Timing of diuretics in diuresis renography

The aim of this systematic literature review was to obtain an overview of when to administer the diuretics in relation to the radiopharmaceutical during a diuresis renography. A systematic literature search was performed in three different databases (Embase, PubMed/Medline and Cochrane Library) together with an information specialist. The review question was: when should diuretics be administered in relation to the radiopharmaceutical in a diuresis renography? Studies of adults were included together with guidelines published in collaboration with an organization. Seventeen articles and four guidelines were retrieved in the literature search. The F − 15 method (diuretics administered 15 min before the radiopharmaceutical) was the one that was studied and described most and was compared with other time points for diuretic administration. The retrieved articles and guidelines report of advantages with different time points for diuretics. Both F − 15 and F + 0 are reported to clarify washout in equivocal cases compared to F + 20. No consensus could be found for a preferred time point of diuretics administration during a diuresis renography.


Introduction
A diuresis renography is an examination where a diuretic, commonly furosemide, is administered during radionuclide renography to distinguish between obstruction and prolonged renal drainage [1,2]. Furosemide increases the urine flow rate and has a rapid onset. Its renal action begins within the first few minutes after intravenous diuretic administration and the maximal urinary flow rate occurs after approximately 15 min [3]. However, in an obstructed kidney, the washout can remain slow even after diuretic administration with a prolonged retention of radiopharmaceutical proximal to the obstruction [4].
There is variability in the methodology of renographies between different Nuclear Medicine departments, mostly concerning the timing of the diuretic administration in relation to the radiopharmaceutical administration.
A study or a method where the diuretic is administered after the radiopharmaceutical is described as F+ and before the radiopharmaceuticals as F−. The F + 20 method, i.e. diuretics given 20 min after the radiopharmaceutical, has been considered to be the traditional method [2].
There have been reports of modified methods of the traditional diuresis renography where other time points for diuretic administration were described. One such method was the F − 15 where the diuretics were administered 15 min before the radiopharmaceutical and another method was F + 0 with the diuretics administered at the same time as the radiopharmaceutical, summarized by O'Reilly [2]. Other time points of diuretics are used as well in diuresis renographies.

Aim
The aim of this literature review was to obtain an overview of when to administer the diuretics in relation to the radiopharmaceutical during a diuresis renography. Is there a preferred time point of diuretics administration during a diuresis renography?

Materials and methods
This systematic literature review was registered in the Prospero database (CRD42020167484) and followed the method "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) [5]. The PICO method, where four different areas are described (Population, Intervention, Comparison, Outcome) [6] was used to address the review question. The PICO aimed to give an overview of when to administer diuretics in relation to the radiopharmaceutical in diuresis renography, Table 1.

Literature search
The primary literature search was performed in May 2019 in three different databases for published articles and guidelines (Embase, PubMed/Medline and Cochrane Library) together with an information specialist. A secondary search was performed in February 2021 to include newer publications.
Synonyms of the words renography and diuretics were combined and used as search expressions to address the PICO question, Appendix 1. There was no limitation as to the publication year in the literature search process.
Duplicates were removed before two researchers (AKB and HG) individually read the retrieved titles and abstracts from the literature search. Abstracts that were selected by at least one reader were read independently in full text by both readers.
The collected articles and guidelines had to have been published in a paper listed in the Web of Science and written in English to be selected for full-text reading. Guidelines of relevant topics published in collaboration with an organization were also included. The content of the articles and guidelines had to concern diuresis renographies of adults where the timing of furosemide in relation to a radiopharmaceutical were studied or described. Non-original articles, articles on topics not relevant to the study, or articles that only included children were excluded, Appendix 2. Disagreements after full-text reading were resolved by consensus between the two readers. Basic information, such as author, country, year of publication, study type and number of participants were noted for each included article.
The radiopharmaceuticals that were used in the performed renographies and the different timepoints of the administered diuretics were noted as well.

Data extraction
Data extraction was performed and double-checked by two researchers (AKB and CS). Due to the lack of homogenous numerical results, a meta-analysis could not be performed, and the results are reported in a narrative format.

Quality assessment
A quality assessment form influenced by QUADAS-2 and the Newcastle-Ottawa scale was created and used when assessing the included articles [7,8]. The quality assessment form contained nine questions in four different domains as well as a domain question which summarized each domain, Table 2.
Each article was graded individually by two researchers (AKB and HG) using a three-grade scale when assessing the different domain questions (low risk or high risk for bias, and unclear). Guidelines were not included in the quality assessment process. No exclusions were made during this process.

