[18F]FDG PET/CT Imaging Disproves Renal Allograft Acute Rejection in Kidney Transplant Recipients with Acute Kidney Dysfunction: A Validation Cohort

[18F]FDG PET/CT Imaging Disproves Renal Allograft Acute Rejection in Kidney Transplant Recipients with Acute Kidney Dysfunction: A Validation Cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report [18F]FDG PET/CT Imaging Disproves Renal Allograft Acute Rejection in Kidney Transplant Recipients with Acute Kidney Dysfunction: A Validation Cohort Pierre Lovinfosse, Laurent Weekers, Hans Pottel, Antoine Bouquegneau, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-434469/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jun, 2021 Read the published version in European Journal of Nuclear Medicine and Molecular Imaging → Version 1 posted 4 You are reading this latest preprint version Abstract Purpose. [ 18 F]FDG-PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. Methods. We prospectively performed 86 [ 18 F]FDG-PET/CT in 79 adult KTRs who underwent per cause transplant biopsy for suspected AR. Biopsy-proven polyoma-BK nephropathies (n=7) were excluded. PET/CT was performed 192 ± 18 minutes after administration of 254.4 ± 30.4 MBq of [ 18 F]FDG. The SUV mean was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey’s studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate “AR” from non-pathological (“normal” + “borderline”) conditions. Results. The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m². Biopsies were categorized in 4 groups: “normal” (n=54), “borderline” (n=9), “AR” (n=14) or “others” (n=2). The median [min; max] mSUV mean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12] and 1.84 [1.57; 2.12] in “normal”, “borderline”, “AR” and “others” groups, respectively. ANOVA demonstrated a significant difference of mSUV mean among groups ( F=13.25, p<0.0001 ). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively. Conclusion. [ 18 F]FDG - PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI. Nuclear Medicine & Medical Imaging [18F]FDG-PET/CT kidney transplant acute rejection diagnosis Banff Figures Figure 1 Figure 2 Introduction The prompt diagnosis of acute kidney allograft rejection (AR) is crucial in the management of kidney transplant recipients (KTRs) presenting with acute kidney injury (AKI). It currently relies on the histological analysis of a renal sample obtained by needle biopsy, following the gold-standard Banff classification 1 . In clinical routine, the vast majority of per cause transplant biopsies show a normal histology 2 . Therefore, various non-invasive diagnostic approaches are currently under investigation to reduce the systematic usage of allograft biopsies 3 – 5 . More specifically, rodent models of allogeneic kidney transplantation (KTx) have demonstrated that 2-deoxy-2-[ 18 F]fluoro-D-glucose Positron Emission Tomography coupled with Computed Tomography ([ 18 F]FDG PET/CT) early and specifically detect AR 6 . In humans, we have similarly underscored the putative usefulness of [ 18 F]FDG PET/CT in the diagnosis of AR in a pilot study of 32 KTRs with AKI 7 . Our “rule out” approach was based on the mean of the mean standardized uptake values (mSUV mean ) in 4 independent volumes of interest (VOI) of the renal cortex, with a diagnostic threshold set at 1.6 to target a negative predictive value of 100%. In the present validation cohort, we prospectively assess this 1.6 threshold of renal mSUV mean in the diagnosis of AR in KTRs with AKI who underwent a transplant needle biopsy for suspected AR. Patients And Methods Patient population and specimens. The study was approved by the institutional review board of the ULiège Academic Hospital (#B707201215598). After written informed consent, adult KTRs undergoing a transplant biopsy for suspected AR were prospectively enrolled between March 2015 and December 2019. Histopathology. Biopsies were assessed by two pathologists according to Banff criteria 1 . Histological lesions were scored as continuous variables (from 0 to 3) on the basis of leucocyte infiltration severity in each component: glomeruli (g); peritubular capillaries (ptc); arteries (v); tubules (t); interstitium (i). Biopsies diagnosed as “normal” were defined as having a Banff [i + t] score < 2 and no features of a disease process. Biopsies diagnosed as “borderline” were defined as having a Banff [i + t] score ≥ 2 (but 0. Biopsies diagnosed as “others” were defined as showing features of an AR-unrelated disease. All biopsies were stained for the polyoma-BK virus. [ 18 F]FDG PET/CT imaging. The present validation cohort followed exactly the same protocol as described in the proof-of-concept study 7 . The PET/CT procedure was performed using cross-calibrated Philips GEMINI TF Big Bore or TF 16 PET/CT systems (Philips Medical Systems, Cleveland, OH, USA) at 191 [min. 179; max. 254] minutes following intravenous injection of a mean dose of 254.4 ± 30.4 MBq of [ 18 F]FDG (to purge as much as possible the radioactive signal from the urinary compartment). No contrast agent or diuretics were infused. A low-dose helical CT (5-mm slice thickness, 120-kV tube voltage, and 40-mAs tube current–time product) centered to the renal transplant was performed, followed by a PET emission scanning with 2 bed positions each lasting 4 minutes. Images were reconstructed using iterative list mode time-of-flight algorithms, and corrections for attenuation, dead-time, random and scatter events were applied. The PET/CT procedure was performed within a 48-hour period of the ultrasound-guided renal transplant biopsy. All [ 18 F]FDG -PET/CT were acquired in fasting conditions before any modification of immunosuppressive regimens. Mean glycaemia at the time of tracer injection was 112 ± 29 mg/dl. Four VOI of 1 ml were manually drawn in the cortical region of both upper (n = 2) and lower (n = 2) poles of the renal transplant at distance from the pelvicalyceal zone, as described previously 9 . The SUV mean was measured in each VOI, with no threshold activity, and the mean of these 4 SUV mean was calculated (mSUV mean ). Statistics. Data were expressed as mean ± standard deviation (SD) or as median [minimum; maximum]. One-way analysis of variance (ANOVA) followed by the post-hoc Tukey’s studentized range test was performed to statistically compare mSUV mean values among groups taking into account the necessary correction for multiple testing. The receiver operating characteristic (ROC) curve was drawn to discriminate “AR” from non-pathological (“normal” + “borderline”) conditions. The correlation between mSUV mean and acute composite (g + i + t + v + ptc) Banff score was calculated. All analyses were done with SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results We performed 86 [ 18 F]FDG PET/CT in 79 KTR with AKI. Each suspicion of AR leading to kidney biopsy and [ 18 F]FDG PET/CT imaging was clinically and statistically independent. The characteristics of the cohort are summarized in Table 1 . The median age was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m². Biopsies were described as “normal” (n = 54), “borderline” (n = 9), “AR” (n = 14) or “others” (n = 2). Biopsy-proven polyoma-BK nephropathies (n = 7) were excluded. AR was antibody-mediated in 2 cases, whereas T-cell-mediated AR was found in 13 cases, respectively. The histological finding in the “other” causes of graft failure was focal segmental glomerulosclerosis with no evidence of AR (n = 2). The median [min; max] mSUV mean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65; 3.12] and 1.84 [1.57; 2.12] in “normal”, “borderline”, “AR” and “others” groups, respectively (Fig. 1 ). ANOVA demonstrated a significant difference of mSUV mean among groups ( F = 13.25, p < 0.0001 ) (Fig. 2 A). The mSUV mean of biopsy-proven AR was significantly higher than “normal” cases ( p < 0.05 ). There was no significant difference between “normal” vs. “borderline” or between “AR” vs. “borderline” groups. A positive correlation between mSUV mean and the acute Banff score was found, with adjusted r² of 0.41 ( p < 0.0001 ) (Fig. 2 B). The area under the ROC curve reached 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively (Fig. 2 C). Of methodological note, the Youden index reached 2.073, with a sensitivity of 57.1% and a specificity of 96.8%. Table 1 Clinical and biological characteristics of the cohort Cohort (n = 86 events) Recipent Age (years) 55 [43; 63] Gender (male/female; n) 47/39 BMI (kg/m 2 ) 27 [22; 30] Donor Donor type (n), DBD/DCD/LD 63/17/6 Age (years) 43 ± 13 Gender (male/female; n) 40/46 Transplantation Rank 1st / 2nd or 3rd (n) 79/7 CIT (min) 644 ± 287 HLA mismatches, A + B + DR/6 (n) 3 [2; 4] Early graft function, immediate/slow/DGF 51/26/9 Status at time of biopsy Maintenance immunosuppression (n) CNI, CsA/FK/none 8/75/3 Anti-metabolites (n) MMF/MPA/Aza/none 