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Establishing Normal Values of Normalized Residual Activity at 20 Minutes and Output Efficiency at 20 Minutes in Normal Renal Units for Tc-99m Ethylenedicysteine Diuretic Renogram for Children Less Than and Equal to 12 Years of Age
*Corresponding author: Dr. Madhusudhanan Ponnusamy, 5015, Department of Nuclear Medicine, SSB, JIPMER, Puducherry - 605 006, India. E-mail: freethinker_13@yahoo.co.in
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Received: ,
Accepted: ,
How to cite this article: Palo A, Sambandan K, Mathiyazhagan P, Ponnusamy M. Establishing Normal Values Of Normalized Residual Activity At 20 Minutes And Output Efficiency At 20 Minutes In Normal Renal Units For Tc-99m Ethylenedicysteine Diuretic Renogram For Children Less Than And Equal To 12 Years Of Age. Indian J Nucl Med. 2025;40:334-8. doi:10.25259/IJNM_15_25
Abstract
Objectives:
The aim of the study was to establish normal values of NORA20 and OE20 in EC diuretic renogram for children ≤12 years of age and to compare the mean values of NORA20 and OE20 of normal renal units with that of obstructed renal units. 99mTc – Ethylene dicysteine (EC) diuretic renogram is used to evaluate pelviureteric junction obstruction (PUJO). Commonly used parameters such as Tmax and T½, are available for semi-quantitative assessment of PUJO, but these are dependent on renal function and can be abnormal in cases with poor renal function and no obstruction. To overcome this limitation, NORA20 and OE20 were introduced as independent renal drainage parameters. However, no normal values for NORA (Normalized Residual Activity) and OE (Output Efficiency) are established for EC diuretic renogram.
Material and Methods:
In children equal to and below 12 years of age who underwent EC diuretic renogram in the department of Nuclear Medicine, 278 normal renal units were analyzed to establish the normal values of the parameters, and the values were compared with those obtained from 96 obstructed renal units.
Results:
The mean value of NORA20 was found to be 0.3577 (Standard deviation [SD] 0.1592), and of OE20 was found to be 92.2084 (SD 3.6717). A statistically significant difference was found between the mean values of the normal and obstructed renal units in both the parameters (P < 0.0001).
Conclusion:
Normal values of NORA20 and OE20 have been established in the pediatric age group for EC diuretic renogram and were found to be 0.3577 (0.1592) and 92.2084 (3.6717), respectively.
Keywords
Diuretic renogram
Ethylenedicysteine
Normalized residual activity
OE
Pelviureteric junction obstruction
INTRODUCTION
The diuretic renogram was introduced by O’Reilly to assess the function and drainage of the kidney in 1978. Later on, it gained widespread acceptance by other physicians for routine usage to assess parenchymal function and drainage in cases of upper urinary tract obstruction before and aft er surgery.
This imaging procedure allows assessment of a drop in renal function or an impedance to outflow of urine from the kidneys that may be seen in pelviureteric junction obstruction (PUJO). The radiopharmaceuticals are typically injected with a diuretic such as furosemide. Many protocols of diuretic renography have been introduced over time, such as the F − 15 and the F + 20 protocols, but the F + 0 protocol is the most commonly used one due to the ease of performance and the shorter duration of examination, thereby reducing the proportion of indeterminate scans and allowing more number of scans to be done per day in centers with high patient load.
While several parameters are available to describe the drainage and parenchymal function of the kidneys, Tmax and T½ are the most commonly used and most commonly provided parameters by soft ware vendors. This is mainly because they are easy to calculate and interpret, and the normal values for various tracers are well established. However, a major limitation of the use of Tmax and T½ is that they can be elevated in a normally functioning obstructed kidney as well as in a poorly functioning nonobstructed kidney. It is, therefore, difficult to differentiate between the two etiologies. To overcome this problem, parameters such as normalised residual activity (NORA) and output efficiency (OE) were introduced. These are independent drainage parameters, and when compared to Tmax and T½, these parameters can assess PUJ obstruction with certainty. NORA and OE are simple and reliable parameters that allow quantification of renal output irrespective of kidney function.