Results
There were 17 articles and four guidelines relevant to the review question, Fig. 1.
Sultan et al. compared the F − 15 method with the F + 15 method and concluded that the F − 15 method resulted in fewer equivocal results than the F + 15 method did [13]. Turkölmez et al. compared three different methods (F − 15, F + 0 and F + 20) with each other in the same patient group. The reported results were that the F + 0 and the F − 15 methods allowed classification of equivocal F + 20 results. Furthermore, that the F + 0 method is a more practical and shorter technique than F − 15 and therefore a better alternative, especially if there is only one opportunity to confirm or exclude obstruction [18]. Adeyoju et al. included three different methods as well and compared the F + 0 method with the F − 15 method or the F + 20 method in their study. They reported that the F − 15 method had the best record in terms of reducing equivocal results compared to both F + 20 and F + 0. Moreover, that the F + 0 method gave similar results to F + 20 but could reduce the time required compared to F + 20 [11]. Liu et al. compared the F + 0 method  Table 3 Articles and guidelines in PICO The table also visualizes the quality assessment in four different domains graded in three different colors: = low risk/low concern, = high risk/high concern, = unclear 1 3 with F − 15 method and reported that a greater part of the patients could complete the diuresis renography with the F + 0 method since more examinations were reported to be disrupted with the F − 15 method due to voiding issues [17]. Three articles reported results concerning administering the diuretics 10 min after the radiopharmaceutical i.e., the F + 10 method [19,20,24]. Tartaglione et al. reported that the F + 10 method (in seated position) could reduce the equivocal findings of the F − 15 method (in supine position) and lead to fewer bladder filling related problems. However, a lower dose of diuretics was administered in the F + 10 method compared to the F − 15 method in this study [19]. Kandeel et al. compared F + 0 with F + 10 and reported a discrepancy in split renal function between F + 0 and F + 10 and in favor of F + 10 [20]. Bäck et al. compared a modified F + 10 method (with a cut-off value for diuretic decision) with the F + 20 method and reported the F + 10 method to be a feasible and acceptable method in clinical practice [24].
Five studies did not compare different methods with each other; instead, they addressed a certain question and described which of the different methods they had used in their studies [12,[21][22][23]25]. Arap et al. described the F + 15 method and reported that diuretic administration allowed differentiation between obstructive and hypotonic processes [21]. Koff et al. presented a methodology and results of diuresis renography where the diuretics were administered 10-20 min after the radiopharmaceutical [22]. O'Reilly et al. described the F + 30 method and reported the method to be a method of investigating equivocal urinary upper tract obstruction with diuretic provocation [23]. Altarac S. introduced and evaluated an obstruction score system based on the F − 15 method [12]. Sachpekidis et al. evaluated the intra-and inter-observer agreement when assessing the renal function in diuresis renography when using the F + 10 method and, reported that the reader's experience is important when calculating renal parameters and that reader training could be of value [25].
Four guidelines published between 1996 and 2018 were found in the literature search process [26][27][28][29], Table 3. The different methods concerning time points for diuretic administration that are described in all four guidelines are F − 15, F + 0, and F + 20 [26][27][28][29]. The F + 10 method is described in two guidelines [26,28]. The F + 30 method and the Fmax (diuretic administration when the activity in the collecting system appears to have reached a maximum) are described in one guideline [26] and the F + 15 method is described in one guideline [28].
The British Nuclear Medicine Society state in their guideline that when an obstruction is known beforehand, the F − 15 or the F + 0 methods could be used and that the F + 0 method often is used in pediatrics [27]. The International Consensus Committee reported in their guideline that the F − 15 method is recommended when the F + 20 is equivocal, or as a one-stop maximal-diuresis renogram instead of the traditional F + 20 method [29]. Another guideline by European Association of Nuclear Medicine in collaboration with Society of Nuclear Medicine and Molecular Imaging states that the F − 15 method could allow better discrimination between obstructed and nonobstructed kidneys. Furthermore, that the F + 10 method (in seated position) has been reported to give comparable or superior results to the F − 15 method and, that the F + 0 method could minimize imaging time and, therefore, be the most convenient method [26].
As a summary, all the described different renography methods can be used when the function and drainage capability are to be assessed. The F + 20 method can be used when the kidneys have not emptied satisfactorily during the first 20 min of acquisition [22,26,27]. The F − 15 method has been reported to agree with F + 20 in unobstructed cases and show less equivocal results and clarification in cases of equivocal results with F + 20 [9-11, 14-16, 26, 29]. The F + 0 method can be used when only one opportunity exists to confirm or exclude obstruction [18]. Furthermore, it can minimize the examination time and make less examinations interrupted because of voiding issues than the F − 15 method [17,26]. The F + 10 method in seated position could reduce the equivocal findings of the F − 15 method. This method has a shorter examination time than the F − 15 and gives information about baseline state [19].
None of the guidelines recommended one single method concerning an optimal time point as to when the diuretics should be administered in relation to the radiopharmaceutical.

Quality assessment
The quality assessment revealed that some studies could introduce bias in more than one domain. However, no exclusion was made during this process. The quality assessment revealed a low risk of bias when assessing the conduct of the index test or its interpretation (domain 2) as well as when the comparison between groups was assessed (domain 3). The highest risk of bias was found in the domain where the flow and timing were assessed (domain 4). The domain where the patient selection was assessed (domain 1) had the most unclear issues, Table 3.

Discussion
A systematic literature review has been performed in three different databases to achieve a broad search. The authors chose to not set a limit in the publication year of the articles in the literature search, which resulted in articles published as early as 1978 and as late as 2020. However, not many published studies could be found in the literature search process. Some studies were included in this study despite the fact that they did not compare different diuresis renography methods with each other. Instead, they studied a certain issue and described a method with a specific time point for diuretic administration in relation to the radiopharmaceutical, these studies are reported separately in the result section.
No exclusions were made during the quality assessment process as we wanted to report results from all included articles found in our literature search. Domain 1 had more unclear issues than the other domains as several of the included studies did not clearly describe how the selection of the study subjects had been performed. Furthermore, a higher score was achieved in domain 3 if the comparison between groups involved the same patients. A higher score was also given when the comparison between groups was performed close to each other (within 2 weeks).
A limitation of this study is that no meta-analysis could be performed. Furthermore, there were few published studies comparing different time points for diuretic administration in a diuresis renography which could be a future area of research. In addition, articles containing only children as study subjects were excluded in the literature search process but articles involving both adults and children were included.

Conclusion
Both F − 15 and F + 0 are reported to clarify washout in equivocal cases compared to F + 20 but no consensus could be found for a preferred time point of diuretics administration during a diuresis renography.