66/12/1/7 mTOR inhibitors: yes/no (n) 4/82 Steroids: yes/stop (n) 70/16 Duration KTx at Biopsy (days) 279 [28; 1923] Donor specific antibodies: yes/no (n) 14/72 Data are expressed as mean ± standard deviation ; median [interquartile range]. AZA, azathioprine; BMI, body mass index; CIT, cold ischemia time; CNI, calcineurin inhibitors; CsA, cyclosporin A; DBD, donor after brain death; DCD, donor after circulatory death; DGF, delayed graft function; FK, tacrolimus; KTx, kidney transplantation; HLA, Human Leucocyte Antigen; LD, living donor; MMF, mycophenolate mofetyl; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin. Discussion In the present prospective validation cohort of 86 [ 18 F]FDG PET/CT performed in 79 KTRs presenting with AKI, the previously proposed mSUV mean threshold of 1.6 significantly discriminated non-rejection, with a sensitivity of 100% 7 . The poor specificity of [ 18 F]FDG PET/CT in detecting AR is most probably due to the radiotracer which accumulates in other inflammatory conditions. Still, the renal allografts with biopsy-proven AR were characterized by a significantly higher uptake of [ 18 F]FDG compared to “normal/borderline” biopsies, with a Youden index of 2.073 corresponding to a specificity of 96.8%. From a clinical point of view, a high negative predictive value appears more appropriate in the management of KTR with AKI in order to certify that no diagnosis of AR is missed or delayed. The pathophysiological hypothesis of such a preferential accumulation of the radiotracer in case of AR relies on the increased metabolic activity of infiltrating inflammatory cells, as suggested by the significant correlation between renal mSUV mean and the severity of leucocyte infiltrates as quantified by the acute Banff score 6 . The clinical significance and treatment of borderline changes remain highly debated, which prompts the ongoing development and validation of various biofluid-based biomarkers of clinically relevant AR 1 , 5 . All cases with biopsy-proven polyoma-BK nephropathy were excluded from our analysis since the diagnostic procedure has been standardized via polymerase chain reaction (PCR)-based screening for BK virus replication in urine and/or blood specimens 8 . Stricto sensu , a needle biopsy of the renal allograft should only be performed after negative PCR results. The median mSUV mean of the allografts with biopsy-proven polyoma-BK nephropathy was 2.20 [1.96; 2.47]. The limitations of our proposed non-invasive diagnostic approach based on [ 18 F]FDG PET/CT in unstable KTR with AKI include (i) the somewhat restricted availability of PET/CT machine, (ii) the minor exposure to radiations originating from both PET and CT procedures, and (iii) the 3-hour delay between [ 18 F]FDG injection and image acquisition. Still, the repeatability and reproducibility of the quantification of kidney allograft [ 18 F]FDG uptake has been reported as consistent 10 . The use of multiple independent VOI distributed right beneath the renal capsula in both upper and lower renal cortices aimed at (i) limiting the noise of the urinary [ 18 F]FDG and (ii) averting sampling error, which also represents one of the main limitations of transplant biopsy 1 . Of technical note, no difference was statistically detected between the SUV mean of the 4 VOI in the present 86-scan cohort, as previously reported 10 . Assessing the global [ 18 F]FDG accumulation in the renal allograft by the means of image segmentation softwares (currently under development and validation) would further help to minimize the sampling error. On the basis of this validation cohort, we postulate that [ 18 F]FDG PET/CT as first-line examination may help save selected patients with AKI from undergoing renal transplant biopsy. Such an invasive procedure would have been avoided in 19 cases of our series, which were characterized by an mSUV mean strictly inferior to the 1.6 threshold and normal histology. Further large prospective multicentric studies are needed to test whether the mSUV mean threshold of [ 18 F]FDG PET/CT imaging, in combination with blood and urinary biomarkers 3 – 5 , helps to pragmatically dictate the need for transplant biopsy in KTR presenting with AKI and suspected AR. Other tracers for inflammation may also be envisioned in this frequent clinical scenario, such as [ 11 C]Methionine or [ 68 Ga]Pentixafor. Declarations Acknowledgments The authors cordially