OBJECTIVE. Specific quantitative measurements have been recommended to assist in the interpretation of technetium-99m mercaptoacetyltriglycine (MAG3) renal studies. Our objective was to define the sex- and age-specific normal ranges for these recommended parameters.
MATERIALS AND METHODS. Data were obtained from a retrospective analysis of 106 subjects who were evaluated for kidney donation. The MAG3 clearance was calculated using a common camera-based method. The relative uptake, prevoid/postvoid and postvoid/maximum count ratios were determined using whole-kidney regions of interest (ROIs). Time to peak, time to half-peak, 20 min/maximum and 20 min/2-3 min count ratios were determined for cortical and whole-kidney ROIs. Residual urine volume was calculated on the basis of the pre- and postvoid bladder counts and voided urine volume.
RESULTS. The mean camera-based MAG3 clearance was 321 ± 69 mL/min/1.73 m2, essentially the same as the mean plasma sample MAG3 clearance in comparable populations. The percentages of relative uptake in the right and left kidneys were 49% and 51% ± 4%, respectively; no difference was seen between men and women. Cortical values were lower than the whole-kidney values (p < 0.001); the mean cortical 20 min/maximum count ratio was 0.19 (SD, 0.07 and 0.04 for right and left kidneys, respectively). The mean postvoid/maximum whole-kidney count ratio was < 0.1, and the mean postvoid residual bladder volume was < 30 mL.
CONCLUSION. Normal limits adjusted for age and sex have been established. Applying normal ranges to quantitative MAG3 parameters may assist in the interpretation of MAG3 scintigraphy and facilitate appropriate patient management.
The use of technetium-99m mercaptoacetyltriglycine (MAG3) has increased significantly since its introduction in 1986 [1, 2]. Because of the favorable imaging characteristics of 99mTc and the more efficient renal extraction of 99mTc MAG3 compared with 99mTc diethylenetriaminepentaacetic acid (DTPA), 99mTc MAG3 has become the radiopharmaceutical of choice in many clinical contexts, particularly for patients with suspected obstruction or impaired renal function [3-6]. Today, 99mTc MAG3 is estimated to be used in approximately 70% of the 590,000 renal scans obtained annually in the United States, but many renal scans are interpreted by diagnosticians in sites that perform fewer than three studies per week [4, 7].
Clearance measurements and other specific quantitative parameters have been recommended to assist in scan interpretation and patient management [8-13]. For example, to assist in the interpretation of angiotensin-converting enzyme inhibition renography, the Santa Fe consensus report  and the Society of Nuclear Medicine procedure guideline on renovascular hypertension  recommend measurements of time to maximum counts (Tmax) and 20 min/maximum (20 min/max) count ratios for whole-kidney and cortical regions of interest (ROIs). The 20 min/2-3 min count ratio has been proposed as a useful parameter to simultaneously evaluate clearance and excretion, and it may be especially useful in monitoring transplantation patients to distinguish between acute tubular necrosis and rejection . A measurement of urine drainage based on a quantitative comparison of postvoid kidney counts with the counts obtained during the prevoid period improves the sensitivity and specificity for detecting an obstructed kidney [17-19]. Finally, the postvoid urine volume can easily be determined at the time of scanning and may provide important additional information regarding excretory function .
This study was conducted to define the normal ranges for these recommended quantitative parameters and to determine if the normal ranges vary on the basis of age or sex.
Materials and Methods
The study population consisted of 127 subjects who were evaluated for kidney donation at Emory University Hospital between February 1998 and March 2001. Review of patient records was approved by the institutional review board. Preoperative imaging studies included 99mTc MAG3 renography as a functional study; most subjects also underwent an anatomic study, either percutaneous contrast renal angiography, MR angiography, or CT angiography. Ten patients were excluded because the technologist entered a whole number—that is, 10.0 mCi (370.0 MBq)—as the dose injected; the dose has to be assayed in a dose calibrator and it is highly unlikely that exactly 10.0 mCi would be in the injection syringe. An incorrect dose entry invalidates the clearance measurement. Five more patients were excluded from analysis because data sets were missing; another four were excluded because of 99mTc MAG3 dose infiltration exceeding 1%, four were excluded because the camera was started late, one was excluded because of an unsuspected renal mass, and one was excluded because of unexpected bilateral renal artery stenosis.
