Introduction
The glomerular filtration rate (GFR) is the standard metric of renal function in clinical routine and decisive for a variety of clinical issues. For example, staging of chronic kidney diseases [
1] and drug dose adjustment in kidney disease patients [
2] are based on GFR measurements. Prior to organ transplantation, GFR estimates are performed in living kidney donors to analyse the renal function [
3]. In nuclear medicine, the GFR is used to ensure an adequate kidney function in radionuclide therapy patients [
4,
5].
As the GFR cannot directly be measured, several indirect methods are established in routine clinical practice [
6]. These include urinary or plasma clearance measurements of endogenous and exogeneous filtration markers or estimations based on serum measurements of endogenous filtration markers [
7]. Mostly, the GFR is derived from serum creatinine or serum cystatine C [
6]. Various established equations can be used for a serum creatinine-derived estimation with the Chronic Kidney Disease—Epidemiology Collaboration (CKD-EPI) equation yielding most accurate results, particularly in individuals with higher GFR rates [
8,
9]. The clinical gold standard of GFR measurement by urinary inulin clearance is, in contrast, not routinely performed due to the laborious procedure requiring continuous inulin injection and urine collection and the limited availability of the substance [
2].
Renography in planar scintigraphy technique using radioactively-labelled markers like [
51Cr]Cr-ethylenediamine-tetraacetic acid ([
51Cr]Cr-EDTA), [
99mTc]Tc-diethylenetriamine-pentaacetic acid ([
99mTc]Tc-DTPA), or [
99mTc]Tc-mercaptoacetyltriglycine ([
99mTc]Tc-MAG3) is clinically well established to evaluate renal perfusion, functional uptake, cortical transit, and urinary excretion [
10]. Moreover, for the renal scintigraphy tracers [
51Cr]Cr-EDTA and [
99mTc]Tc-DTPA, which are in good agreement with the criteria of an ideal exogenous filtration marker to be freely filtered, not protein bound, not tubularly reabsorbed or secreted, and not renally metabolized [
6], simultaneous renography and estimation of the GFR is possible [
11]. However, repeated blood sampling over a period of several hours is required for an accurate GFR estimation [
11,
12].
Alternatively, dynamic renal PET imaging can be performed using glomerularly filtered PET tracers like [
68Ga]Ga-1,4,7-triaza-cyclononane-1,4,7-triacetic acid ([
68Ga]Ga-NOTA), [
68Ga]Ga-1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid ([
68Ga]Ga-DOTA), or [
68Ga]Ga-EDTA. On the one hand, advantages of imaging in PET technique are a higher spatial and temporal resolution, higher sensitivity, absolute quantification, and 3-dimensional (3D) imaging [
13] resulting in an improved visualization of the renal parenchyma. On the other hand, dynamic renal PET bears the potential to estimate the GFR from PET images without venous blood sampling depending on the applied PET tracer [
14‐
16]. For example, [
68Ga]Ga-DOTA may be well suited as tracer for a PET-derived GFR estimation, as DOTA, which is used as Gd-DOTA in MR contrast agents, exhibits similar pharmacokinetics to DTPA [
17,
18] and is almost exclusively cleared from the blood by glomerular filtration [
19,
20]. A sophisticated method for PET-derived GFR estimation is compartmental kinetic modelling. Promising results for this technique were recently described for [
68Ga]Ga-NOTA, a similar tracer to [
68Ga]Ga-DOTA, in rats [
14], but, to the best of our knowledge, it has not yet been evaluated in humans.
In our institution, PSMA- and DOTATOC-/DOTATATE-radionuclide therapy patients routinely undergo renography to monitor renal function, mostly in [99mTc]Tc-MAG3 or [99mTc]Tc-DTPA scintigraphy technique. We recently started to, alternatively, perform dynamic [68Ga]Ga-DOTA PET/CT imaging. We here report the, to our knowledge, first evaluation of human renal [68Ga]Ga-DOTA PET/CT imaging in comparison to renal scintigraphy. Additionally, we performed a PET-derived GFR estimation by single-compartmental tracer kinetic modelling to translate the method that was previously described in rats to human data. The results are compared to serum creatinine-derived measurements.