thank the surgeons (C. Coimbra Marques, A. De Roover, O. Detry, E. Hamoir, P. Honoré, L. Kohnen, N. Meurisse and J-P Squifflet), the physicians (P. Erpicum, O. Hanssen, L. Vanovermeire and P. Xhignesse) and the members of the local transplant coordination center (M-H. Delbouille, J. Monard, S. Princen and A. Waromes), as well as the staff of the Division of Nuclear Medicine of the University of Liège Hospital in Liège, Belgium. FJ is a Fellow of the Fonds National de la Recherche Scientifique, and received support from the University of Liège (Fonds Spéciaux à la Recherche) and from the Fondation Léon Fredericq. Conflict of interest: none. Funding. FJ is a Fellow of the Fonds National de la Recherche Scientifique, and received support from the University of Liège (Fonds Spéciaux à la Recherche) and from the Fondation Léon Fredericq. Conflicts of interest/Competing interests. The authors declare no conflict of interest Availability of data and material. The data will be made available on request. Code availability. N/A Authors' contributions. LP, LW, RH and FJ designed the study; RH and FJ secured the funding of the study; HP performed the statistical analyses; LW, AB, CB recruited the patients and filled the medical files; AB performed the kidney biopsies; CB and SG scored the biopsies; LP and RH scored the [ 18 F]FDG - PET/CT images; LP and FJ wrote the manuscript; all authors approved the final version of the manuscript Ethics approval. The study was approved by the institutional review board of the ULiège Academic Hospital (#B707201215598). Consent to participate. After written informed consent, adult KTRs undergoing a transplant biopsy for suspected AR were prospectively enrolled between March 2015 and December 2019. References Loupy A, Haas M, Roufosse C, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant 2020;20:2318-31. Paquot F, Weekers L, Bonvoisin C, Pottel H, Jouret F. "Acute kidney dysfunction with no rejection" is associated with poor renal outcomes at 2 years post kidney transplantation. BMC Nephrol 2019;20:249. Hanssen O, Erpicum P, Lovinfosse P, et al. Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients. Part I. In vivo imaging methods. Clin Kidney J 2017;10:97-105. Erpicum P, Hanssen O, Weekers L, et al. Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients, part II: omics analyses of urine and blood samples. Clin Kidney J 2017;10:106-15. Tinel C, Devresse A, Vermorel A, et al. Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection. Am J Transplant 2020;20:3462-76. Reuter S, Schnockel U, Schroter R, et al. Non-invasive imaging of acute renal allograft rejection in rats using small animal F-FDG-PET. PLoS One 2009;4:e5296. Lovinfosse P, Weekers L, Bonvoisin C, et al. Fluorodeoxyglucose F(18) Positron Emission Tomography Coupled With Computed Tomography in Suspected Acute Renal Allograft Rejection. Am J Transplant 2016;16:310-6. Costa C, Cavallo R. Polyomavirus-associated nephropathy. World journal of transplantation 2012;2:84-94. Jadoul A, Lovinfosse P, Weekers L, et al. The Uptake of 18F-FDG by Renal Allograft in Kidney Transplant Recipients Is Not Influenced by Renal Function. Clin Nucl Med 2016;41:683-7. Jadoul A, Lovinfosse P, Bouquegneau A, et al. Observer variability in the assessment of renal (18)F-FDG uptake in kidney transplant recipients. Sci Rep 2020;10:4617. Cite Share Download PDF Status: Published Journal Publication published 30 Jun, 2021 Read the published version in European Journal of Nuclear Medicine and Molecular Imaging → Version 1 posted Reviews received at journal 02 May, 2021 Reviewers invited by journal 23 Apr, 2021 Editor assigned by journal 18 Apr, 2021 First submitted to journal 16 Apr, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-434469","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":23220967,"identity":"3a26076a-4b46-4970-b44a-6adac1fccd3a","order_by":0,"name":"Pierre Lovinfosse","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Lovinfosse","suffix":""},{"id":23220968,"identity":"2fdf5b33-7f97-4ee7-936d-a82e6b33f582","order_by":1,"name":"Laurent Weekers","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Laurent","middleName":"","lastName":"Weekers","suffix":""},{"id":23220969,"identity":"90bef1cd-5759-43ac-b71c-cf872bd48b4a","order_by":2,"name":"Hans Pottel","email":"","orcid":"","institution":"KU Leuven - Campus Kulak: Katholieke Universiteit Leuven - Campus Kulak