drainage rates calculated., Results: The models were optimized, with a mean (range) r2 of 0.811 (0.68-0.88). There were continuous low drainage rates for all type 4 renograms, with no quadrupling of the flow rate, as predicted by the standard model., Conclusion: The standard model is unlikely to be correct and the Homsy sign is probably an artefact seen in patients with impeded urinary drainage. Computer modelling of individual renograms is feasible and can provide useful insights into the pathophysiology of renal uptake and drainage.

About 14 years have passed since Fritzberg et al. developed 99mTc-MAG3 in 1986. The biological properties of this radiopharmaceutical are somewhat different from radioiodine labeled hippurate: it exhibits higher protein binding, slower blood clearance, higher extraction efficiency by tubular cells and larger excretion into the bile than the latter. Nonetheless, it has been widely used as the agent of choice for renal scintigraphy, diuresis renography, captopril augmented renography, and renal transplant. Renal scintigraphy with 99mTc-MAG3 can provide excellent image quality even in the presence of severely decreased renal function. 99mTc-MAG3 is also used as an alternative to radio-hippurate for quantitative measurement of effective renal plasma flow. In this review, I focused on its pharmacokinetics, simplified quantitative methods and clinical application in renal diseases.

Background: Chronic allograft nephropathy (CAN), a major problem in renal transplantation, is related to both alloantigen-dependent and -independent processes. Because dietary salt intake modulated glomerular production of transforming growth factor-beta, which has been shown to play an important role in CAN, we hypothesized that dietary salt would directly enhance renal injury in a rodent model of CAN., Methods: Dietary NaCl was increased from 1.0% (normal) to 8.0% in a group of Fisher/Lewis rats 25 days following orthotopic renal transplantation and was continued until 16 weeks after transplantation., Results: Blood pressure, which was recorded using radiotelemetry in the first eight-weeks post-transplantation, did not differ between the groups, but allograft recipients on the 8.0% NaCl diet rapidly demonstrated increased urinary albumin excretion. Renal function determined by dynamic functional imaging was worse in allograft recipients on the 8.0% NaCl diet by six weeks following transplantation. Histologic examination at 16 weeks confirmed a significant increase in allograft damage in the 8.0% NaCl group compared with allografts from rats on 1.0% NaCl diet. These findings included glomerulosclerosis and tubulointerstitial injury that consisted of fibrosis, tubular atrophy and dilation, intratubular casts, and tubular epithelial cell damage. Small arteries and arterioles did not show evidence of damage from hypertension or other abnormality., Conclusions: In this model of CAN, renal allograft dysfunction preceded hypertension and was accelerated significantly by an increase in dietary salt.

We compared single-sample methods, proposed by Russell et al. and Bubeck et al., and camera-based methods in calculating 99mTc-MAG3 clearance, and determined camera-based methods that provide estimates comparable to those measured by the Russell method. Twenty-one patients underwent 99mTc-MAG3 renal scintigraphy, and clearance was measured by the Russell method and Bubeck method. Various renogram parameters were determined based on the slope of the renogram and area under the renogram, and correlated with the clearance measured by the Russell method. Camera-based clearance was calculated with the obtained regression equations and with equations determined previously using the Bubeck method as a standard. The Bubeck method provided lower measures than the Russell method in high renal function. Clearance measured by the Russell method was well correlated with renogram parameters, and clearance calculated with the obtained regression equation was comparable to that measured by the Russell method. When camera-based clearance was predicted with the previous equation, it was lower than the result obtained by the Russell method in high function. In conclusion, there are systematic differences in 99mTc-MAG3 clearance calculated by different methods. The camera-based methods obtained in this study appear to facilitate comparison of results obtained by the Russell method and camera-based method.

Error estimates for arteriovenous difference were calculated by two models, a lag time model and a compartmental model, using Tc99m-diethylenetriaminepentaacetic acid (DTPA) plasma clearance curves from 40 subjects and Tc99m-MAG3 (mercaptoacetyltriglycine) curves from 18 subjects. It was found that correcting for the effect of the initial bolus largely cancelled the conventional arteriovenous difference, so that the net error was negligible.

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.

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.

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.

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.