Of the remaining 106 potential renal donors, 54 had normal results on MR angiography, 32 had normal results on percutaneous angiography, and five had normal results on 3D CT. Anatomic data were not obtained or not available in the remaining 15 subjects. A creatinine clearance was obtained in 99 of the 106 subjects (mean = 133 ± 38 mL/min/1.73 m2). All but four subjects (two men and two women) had a normal 24-hour urinary creatinine clearance (normal range for our laboratory is 90-139 mL/min/1.73 m2 for men and 80-125 mL/min/1.73 m2 for women). The four subjects with a reduced creatinine clearance had serum creatinine values ranging from 0.9 to 1.1 mg/dL, which all fall within our normal laboratory range of 0.6-1.4 mg/dL; in addition, three had normal results on MR angiography and the fourth had normal results on 3D CT. Because of the normal serum creatinine values, absence of history of renal disease, and normal findings on anatomic studies, these patients were included in the data analysis. A creatinine clearance was not obtained in seven subjects; five of the same seven subjects had a normal serum creatinine level (mean, 1.04 mg/dL; range, 0.6-1.2 mg/dL), and in the remaining two subjects the serum creatinine level was not measured or not available.
These remaining 106 subjects constituted the study group. Forty-four men and 62 women were evaluated. The mean age of the subject population was 39.9 ± 10.8 (SD) years (mean age for men, 41.0 ± 11.9; for women, 39.1 ± 9.9 years). The mean body surface area (BSA) for men was 2.04 m2 and for women was 1.80 m2.
Each study was performed with 7-11 mCi (259-407 MBq) of 99mTc MAG3 (Mertiatide, Mallinckrodt Medical). Radiochemical purity was 95.0% ± 2.7% (Sep-Pak Cartridge, Millipore).
The subjects were hydrated with approximately 500 mL of water 30 minutes before the study. Images were acquired in a 128 × 128 matrix with a 15-inch (38-cm) field-of-view gamma camera fitted with a low-energy all-purpose collimator. Each subject was imaged supine with the kidneys and bladder in the field of view. After the IV injection of 99mTc MAG3, serial 2-seconds-per-frame digital images were obtained for the first 48 seconds followed by 15-seconds-per-frame images (n = 16) and 30-seconds-per-frame images (n = 40), for a total study duration of 24 minutes 48 seconds. Time 0 was defined as the 16-second interval required for the dose to reach the kidney .
At the end of the acquisition, one additional postvoid 2-minute image was obtained of the kidneys with the patient in the supine position, and 1-minute anterior prevoid and postvoid bladder images were also obtained to determine residual urine volume  and postvoid (30 minutes) over maximum (postvoid/max) count ratios. The data were processed using the QuantEM 2.0 software (developed at Emory University and licensed by Emory University to GE Healthcare), which was developed specifically for 99mTc MAG3 renography [21, 22]. Processing details are summarized in the following text. The display of a representative study is shown in Figure 1.
Counting the Dose Injected
All subjects received a dose of 7-11 mCi (259-407 MBq) of 99mTc MAG3. Dead-time losses may be significant when counting larger doses, depending on the camera used. To avoid dead-time losses and determine the counts injected, a small syringe of approximately 1 mCi (37 MBq) was counted by placing it in a syringe holder 30 cm above the face of the camera. The small syringe and the syringe containing the dose to be injected were counted in a dose calibrator to yield the injected dose-to-small-syringe count ratio. The software multiplied the counts in the small syringe by the injected dose-to-small-syringe count ratio to obtain the counts in the injection syringe; the decay-corrected counts in the postinjection syringe were then subtracted from the counts in the injection syringe to yield the counts actually injected.
Infiltration was calculated by first drawing an ROI over the injection site at the conclusion of the study. Counts in the injection site ROI were corrected for decay and divided by dose injected to obtain a conservative estimate of the infiltrated dose. Four subjects were excluded from the study because of infiltration that exceeded 1% of the injected dose.