Kortrijk","correspondingAuthor":false,"prefix":"","firstName":"Hans","middleName":"","lastName":"Pottel","suffix":""},{"id":23220970,"identity":"80f5b5b8-2488-432d-abf1-bd3e16b8724d","order_by":3,"name":"Antoine Bouquegneau","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Antoine","middleName":"","lastName":"Bouquegneau","suffix":""},{"id":23220971,"identity":"b17bc261-c665-43d6-bb99-b6997a93b693","order_by":4,"name":"Catherine Bonvoisin","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"","lastName":"Bonvoisin","suffix":""},{"id":23220972,"identity":"d7e746df-0fe1-400b-a1d1-5c029575d063","order_by":5,"name":"Christophe Bovy","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Christophe","middleName":"","lastName":"Bovy","suffix":""},{"id":23220973,"identity":"c14de2e4-aa0c-4bdc-9b6e-6f46802e6008","order_by":6,"name":"Stephanie Grosch","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Grosch","suffix":""},{"id":23220974,"identity":"fed06a6f-0ed3-4269-b6dd-3655127303a1","order_by":7,"name":"Roland Hustinx","email":"","orcid":"","institution":"Liege University: Universite de Liege","correspondingAuthor":false,"prefix":"","firstName":"Roland","middleName":"","lastName":"Hustinx","suffix":""},{"id":23220975,"identity":"f1b681f0-a9c3-4b70-bd6d-3544c291a670","order_by":8,"name":"Francois Jouret","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYBAC9gYwJQHEB8AsOQZ2RrBYAi4tPAdQtRgYMzATpwUODBIbmCEs3FqkDz978KPCwp6B8fAx6YqKP+kbDjM3PvxSwZDHj0sLX5q5Yc8ZicQGhmNpkmfOGORuOMzYbCxzhqFYsgG7FnseBjNpxjYJoDPOmEk2toG1tElLtjEkbjiAXQsPD/s3kBZ7iJZ/BukGhxnbf0v+Y0jcj1MLD9gWYCiBtDQYJAC1tDF+bADagssvPDxlkiC/tDEcS7ZsOGZsOBPoF2mGYxLFErgdtk3iR0WdPb/E4YM3G2rk5PmOtz/8+KPGJo8fh/fhgA3ZUGYecOQSAsiGMv4gQsMoGAWjYBSMGAAAB3FU9DGfTK8AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2547-6593","institution":"Centre hospitalier universitaire de Liege","correspondingAuthor":true,"prefix":"","firstName":"Francois","middleName":"","lastName":"Jouret","suffix":""}],"badges":[],"createdAt":"2021-04-17 16:02:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-434469/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-434469/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00259-021-05467-0","type":"published","date":"2021-06-30T06:09:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":8524246,"identity":"a9e80d62-272b-4cdc-8b97-5105abebef29","added_by":"auto","created_at":"2021-04-27 21:57:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":606078,"visible":true,"origin":"","legend":"Representative [18F]FDG PET/CT imaging in kidney transplant recipients with biopsy-proven normal histology versus acute rejection\nPositron-emission tomography (PET, top panels), computed tomography (CT, middle panels) and combined PET/CT images taken after administration of [18F]FDG are shown for kidney transplant recipients with biopsies showing normal histology (left column; mSUVmean of 1.5; acute Banff score of 0) or T-cell-mediated acute rejection (right column; mSUVmean of 3.1; acute Banff score of 8). The arbitrary scale of standard uptake value (SUV, from 0 to 5) is illustrated. \n","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-434469/v1/35018b1e74c0fe289192dbc8.png"},{"id":8524245,"identity":"53a537ee-1e92-4906-a31d-8919f949b798","added_by":"auto","created_at":"2021-04-27 21:57:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53161,"visible":true,"origin":"","legend":"Summary of the statistical results of 18F-FDG PET/CT analysis\nA: Boxplot of the mean values of the renal allograft mean SUVmean according to the histopathological categories: normal (n=54); borderline (n=9); acute rejection (AR) (n=14); others (n=2). ANOVA: F-score=13.25, p-value\u003c0.0001. B: Positive correlation between the mean SUVmean and the acute Banff score (R2 = 0.41, p-value\u003c0.0001). C: ROC curve of [18F]FDG PET/CT imaging in the discrimination of biopsy-proven AR from non-pathological biopsies (normal + borderline). The area under the curve is 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 are 100% and 30%, respectively. The Youden index is 2.073, with a sensitivity of 57.1% and a specificity of 96.8%. \n","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-434469/v1/4004c03ee6092e198db5dcf4.png"},{"id":16763880,"identity":"8832b831-4806-4bc6-951a-ccf2aa0bcfef","added_by":"auto","created_at":"2021-12-27 06:09:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":911358,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-434469/v1/eafd78d8-0fcc-4aae-972c-c42eb8db2a87.