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Ga‑FAPI Uptake Correlates With The State Of Chronic Kidney Disease

Jul 08, 2024

Abstract

Purpose Kidney fibrosis leads to a progressive reduction in kidney function ultimately resulting in kidney failure. Diagnostic tools to detect kidney fibrosis are all invasive requiring kidney biopsies with subsequent histological validation. In this retrospective study, the diagnostic value of three different radiotracers for the noninvasive prediction of kidney fibrosis was analyzed, taking into account the glomerular filtration rate (GFR) and the intra-renal parenchymal radiotracer uptake.

Methods In 81 patients receiving either one of the following molecular imaging probes,[68 Ga]Ga-FAPI, [68 Ga]Ga-PSMA, or[68 Ga]Ga-DOTATOC, kidney function parameters were correlated with SUVmax and SUVmean of the renal parenchyma and background activity measured in lung parenchyma, myocardium, gluteal muscle, and the abdominal aorta. Patients were clustered according to their chronic kidney disease (CKD) grade, and a regression analysis and one-way ANOVA were conducted in this retrospective analysis.

HERBS FORMULA FOR KIDNEY HEALTH PROBLEM

HERBS FORMULA FOR KIDNEY HEALTH PROBLEM


Results We found a negative correlation between GFR and[68 Ga]Ga-FAPI uptake for both SUVmax and SUVmean values, whereas background activity showed no correlation with GFR. [68 Ga]Ga-DOTATOC and [68 Ga]Ga-PSMA did not correlate between the CKD stage and intra-renal parenchymal radiotracer uptake. Only [68 Ga]Ga-PSMA background activity exhibited a positive correlation with GFR suggesting an unspecifc binding/retention potentially due to longer circulation times.
Conclusion There is a signifcant negative correlation between renal parenchymal [68 Ga]Ga-FAPI uptake and GFR, which was not the case for [68 Ga]Ga-DOTATOC and [68 Ga]Ga-PSMA. This correlation suggests a specific binding of FAPI rather than potential unspecific retention in the renal parenchyma, underlining the potential value of [68 Ga]Ga-FAPI for the noninvasive quantitative evaluation of kidney fibrosis.
Keywords: Fibroblast-activation-protein · Kidney fbrosis · FAPI PET/CT · DOTATOC PET/CT · PSMA PET/CT


Introduction 

Kidney fibrosis is a chronic disease with the risk of a fast deterioration towards kidney failure and need for dialysis and a higher cardiovascular risk. Chronic kidney disease (CKD) is defined as kidney damage or impaired glomerular filtration rate ((GFR) < 60 mL/min/1.73 m2 ) for at least 3 months, irrespective of cause [1]. Therefore, the GFR, albuminuria, and diagnostic tools like ultrasound and computed tomography to evaluate the kidney structure are important components in diagnosing CKD [2]. An early diagnosis is vital to achieve a better prognosis and an early therapeutic intervention/treatment of the causing disease (e.g., hypertension, diabetes mellitus, chronic glomerulonephritis). The current reference diagnostic tools for detecting renal fibrosis are invasive and require the execution of a biopsy followed by histological confirmation. The latter has its associated risks, is highly demanding for the patient, and is time-consuming. Therefore, the need grows for a less invasive and faster diagnostic modality.

Previous attempts to noninvasively detect kidney fibrosis have been done with functional MRI which has not been amplified in clinical use yet. Possible MRI target structures or processes in fibrotic kidneys are elastin imaging [3], the collagen-binding adhesion protein CNA35 [4], deoxyhemoglobin levels, diffusion-weighted imaging to quantify the deposition of extracellular collagen, and microvascular perfusion [5]. The feasibility of PET imaging in kidney fibrosis detection has been evaluated. The predominantly applied PET tracer [ 18F]FDG can identify kidney cyst infections and showed also a potential to diagnose acute rejection after kidney transplantation [6]. The potential of different imaging approaches for kidney diseases has recently been reviewed [7]. A recent study by Zhou et al. has compared the degree of renal fibrosis determined by kidney biopsy with the tracer uptake of [ 68 Ga]Ga-FAPI in thirteen patients. An increased tracer accumulation is correlated to a higher degree of kidney fibrosis as defined by immunohistopathology [8]. We set up a slightly different "real-world" study evaluating the potential value of FAPI and other molecular imaging probes for the detection and determination of different degrees of CKD. Next to [ 68 Ga]Ga-FAPI-04 (fibroblast activation protein inhibitor), also [ 68 Ga]Ga-PSMA (prostate-specific membrane antigen) and [ 68 Ga]Ga-DOTATOC (DOTA-Phe1-Tyr3-Octreotid) were investigated.

It is known that in the early stages of renal fibrosis, an accumulation of fibroblasts occurs in the renal parenchyma [9]. Several studies have shown that the radiotracer [ 68 Ga] Ga-FAPI binds to fibroblast-activation-protein (FAP) in fibroblasts of tumor tissue [10]. This binding of FAP also occurs in non-tumor tissue such as in hepatic fibrotic samples [11]. The binding principle has been applied in this study to analyze whether the expression of FAP binding of [ 68 Ga]Ga-FAPI in renal-parenchymal tissue correlates with the CKD stage of the patients. The abovementioned study (Zhou et al., 2021) has already been able to show that the concept of FAP expression works also for CKD; however, there was no comparison to a healthy cohort included.