ROIs and Background Correction
Whole-kidney ROIs were automatically assigned over each kidney using the 2- to 3-minute postinjection image and were modified by the operator as necessary. An automated cortical ROI was assigned using an algorithm to identify the area of the renal pelvis and calyces and then subtracting that area from the whole-kidney ROI to generate the cortical ROI. A 2-pixel-wide C-shaped perirenal background ROI was generated 1 pixel outside of the whole-kidney ROI. To calculate relative uptake, the counts per pixel in the C-shaped perirenal background ROI were normalized to the number of pixels in the whole-kidney ROI and subtracted from counts in the whole-kidney ROI to determine the background-corrected counts.
The background-corrected counts were then corrected for renal depth using published equations [23, 24] with weight in kilograms and height in centimeters:
and were subsequently corrected for attenuation [21, 22]. To generate the background-subtracted renogram curve, an automated C-shaped perirenal background ROI was assigned so that the background ROI would not overlap the ureter and would lead to an inappropriately high background correction when there was marked retention of activity in a ureter or enlarged renal pelvis. The counts per pixel in the C-shaped perirenal background ROI were normalized to the number of pixels in the kidney ROI and subtracted from counts in the whole-kidney and cortical ROIs to determine the background-corrected counts used to generate the renogram curve.
The clearance of 99mTc MAG3 was measured in all subjects using a camera-based method without blood or urine sampling as previously described . Briefly, the counts in the kidneys from 1 to 2.5 minutes after injection were corrected for background, renal depth, and attenuation and then were divided by the dose injected to calculate the percentage of injected dose in the kidneys at the 1- to 2.5-minute interval. The value was adjusted for BSA, and a regression equation was used to convert the BSA-adjusted percentage of dose in the kidney at 1-2.5 minutes to a MAG3 clearance .
The following parameters were generated from the 99mTc MAG3 renograms: time to maximum counts (Tmax), time to half-peak counts (T½), the ratio of renal counts at 19-20 minutes to the maximum counts (20 min/max), and the ratio of counts at 19-20 minutes to the 2- to 3-minute counts (20 min/2-3 min). These parameters were generated for both whole-kidney and cortical or parenchymal ROIs; the terms “cortical” and “parenchymal” are used interchangeably and refer to an ROI over the renal cortex or parenchyma that excludes any activity in the collecting system (calyces or pelvis). Relative renal uptake was determined using whole-kidney ROIs and the 1- to 2.5-minute interval as described previously. The whole-kidney ROI was repositioned over the postvoid image of the kidney, and whole-kidney postvoid/prevoid and postvoid/maximum count ratios (postvoid/max) were generated. Finally, the camera-based MAG3 clearance (mL/min/1.73 m2) was calculated for each subject.
Postvoid urine determinations were available in 63 subjects; in the remaining subjects, the data were either not obtained or not recorded.
The mean, SD, range, and percentiles were used to describe the normal values. Two-way analysis of variance was used to determine whether a difference existed between sex and age groups (≤ 40 years vs > 40 years). No change was made. Adults 40 years old were included in the younger age group for purposes of analysis; hence, ≤ 40 years. A simple linear regression analysis was used to determine the association between MAG3 clearance and age. Statistical tests were performed at the 5% level of significance.
MAG3 and Creatinine Clearances
The MAG3 and creatinine clearances were normalized to 1.73 m2. The mean BSA-corrected MAG3 and creatinine clearances were significantly higher in men than in women (p < 0.001); however, no decrease was seen in the MAG3 clearance with age for either men or women (Table 1). For adult men, the lower range of a normal MAG3 clearance defined by the fifth percentile was 238 mL/min/1.73 m2 versus 226 mL/min/1.73 m2 for women.
TABLE 1: Camera-Based MAG3 Clearances
MAG3 Clearance (mL/min/1.73 m2)
No. of Patients
Note—Difference is significant (p < 0.05) between men and women. MAG3 = mercaptoacetyltriglycine
The relative uptake was 51% ± 4.0% for the left kidney and 49% ± 4.0% for the right kidney (Table 2). No significant difference was seen in relative uptake between men and women or between the two age groups.