In addition to diethylenetriamine pentaacetate (DTPA), mercaptoacetyltriglycine (MAG3) is used widely in the United States of America and elsewhere, whereas ethylene dicysteine (EC) is the radiopharmaceutical used widely in India and several other countries of the global south. Studies have established normal values of various parameters, including NORA and OE for DTPA and MAG3, but to the best of our knowledge, normal values of NORA and OE have not been established for EC. Knowing standard normal values for NORA and OE will enable diagnosing a PUJ obstruction with certainty without relying heavily on the parenchymal function of the affected kidney. The current study was designed with the primary objective of establishing normal values of NORA20 and OE20 in children below 12 years of age and the secondary objective of comparing the values of obstructed renal units with the values obtained of the normal renal units.
MATERIAL AND METHODS
Study type and subjects
Prior approval from the institute’s ethics committee was obtained before commencing the study. This cross-sectional analytical study was performed on patients undergoing EC diuretic renogram to rule out renal outflow obstruction. The inclusion criteria were patients of age ≤144 months (12 years) referred to the department of Nuclear Medicine for Tc-99 m EC diuretic renogram. Two renal groups were considered: Normal renal units (contralateral kidney) and obstructed renal units. Normal renal units were defined based on criteria described in previous studies, as kidneys that were normal sized for age on the ultrasound (USG KUB) and had normal intravenous urogram and micturating cystourethrogram (if available) and had normal estimated glomerular filtration rate for age.[1-4] Obstructed renal units were defined as renal units with primary PUJ obstruction diagnosed by antenatal or postnatal USG KUB. Inclusion criteria: Patients of age ≤144 months (12 years) referred to the department of Nuclear Medicine for Tc-99 m EC diuretic renogram. Exclusion criteria for primary objective: (i) bilateral hydronephrosis and (ii) single kidney with hydronephrosis.
Validation of algorithm
An algorithm was developed using MATLAB (The Mathworks, Inc.,) for the calculation of NORA20 and OE20 values as per standard definitions and guidelines.[5] The developed algorithm was validated by comparing the values obtained from Tc-99 m DTPA renogram of healthy voluntary kidney donors with those obtained in the study by Beatović et al., which used the International Atomic Energy Association (IAEA) soft ware package. An arbitrary difference of 5% between the mean values from the two groups was deemed acceptable.[6]
Brief scan procedure
Patients who satisfied the inclusion and exclusion criteria were enrolled in the study aft er obtaining consent. The dose of activity of 99mTc EC was administered intravenously as per the recommendations of European Association of Nuclear Medicine/Society of Nuclear Medicine and Molecular Imaging guidelines, along with 1 mg/kg of furosemide was administered (F + 0 protocol). Dynamic images of abdomen and pelvis were acquired in posterior projection for 22 min on 64 × 64 image matrix, at the rate of 1 s per frame for 1 min (perfusion images), followed by 15 s per frame for the remainder of the study (parenchymal phase and excretory phase). Immediate postvoid and 2 h delayed images of the abdomen and pelvis were acquired in the posterior view on a 128 × 128 matrix for 120 s.[7]
Analysis to extract NORA and OE
NORA20 and OE20 were calculated from the images of EC diuretic renogram as per definitions given in the International Scientific Committee on Radionuclides in Nephrourology (ISCORN).[5]
Statistical analysis
Mean and standard deviation (SD) of NORA20 and OE20 were calculated. The continuous and discrete variables were expressed as mean and SD if they followed a normal distribution or as median and interquartile range if they followed a nonnormal distribution. The normality of data was assessed using the Kolmogorov–Smirnoff test. Comparison of means was done using unpaired ‘t’ test using PS soft ware by Informer Technologies, Los Angeles, United States (Power and Sample Size Calculation version 3.1.6). P value of < 0.05 was considered as significant.
RESULTS
Validating of the algorithm
The mean values SD of NORA20 and OE20 of 40 renal units of 20 prospective voluntary kidney donors (11 females and 9 males) calculated on MATLAB were 0.60 (0.12) and 84.62 (3.42), respectively. The differences in the mean values of NORA20 and OE20 calculated in this study and those obtained by Slobodanka Lj. Beatovic et al. were 4.87% and 3.74%, respectively.[6] The algorithm was therefore considered valid for further use in the study.