The second radiotracer analyzed in this study is [ 68 Ga] Ga-DOTATOC. The compound is an octreotide DOTA-conjugated peptide that can bind to somatostatin receptors (SSTRs) with a strong tendency towards the SST-2 receptor [12]. It has been shown that diseased kidneys have an increased somatostatin receptor expression [13]. On this basis, we investigated whether a correlation exists between the binding of [ 68 Ga]Ga-DOTATOC in renal parenchyma and the stage of kidney disease, thus whether this radiotracer has a potential diagnostic strength for the detection of kidney fibrosis.

Prostate-specific membrane antigen (PSMA) normally binds to prostate tissue, showing an increased expression in tumor tissues [14]. Thus, it has been widely accepted as a target for imaging and radionuclide therapy for prostate cancer [15]. Additionally, PSMA physiologically binds to cells of the proximal tubules of the kidneys, as well as salivary glands and brain tissue [16]. Therefore, its physiological accumulation in the kidneys could potentially serve as a diagnostic correlate for kidney disease.


HERBS FORMULA FOR KIDNEY HEALTH PROBLEM

Study and methods

Study design

We retrospectively analyzed the PET data of a total of 81 patients who presented to the nuclear medicine department of the RWTH Aachen University Hospital or the nuclear medicine department of the Heidelberg University Hospital between August 2017 and October 2020. Sixteen patients received [68 Ga]Ga-FAPI-04 and four patients [68 Ga]GaFAPI-46, of which 15 were male and 5 were female, with a mean age of 69.2 years (some of these patients have already been part of other investigations with a different scope [10,24]). A total of 34 patients received the [68 Ga]Ga-PSMA radiotracer, all male patients with a mean age of 73 years.

[68 Ga]Ga-DOTATOC was employed in 27 patients, 16 males and 11 females with a mean age of 64 years. Further information on the total number of patients and patient characteristics are displayed in Table 1, and for each ratetracer, the number of patients with the respective stage is listed.


Table 1 Total number of patients of each CKD category in the different radiotracer groups

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All patients gave their informed consent for their clinical data to be used for retrospective analysis and the study got approval from both ethics committees at the RWTH Aachen University Hospital and Heidelberg University Hospital. The necessary clinical data, such as laboratory values, patient history, and PET/CT imaging, were retrieved from the RWTH Aachen University Hospital and Heidelberg University Hospital databases. The laboratory values were determined by the Laboratory Diagnostic Center (LDZ) of the RWTH Aachen University Hospital and the Central Laboratory of the Heidelberg University Hospital. Inclusion
criteria included the use of the radiotracer in a recent PET/CT scan (from August 2017 up to and including October 2020) in the department of nuclear medicine of the RWTH Aachen University Hospital and Heidelberg University Hospital. Exclusion criteria were the inability to provide recent imaging or laboratory values (GFR and creatinine values older than 3 months) for the determination of the CKD stage. Furthermore, patients were excluded, if they underwent a nephrectomy before the image analysis or showed signs of obstruction of the ureteral system.

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PET/CT imaging and radiotracer synthesis 

Synthesis and labeling of [ 68 Ga]Ga-FAPI-04 and [ 68 Ga]GaFAPI-46 have already been described previously [17, 18]. The PET/CT imaging in Heidelberg for [ 68 Ga]Ga-FAPI was performed analogously to the PET/CT protocol previously described by Kratochwil et al. [10] using a Biograph mCT Flow scanner (Siemens). Following the regulations of the German Pharmaceuticals Act §13(2b), the indication for the exam and labeling of the FAPI tracers was done under the direct responsibility of the applying physician.

The injected activity for the [ 68 Ga]Ga-FAPI examinations was calculated using a range of 113–340 MBq injected activity. The PET scans were started 1 h after injection, and the patients were examined in a craniocaudal direction. Patients received 2 MBq/kg body weight either [ 68 Ga] Ga-DOTATOC or [ 68 Ga]Ga-PSMA (University Hospital RWTH Aachen) and were examined 60 min after injection. PET/CT acquisition was performed on a Philips Gemini TF 16 PET/CT (Philips Medical Systems, Best, The Netherlands). Patients were examined in craniocaudal orientation for [ 68 Ga]Ga-DOTATOC and caudocranial orientation for [ 68 Ga]Ga-PSMA with their arms raised to decrease beam-hardening artifacts. First, a low-dose whole-body CT from the base of the skull to the upper thigh was performed without a contrast medium for attenuation correction purposes. CT parameters for the low-dose unenhanced CT were used analog to the protocol by Behrendt et al. [19]. 

The 68 Ga-PSMA-HBED-CC tracer for the PET/CT scans was produced by the in-house radiopharmacy using a previously reported method [20]. As [ 68 Ga]Ga-DOTATOC, it was synthesized using the cassette-based synthesis module GRP-3 V from Scintomics [21].


3HERBS FORMULA FOR KIDNEY HEALTH PROBLEM

Clinical PET/CT imaging and data analysis

The evaluation of all the images for each radiotracer was carried out individually by a single observer with numerous years of experience in the field of nuclear medicine. This was done to ensure no inter-observer variation which could decrease the accuracy in the evaluation of the images. Moreover, the image analysis was carried out before the determination of the patient's CKD stage and GFR by the observer. This was done to ensure the absence of any bias in the evaluation of the images.

The focus of this study was to analyze the PET images, to visualize the uptake of the radiotracers in the pre-determined locations. For better anatomical visualization, the PET images were fused with a low-bodydose CT. Renal uptake of all three radiotracers was quantifed using SUVmax (standardized uptake value maximum) and SUVmean (standardized uptake value mean) at separate locations of the renal parenchyma (superior, middle, and inferior renal cortex) as illustrated in Fig. 1. Background activity was measured in lung parenchyma, myocardium, and gluteal muscle and includes blood pool activity which was measured in the abdominal aorta at the level of the renal arteries.





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