Discussion
Several PET tracers have been proposed for renal imaging in humans including the GFR tracers [
68Ga]Ga-EDTA, [
68Ga]Ga-NOTA, and [
68Ga]Ga-DOTA [
13‐
16] and renal perfusion tracers like
82Rb and [
15O]H
2O [
27,
28]. Possible advantages of renal PET imaging over conventional scintigraphy imaging are an improved image quality, resolution, and contrast [
27]. This can allow a more precise delineation of renal parenchyma, blood vessels, and background [
29]. Particularly, the evaluation of patients with complex anatomy might benefit from 3D PET imaging [
13]. Moreover, in times of supply shortages of
99Mo/
99mTc-generators [
30], renal PET
68Ga-based tracers may be an appropriate alternative to renal scintigraphy and may allow optimized utilization of cost-intensive
68Ge/
68Ga-generators.
In this study, visual interpretation of dynamic [
68Ga]Ga-DOTA PET images and renal cortical TACs in radionuclide therapy patients revealed the same results as conventional scintigraphy indicating that [
68Ga]Ga-DOTA PET is a suitable alternative. Image quality of renal PET was higher than of renal scintigraphy images. Additionally, the examination of renal parenchyma in high resolution PET images allowed for assessment of kidney morphology. In one patient, a kidney cyst was detected (Fig.
2). To evaluate a possible benefit in clinical routine, a systematic comparison with [
99mTc]Tc-DMSA SPECT imaging as a gold standard for examination of renal parenchyma would be desirable in future studies.
Glomerularly filtered PET tracers allow an estimation of the GFR by different methods. Hofman et al. [
15] reported that a GFR estimation by repeated [
68Ga]Ga-EDTA plasma sampling (comparable to [
51Cr]Cr-EDTA plasma sampling) is feasible. Moreover, a good correlation between the PET-derived rate of excretion into bladder, ureters, and kidneys (measured in 10-min dynamic PET scans) and the plasma sampling-derived GFR was observed [
15]. However, using this approach, the GFR cannot directly be calculated, but is indirectly derived from a correlation with the plasma sampling-derived values which can themselves be erroneous.
An alternative is to directly calculate the GFR without laborious and invasive repeated blood sampling from dynamic PET data by compartmental tracer kinetic modelling of glomerularly filtered PET tracers. Lee et al. [
14] described the feasibility of a GFR calculation by single-compartmental tracer kinetic analysis from [
18F]fluoride and [
68Ga]-NOTA PET data in rats. In this study, we report the, to our knowledge, first investigation of a human GFR estimation by compartmental tracer kinetic modelling of dynamic PET data.
The determined fit functions based on a simple 1-tissue compartment model introduced for preclinical PET imaging were of limited quality and showed differences to the actual measurements. This was also reported in the preclinical study for [
68Ga]Ga-NOTA [
14]. A possible reason is spill-over from urinary radioactivity levels. An implementation of a dual spill-over correction to our model for urine activity did not yield satisfying results. An explanation might be a complex variability of urine spill-over that cannot be represented in a linear kinetic model. As an analysis of the urine time-activity-curves showed a major contribution of urine activity in the minutes 2 to 10 after tracer injection (delayed to the maximum of renal time-activity curves), we excluded this interval from kinetic modelling and yielded substantial improvements in fit quality of modelled time-activity curves (Fig.
5 and Table
3).
Regarding all patients, PET-based GFR
PET estimations showed a high correlation to the serum creatinine-derived GFR
CKD values that are commonly used in clinical routine practice (Fig.