Normalised residual activity20 and OE20 of normal and obstructed units
A total of 278 normal renal units from 261 participants for the primary objective and 96 obstructed renal units from 93 participants for the secondary objective were included for analysis in this study. Sixty-four renal units satisfying the inclusion criteria were excluded from this study as the duration of the dynamic scan was found to be less than the required 20 min. The median age for the normal group was 24 months, and the interquartile range was 56 months. The majority of participants were males (73%). Of the 93 patients with obstructed renal units, 14 patients had bilateral hydronephrosis, and the rest had unilateral PUJO.
The mean value SD of NORA20 and OE20 for normal units was 0.3577 (0.1592) and 92.2084 (3.6717), respectively. No statistically significant difference was found between values of NORA20 and OE20 in normal units between various age groups and sex. The standard error of mean for NORA20 and OE20 was found to be 0.0111 and 0.8023, respectively.
The mean SD of NORA20 and OE20 in obstructed renal units were 1.5601 (0.32) and 64.2919 (13.98), respectively. Figures 1 and 2 show box and whisker plots showing distribution of values of NORA20 and OE20 obtained in our study.
- Box and whisker plot for NORA20 values of normal (group 1) and obstructed (group 2) renal units (original)
- Box and whisker plot for OE20 values of normal (group 1) and obstructed (group 2) renal units (original)
Age-wise NORA20 and OE20 in normal and obstructed renal units
Comparison of NORA20 and OE20 values between normal and obstructed renal units for various age groups has been given in Table 1.
| NORA20 | OE20 | |||||||
|---|---|---|---|---|---|---|---|---|
| Normal | Obstructed | Normal | Obstructed | |||||
| Age | Mean | SD | Mean | SD | Mean | SD | Mean | SD |
| 0–6 months | 0.3722 | 0.1226 | 1.6146 | 0.4536 | 92.6658 | 2.6166 | 63.4759 | 14.4876 |
| 6–12 months | 0.4536 | 0.1886 | 1.6547 | 0.5214 | 91.3892 | 4.7500 | 55.4792 | 14.3564 |
| 1–2 years | 0.4135 | 0.2966 | 1.4653 | 0.2146 | 90.7579 | 4.9829 | 66.2886 | 10.5743 |
| 2–5 years | 0.3266 | 0.1076 | 1.5893 | 0.3843 | 92.3444 | 3.7741 | 63.0554 | 19.0983 |
| 5–10 years | 0.3338 | 0.1215 | 1.5601 | 0.3843 | 92.5364 | 3.4224 | 64.2919 | 13.9825 |
| 10–12 years | 0.3077 | 0.0576 | 1.2861 | 0.1883 | 93.2108 | 1.8837 | 69.6530 | 5.1512 |
SD: Standard deviation, NORA20: Normalised residual activity20, OE20: Output efficiency20
Unpaired t-test revealed statistically significant differences in NORA20 and OE20 values between normal and obstructed renal units across all age categories (P < 0.0001).
Adequate power was achieved for each age category comparison between normal and obstructed renal units.
DISCUSSION
The ISCORN consensus of 2008 extensively analyzed various quantitative, semi-quantitative, and visual parameters to assess transit times and identify outflow tract obstruction.[5] Among these parameters, Tmax and T½ are the most widely used due to their ease of interpretation and low computational requirements. However, these parameters are strongly dependent on renal function. Consequently, the values will be abnormal in kidneys with poor renal function, even in the absence of functional or anatomical obstruction.
The ISCORN consensus also describes more sophisticated parameters such as normalized outflow activity (NORA) and outflow efficiency (OE), which are independent drainage parameters. While OE is a more independent drainage parameter than NORA, NORA offers the advantage of being computationally simpler. Measurement of transit times continues to be considered the gold standard parameter for assessing outflow tract obstruction. However, with the increasing use of the F + 0 protocol, the prerequisites of system stationarity and linearity are not always maintained. Consequently, deconvolution analysis, which is typically employed to calculate transit times, may not be reliably applied in such cases.