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003e[18F]FDG PET/CT Imaging Disproves Renal Allograft Acute Rejection in Kidney Transplant Recipients with Acute Kidney Dysfunction: A Validation Cohort\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eThe prompt diagnosis of acute kidney allograft rejection (AR) is crucial in the management of kidney transplant recipients (KTRs) presenting with acute kidney injury (AKI). It currently relies on the histological analysis of a renal sample obtained by needle biopsy, following the gold-standard Banff classification\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In clinical routine, the vast majority of \u003cem\u003eper cause\u003c/em\u003e transplant biopsies show a normal histology\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Therefore, various non-invasive diagnostic approaches are currently under investigation to reduce the systematic usage of allograft biopsies\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. More specifically, rodent models of allogeneic kidney transplantation (KTx) have demonstrated that 2-deoxy-2-[\u003csup\u003e18\u003c/sup\u003eF]fluoro-D-glucose Positron Emission Tomography coupled with Computed Tomography ([\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT) early and specifically detect AR\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In humans, we have similarly underscored the putative usefulness of [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in the diagnosis of AR in a pilot study of 32 KTRs with AKI\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Our \u0026ldquo;rule out\u0026rdquo; approach was based on the mean of the mean standardized uptake values (mSUV\u003csub\u003emean\u003c/sub\u003e) in 4 independent volumes of interest (VOI) of the renal cortex, with a diagnostic threshold set at 1.6 to target a negative predictive value of 100%. In the present validation cohort, we prospectively assess this 1.6 threshold of renal mSUV\u003csub\u003emean\u003c/sub\u003e in the diagnosis of AR in KTRs with AKI who underwent a transplant needle biopsy for suspected AR.\u003c/p\u003e "},{"header":"Patients And Methods","content":"\u003ch2\u003ePatient population and specimens.\u003c/h2\u003e\n\u003cp\u003eThe study was approved by the institutional review board of the ULi\u0026egrave;ge Academic Hospital (#B707201215598). After written informed consent, adult KTRs undergoing a transplant biopsy for suspected AR were prospectively enrolled between March 2015 and December 2019.\u003c/p\u003e\n\u003ch2\u003eHistopathology.\u003c/h2\u003e\n\u003cp\u003eBiopsies were assessed by two pathologists according to Banff criteria\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Histological lesions were scored as continuous variables (from 0 to 3) on the basis of leucocyte infiltration severity in each component: glomeruli (g); peritubular capillaries (ptc); arteries (v); tubules (t); interstitium (i). Biopsies diagnosed as \u0026ldquo;normal\u0026rdquo; were defined as having a Banff [i\u0026thinsp;+\u0026thinsp;t] score\u0026thinsp;\u0026lt;\u0026thinsp;2 and no features of a disease process. Biopsies diagnosed as \u0026ldquo;borderline\u0026rdquo; were defined as having a Banff [i\u0026thinsp;+\u0026thinsp;t] score\u0026thinsp;\u0026ge;\u0026thinsp;2 (but \u0026lt;\u0026thinsp;i2-t2, and v\u0026thinsp;=\u0026thinsp;0), and no feature of a specific disease process. Biopsies diagnosed as \u0026ldquo;AR\u0026rdquo; were defined as having a Banff [i\u0026thinsp;+\u0026thinsp;t] score\u0026thinsp;\u0026ge;\u0026thinsp;i2 and \u0026ge;\u0026thinsp;t2 and/or v\u0026thinsp;\u0026gt;\u0026thinsp;0. Biopsies diagnosed as \u0026ldquo;others\u0026rdquo; were defined as showing features of an AR-unrelated disease. All biopsies were stained for the polyoma-BK virus.\u003c/p\u003e\n\u003ch2\u003e[ \u003csup\u003e 18 \u003c/sup\u003e F]FDG PET/CT imaging.