TABLE 2: Relative Uptake of MAG3
Area of Uptake
No. of Patients
Note—No significant difference was seen in relative uptake between men and women or between younger (≤ 40 y) and older (> 40 y) adults. MAG3 = mercaptoacetyltriglycine
Time to maximum counts (Tmax)—The Tmax for both kidneys was significantly greater in women than in men (p < 0.05) using whole-kidney ROIs, but no significant difference was seen between the sexes when a cortical ROI was used to calculate the Tmax; moreover, the Tmax for both the right and left kidneys using cortical ROIs was significantly less than the Tmax obtained with whole-kidney ROIs (p < 0.005) (Tables 3 and 4).
TABLE 3: Normal 99mTc MAG3 Curve Parameters Using Whole-Kidney Regions of Interest
Note—No significant difference was seen between younger (≤ 40 y) and older (> 40 y) adults. MAG3 = mercaptoacetyltriglycine, Tmax = time to maximum counts, T½ = time to half-peak counts, 20 min/max = ratio of renal counts at 19–20 minutes to maximum counts, 20 min/2–3 min = ratio of counts at 19–20 minutes to 2–3 minute counts
Significant difference (p < 0.05) between men and women
TABLE 4: Normal 99mTc MAG3 Curve Parameters Using Regions of Interest over the Renal Cortex
Note—MAG3 = mercaptoacetyltriglycine, Tmax = time to maximum counts, T½ = time to half-peak counts, 20 min/max = ratio of renal counts at 19–20 minutes to maximum counts, 20 min/2–3 min = ratio of counts at 19–20 minutes to 2–3 minute counts
There is a standard difference (p < 0.05) between men and women
Time to half-maximum counts (T½)—The T½ was calculated from the time of the maximum counts to the time when the renogram curve decreased to half of the maximum counts. The T½ for the right kidney using whole-kidney ROIs was significantly higher in women than in men—8.29 minutes versus 5.64 minutes, respectively—but this difference was minimized when cortical ROIs were used (Tables 3 and 4). The mean values for cortical T½ were significantly less than the mean whole-kidney T½ values for both men and women (p < 0.01).
Twenty-minute/maximum count ratio (20 min/max)—The mean right cortical 20-min/max count ratio was 0.19 ± 0.07 for the right kidney and 0.19 ± 0.04 for the left kidney. Both were significantly less than the whole-kidney values (p < 0.001) (Tables 3 and 4). No significant difference was seen between men and women, and no significant change with age.
Twenty-minute/2-3 minute count ratio (20 min/2-3 min)—The mean right cortical 20 min/2-3 min ratio was 0.16 ± 0.07 for the right kidney and 0.15 ± 0.04 for the left kidney (Table 4). No significant difference was seen between sexes and no significant change with age.
Postvoid/maximum renal count ratio— The postvoid/max renal count ratio was determined using whole-kidney ROIs (Table 5). The mean left postvoid/max count ratio was 0.09 ± 0.03. No significant difference was seen between the right and left kidneys, nor was there a significant difference between men and women. The postvoid/max ratio increased slightly with age for the left kidney (p < 0.05), but the mean values for both age groups and both sexes were all < 0.1.
TABLE 5: Postvoid to Maximum and Postvoid to Prevoid Count Ratios Using Regions of Interest over Entire Kidney
A minor but significant difference was seen in postvoid-to-prevoid and in postvoid-to-maximum count ratios for left kidney between younger (≤ 40 y) and older (> 40 y) adults. No significant difference was seen between men and women
Postvoid/prevoid renal count ratio—The postvoid/prevoid renal count ratio was also determined using whole-kidney ROIs (Table 5). The mean left postvoid/prevoid count ratio was 0.59 ± 0.15, and the mean right postvoid/prevoid count ratio was 0.52 ± 0.19. No significant difference was seen between men and women. The postvoid/prevoid ratio increased slightly with age for the left kidney (p < 0.05).
Voided Volume and Residual Bladder Volume
No significant difference was seen in the voided volume between men and women. When the data were analyzed by age groups, no significant difference was seen in voided volume between men and women younger than or equal to 40 years old, but a significant difference was seen in voided volume between younger (≤ 40 years) and older (> 40 years) men (p < 0.01) (Table 6). No significant difference was seen in the residual urine volumes of men and women (Table 6). For women and men ≤ 40 years, the 95th percentile for residual bladder volume did not exceed 42 mL. Older men had a significantly higher residual volume than younger men (Table 6), possibly due to prostatic hypertrophy.