These parameters are applicable for all renal radiopharmaceuticals such as Tc-99 m labeled DTPA, MAG3, and EC. Tubular radiopharmaceuticals MAG3 and EC have higher extraction fraction and clearance than DTPA and are preferred in the evaluation of urinary drainage in children. When compared to MAG3, EC has a higher extraction fraction and clearance and is commonly used in several countries, including India, in the setting of upper urinary tract obstruction in both children and adults. This study establishes reference values for NORA20 and OE20 in EC diuretic renogram (F + 0 protocol) in children.
Interestingly, the OE20 values obtained in this study for the F + 0 protocol were closely comparable to those obtained by Chaiwatanarat et al. for 11 adults (22 renal units) using the F + 18 protocol.[8] It is worth noting that OE20 values obtained in our study were slightly higher, and NORA20 values were slightly lower than those reported in the aforementioned study, which can be attributed to the forced diuresis caused by the administration of furosemide. However, the comparability of values suggests that the NORA20 and OE20 values obtained for children using the F + 0 protocol may be applicable to adults and the F + 20 protocol as well.
In a very similar study done in children having normal, hydronephrotic, and obstructed renal units by Nogarède et al. on MAG3 diuretic renogram (F + 0 protocol), the NORA20 values obtained fell in a similar but relatively narrower range between 0.04 and 1.60 than in our study. The range of NORA20 values in our study is 0.07699 and 2.0153.[9] The corresponding OE20 values in their study were 76 and 99.9 for OE20. Similarly, in the present study, the OE20 values in normal kidneys ranged between 36.2756 and 99.1663, compared to the OE20 values for MAG3, which ranged between 76 and 99.9.
A statistically significant difference (P < 0.0001) was found in the NORA20 and OE20 values obtained for the normal and obstructed groups. The obstructed groups exhibited a wide range of NORA20 and OE20 values, which may be dependent on factors such as the duration of obstruction, kidney size, transpelvic diameter of the kidney, or the age of the child. To establish a clearer understanding of the relationship, if any, between NORA, OE, and the degree and duration of obstruction, further studies involving a larger sample size will be required. In addition, as this study did not include follow-up observations of obstructed cases, studies may be designed in future to analyze the changes in NORA20 and OE20 values aft er intervention to gain insights into their usefulness.
Strengths and limitations
It is the first study to the best of our knowledge that establishes normal values of NORA20 and OE20 for 99mTc EC in the pediatric age group. The study included a sufficient sample size from both the normal and the obstructed renal units. The algorithm developed for this study was validated by comparing the obtained values with those from the study that used a validated IAEA soft ware.
Another strength of the study lies in the ease of use of the soft ware built using MATLAB that was internally developed in our department. The soft ware developed by us offers a highly user-friendly interface, making it accessible to users of all skill levels. Its straightforward navigation and clear instructions reduce the learning curve, allowing users to efficiently accomplish their tasks. The overall process of calculating NORA20 and OE20 values using the MATLAB soft ware is also very time-saving.
One of the limitations in our study is that the normal and obstructed units were determined based on the available information, as has been done in similar studies.
A few other limitations in our study were that the normal renal units selected were the contrarenal units of the evaluated patients who had normal blood and radiological parameters, but it was not confirmed or proved that the units were indeed normal. In addition, some of the mildly hydronephrotic but nonobstructed kidneys were considered as normal for the purpose of this study. Furthermore, since no gold standard definition of true obstructed units is established and no follow-up of patients with reported obstructed renal units was done in the study, it could not be established whether the renal units labeled as obstructed were indeed obstructed. Sixty-four participants were excluded from analysis in the study since the total dynamic scan duration was <20 min.
CONCLUSION
The normal values of NORA20 and OE20 are established and are 0.3577 (0.1592) and 92.2084 (3.6717), respectively. These values showed a statistically significant difference between normal and obstructed units. Further studies can help ascertain its diagnostic accuracy in the diagnosis of PUJO and the prognosis in children with pediatric hydronephrosis.
Ethical approval:
The research/study approved by the Institutional Ethics Committee at JIPMER, number 24100, dated April 2021.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The author(s) confirms that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using the AI
Financial support and sponsorship: Nil.
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