6). Interestingly, for complete 30-min data sets, correlation was not improved for the modified model excluding spill-over biased data. However, if only the first 15 min of dynamic PET data were included, the correlation was higher for the modified model. A possible explanation is that GFR
CKD, which was used as reference standard in this study, itself is prone to errors and, therefore, cannot be regarded as universal gold standard [
7]. However, defining an improved reference standard is difficult, as all available methods are restricted by specific limitations. A direct absolute GFR measurement is ethically not justified. The clinically-established GFR measurement by urine creatinine clearance is limited due to frequent urine collection errors [
2]. Nuclear medicine examination techniques like [
99mTc]Tc-DTPA scintigraphy would require multiple tracer injections in short temporal distance for a direct comparison. Most likely, a comparison against the clinical gold standard of a GFR derivation by inulin clearance could be used to validate the accuracy of GFR
PET in future studies, but the procedure is laborious, invasive, and not established in clinical routine practice.
If patients with urinary obstruction were excluded, the correlations of GFR
PET to GFR
CKD were increased; for the evaluation of complete 30-min data set, in this group, an excellent correlation was found (Fig.
7). In patients with urinary obstruction, the shape of the time-activity curves with plateau formation might lead to an impeded description by the applied mathematical model, as a urinary efflux might insufficiently be described by a linear model with a kinetic constant k
2. Consequently, the assumption of a linear differential equation for the temporal change of activity in the renal cortex might lead to deviations due to the time-dependent urinary reflux. More complex kinetic models might be necessary for a more accurate GFR calculation in patients with urinary obstruction; these may involve additional compartments, higher-order transfer between compartments, or an explicit spill-over correction of urinary radioactivity levels. Future studies including more patients with urinary obstruction are required for a detailed investigation and establishment of an optimized kinetic model.
A good agreement was demonstrated between GFRPET-30 (derived from complete 30-min PET data sets) and GFRPET-15 (derived from reduced 15-min PET data sets) for both the standard model and the modified model to exclude urine spill-over. Therefore, an evaluation of urinary efflux and a PET-based GFR examination within 15 min examination time appears feasible by dynamic [ 68Ga]Ga-DOTA PET. Short examination times increase patient comfort and can decrease contact time and thus the risk of infection in the ongoing COVID-19 pandemic.
Possible scenarios for an application of PET-derived GFR measurements could include monitoring in pharmacological trials, as repeated measurements might allow for quasi-real time assessment of kidney function in patients/probands with unimpaired kidney function. Prior to a broader implementation of the technique, larger studies should be performed to validate the results of our first experiences. These could also include a repeatability analysis to assess the reliability of the technique.
The study faces several limitations. First, the number of patients was low and included patients presented concomitant malignant comorbidities but no chronic kidney diseases. Particularly, an investigation of patients with low GFR values would be of additional interest to validate the method for patients with decreased renal function. Next, PET data were compared to mixed [99mTc]Tc-DTPA and [99mTc]Tc-MAG3 renal scintigraphy results which were acquired in variable temporal distance to the PET scans. However, an influence on the assessment of urinary extraction is unlikely and GFRPET results were compared to GFRCKD results derived from creatinine serum levels which were taken on the day of the PET scan. Finally, we noticed that respiratory motion had some influence on the location of the kidneys in different time frames, thus potentially contributing to the limited quality of compartment model fits. Respiratory gating/motion correction may minimize this effect in future investigation.
Potential improvements for future approaches of PET-derived GFR measurements may include an evaluation of the other glomerularly filtered PET-tracers [
68Ga]Ga-EDTA and [
68Ga]Ga-NOTA. These exhibit a lower protein binding fraction (0.1 ± 0.0% for [
68Ga]Ga-NOTA and 1.2 ± 0.6% for [
68Ga]Ga-EDTA versus 2.8 ± 0.6% for [
68Ga]Ga-DOTA after 10 min in human serum), which could lead to higher accuracy of kinetic modelling [
16]. Moreover, a high accuracy of a GFR derived by kinetic modelling of PET data for the tubularly-secreted PET tracer [
18F]fluoride was reported in rats [
14]. If an exclusive excretion by glomerular filtration is no prerequisite for PET-derived GFR measurements, an evaluation of the feasibility of GFR estimations from dynamic PET data using DOTATOC/DOTATATE and PSMA tracers might be of clinical interest, as tracer uptake and kidney function could be evaluated in a single PET examination prior to radionuclide therapy.
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