TABLE 6: Bladder Voided Volume and Residual Volume
Note—No significant difference was seen in voided volume or residual bladder volume between mean and women. A significant difference in residual bladder volume was seen between younger (≤ 40 y) and older (> 40 y) men
One woman had a residual volume of 256 mL; this value was considered to be abnormal and was deleted from the analysis
MAG3 is the most widely used renal radiopharmaceutical in the United States; however, the mean and normal ranges for many of the recommended quantitative parameters used as adjuncts to image interpretation have not been determined; have not been comprehensively defined for age, sex, and both cortical and whole-kidney ROIs; or have been based on abstract publications or publications with a limited number of patients [25-29]. This study presents the mean and normal ranges for recommended MAG3 renogram parameters and the normal values for the postvoid kidney to maximum count ratio, the residual urine volume, and the MAG3 clearance using a common camera-based technique.
The tables provide the mean, SD, minimum, maximum, fifth percentile, and 95th percentile for each of the variables. We have elected not to provide CIs to determine a normal range because CIs depend on the sample size; a larger sample size will result in a smaller CI. We believe more useful values are the actual data representing the fifth and 95th percentiles. For example, if a sampled population were unchanged, the fifth and 95th percentiles would tend to remain constant even if the sample size were increased, whereas the CIs would decrease.
Optimally, the best cutoff value to separate normal from abnormal values would be obtained by comparing results obtained in normal and diseased populations. In practice, however, it is often difficult to generalize such a comparison because the degree of abnormality can vary substantially depending on the selection criteria used to define the disease population. For a new patient, we consider any value lying outside of the fifth or 95th percentile to be abnormal. Sometimes, as with the Tmax, values outside the lower range of normal are likely to represent a processing or quality-control problem rather than an abnormality of renal function. An expanded review page shows the patient values for selected measurements and the normal ranges for these values (Fig. 2). This display can be customized to display all or a selected sample of the calculated values; abnormal results are highlighted in red on the computer display. A similar format could be incorporated into other software programs to display the normal range and flag abnormal results.
A measurement of the MAG3 clearance can easily be obtained at the time of the renogram, and the clearance measurement can often aid in the interpretation of the study and facilitate appropriate patient management [8-13]. Plasma sample clearance methods are considered to be superior to camera-based clearances  and can be calculated with reasonable accuracy from a single plasma sample obtained 40-45 minutes after injection . However, many nuclear radiology services in the United States do not offer plasma sample clearances because of the additional technical expertise required to perform a plasma sample measurement and the necessity of complying with CLIA (Clinical Laboratory Improvement Act) regulations required for in vitro plasma sample clearances. Instead, they elect to perform a camera-based clearance.
Camera-based clearances are generated at the time of renal scintigraphy, do not require blood or urine collection, and generally provide an acceptable estimate of renal function that is equivalent to or superior to the creatinine clearance [30-32]. Other studies have been conducted to calculate camera-based MAG3 clearances in normal populations, but they have either used a clearance index expressed as a percentage of the injected dose (not as mL/min), used a technique that is not commercially available, or used software designed for iodine-131 OIH (orthoiodohippurate), which gives a normal MAG3 clearance value almost twice that obtained by plasma and urine sample methods [10-12, 25, 26, 28]. The camera-based clearance technique used in this study has been validated in a multicenter trial , is currently commercially available on GE Healthcare systems, and provides values that appear to be more reproducible than the creatinine clearance . Other vendors provide software to measure the MAG3 clearance using a camera-based technique similar to the one described here, but to our knowledge data comparing the results using software from other vendors have not been published.
The camera-based MAG3 clearance is comparable to the plasma-based MAG3 clearance. This assertion is supported by the fact that the mean and SD for the BSA-corrected camera-based MAG3 clearance (321 ± 69 mL/min/1.73 m2) were essentially the same as for the plasma sample MAG3 clearance measured in two separate populations of potential renal donors at different institutions: 304 ± 70 and 317 ± 74 mL/min/1.73 m2 [14, 15].
A slight decline in the MAG3 clearance with age has been reported by others [10, 24, 25] and parallels a similar decrease in the creatinine clearance with age . We did not observe a decrease in the camera-based MAG3 clearance with age in our subject population; this result may be because of the relatively high clearances in the older members of the population because there was also no decrease in creatinine clearance with age. In addition, the ratio of the SD of the MAG3 clearance in healthy subjects to the mean MAG3 clearance (21%) was less than that of the ratio of the SD of the creatinine clearance to the mean creatinine clearance (29%); this ratio provides a measure of dispersion of the data. Dispersion is less with the camera-based MAG3 clearance, and this finding suggests the camera-based MAG3 clearance is at least comparable to and probably superior to the creatinine clearance in defining normal renal function. Finally, data also suggest that the camera-based MAG3 clearance is superior to the creatinine clearance for monitoring changes in renal function .
Camera-based MAG3 clearances are available on most nuclear medicine camera and computer systems. The particular software program, QuantEM, that we used for this study is currently available on the GE Healthcare Xpert computer system and an upgraded version, QuantEM 2.0, will soon be available that could be used by other vendors. As with the study by Klingensmith et al. , other inhouse or commercial camera-based software programs for determining the MAG3 clearance should obtain results comparable to those reported here so long as the programs incorporate similar quality-control features (dose infiltration, avoiding potential dead-time loses, a standardized time 0) and the vendors provide validation studies to ensure the software is performing as specified.
In women, drainage from the right and left renal pelves appears to be slightly slower than drainage from the right and left renal pelves of men based on a significantly greater whole-kidney time to peak for both kidneys and greater time to half-peak (left kidney) for women compared with men (Table 3). This trend may be related to dilatation of the collecting system during pregnancy that did completely resolve, but we have no data on the reproductive history of women in our sample. This difference is minimized or eliminated by the use of cortical ROIs (Table 4). Our data show that the values for these parameters generated by cortical ROIs are significantly lower than the values generated with whole-kidney ROIs, have less scatter (smaller SD), and support the conclusions of an earlier study that ratios generated using cortical ROIs are more reliable and give a more accurate estimation of the parenchymal function than values generated using whole-kidney ROIs .
Retention of 99mTc MAG3 in the calyces or renal pelvis can distort the Tmax, T½, 20-min/max count ratios, and the 20 min/2-3 min count ratios. Because of the variation in hydration and collecting system activity among healthy subjects, cortical or parenchymal ROIs that exclude the renal pelvis and calyces provide a better assessment of renal function; cortical ROIs may give misleading values when there is significant patient motion or very poor renal function or when the cortical ROI includes activity in the renal calyces or pelvis. The radiologist or nuclear medicine physician interpreting the study should visually inspect the cortical ROI to make certain it is appropriately assigned.
Patients should be encouraged to void once the dynamic renal images are completed to reduce radiation exposure to the bladder and gonads . Static postvoid images of the kidneys and bladder are easy to obtain and should be a routine step in renal scintigraphy. In all our subjects, the postvoid-to-maximum kidney count ratio for both the right and left kidneys was always less than 0.25. This type of calculation can be particularly useful when assessing patients with suspected obstruction [18, 19]. A postvoid image of the kidneys at approximately 30 minutes after injection of the radiotracer may also reveal unsuspected urinary retention in the bladder and is an easy adjunct to MAG3 renography. A large postvoid residual urine volume may represent bladder outlet obstruction and may also interfere with drainage from the collecting system and lead to a spurious diagnosis of ureteropelvic junction obstruction.
In conclusion, a number of specific parameters have been recommended to assist in the interpretation of MAG3 renography. Normal limits for these recommended parameters, adjusted for age and sex, have been established. Applying these normal limits to quantitative MAG3 parameters should assist in the interpretation of the study, facilitate appropriate patient management, and provide a quantitative basis for the development of decision support systems to assist physicians in the interpretation of renal scintigraphy [36, 37].
Supported by grant ROI LMN07595 from the National Library of Medicine.
Address correspondence to A. Taylor.
This is a Web exclusive article.
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