\u003c/h2\u003e\n\u003cp\u003eThe present validation cohort followed exactly the same protocol as described in the proof-of-concept study\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The PET/CT procedure was performed using cross-calibrated Philips GEMINI TF Big Bore or TF 16 PET/CT systems (Philips Medical Systems, Cleveland, OH, USA) at 191 [min. 179; max. 254] minutes following intravenous injection of a mean dose of 254.4\u0026thinsp;\u0026plusmn;\u0026thinsp;30.4 MBq of [\u003csup\u003e18\u003c/sup\u003eF]FDG (to purge as much as possible the radioactive signal from the urinary compartment). No contrast agent or diuretics were infused. A low-dose helical CT (5-mm slice thickness, 120-kV tube voltage, and 40-mAs tube current\u0026ndash;time product) centered to the renal transplant was performed, followed by a PET emission scanning with 2 bed positions each lasting 4 minutes. Images were reconstructed using iterative list mode time-of-flight algorithms, and corrections for attenuation, dead-time, random and scatter events were applied. The PET/CT procedure was performed within a 48-hour period of the ultrasound-guided renal transplant biopsy. All [\u003csup\u003e18\u003c/sup\u003eF]FDG -PET/CT were acquired in fasting conditions before any modification of immunosuppressive regimens. Mean glycaemia at the time of tracer injection was 112\u0026thinsp;\u0026plusmn;\u0026thinsp;29 mg/dl. Four VOI of 1 ml were manually drawn in the cortical region of both upper (n\u0026thinsp;=\u0026thinsp;2) and lower (n\u0026thinsp;=\u0026thinsp;2) poles of the renal transplant at distance from the pelvicalyceal zone, as described previously\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The SUV\u003csub\u003emean\u003c/sub\u003e was measured in each VOI, with no threshold activity, and the mean of these 4 SUV\u003csub\u003emean\u003c/sub\u003e was calculated (mSUV\u003csub\u003emean\u003c/sub\u003e).\u003c/p\u003e\n\u003ch2\u003eStatistics.\u003c/h2\u003e\n\u003cp\u003eData were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or as median [minimum; maximum]. One-way analysis of variance (ANOVA) followed by the post-hoc Tukey\u0026rsquo;s studentized range test was performed to statistically compare mSUV\u003csub\u003emean\u003c/sub\u003e values among groups taking into account the necessary correction for multiple testing. The receiver operating characteristic (ROC) curve was drawn to discriminate \u0026ldquo;AR\u0026rdquo; from non-pathological (\u0026ldquo;normal\u0026rdquo; + \u0026ldquo;borderline\u0026rdquo;) conditions. The correlation between mSUV\u003csub\u003emean\u003c/sub\u003e and acute composite (g\u0026thinsp;+\u0026thinsp;i\u0026thinsp;+\u0026thinsp;t\u0026thinsp;+\u0026thinsp;v\u0026thinsp;+\u0026thinsp;ptc) Banff score was calculated. All analyses were done with SAS 9.4 (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe performed 86 [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in 79 KTR with AKI. Each suspicion of AR leading to kidney biopsy and [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT imaging was clinically and statistically independent. The characteristics of the cohort are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 ml/min/1.73m\u0026sup2;. Biopsies were described as \u0026ldquo;normal\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;54), \u0026ldquo;borderline\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;9), \u0026ldquo;AR\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;14) or \u0026ldquo;others\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;2). Biopsy-proven polyoma-BK nephropathies (n\u0026thinsp;=\u0026thinsp;7) were excluded. AR was antibody-mediated in 2 cases, whereas T-cell-mediated AR was found in 13 cases, respectively. The histological finding in the \u0026ldquo;other\u0026rdquo; causes of graft failure was focal segmental glomerulosclerosis with no evidence of AR (n\u0026thinsp;=\u0026thinsp;2). The median [min; max] mSUV\u003csub\u003emean\u003c/sub\u003e reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65; 3.12] and 1.84 [1.57; 2.12] in \u0026ldquo;normal\u0026rdquo;, \u0026ldquo;borderline\u0026rdquo;, \u0026ldquo;AR\u0026rdquo; and \u0026ldquo;others\u0026rdquo; groups, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). ANOVA demonstrated a significant difference of mSUV\u003csub\u003emean\u003c/sub\u003e among groups (\u003cem\u003eF\u0026thinsp;=\u0026thinsp;13.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The mSUV\u003csub\u003emean\u003c/sub\u003e of biopsy-proven AR was significantly higher than \u0026ldquo;normal\u0026rdquo; cases (\u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e). There was no significant difference between \u0026ldquo;normal\u0026rdquo; \u003cem\u003evs.\u003c/em\u003e \u0026ldquo;borderline\u0026rdquo; or between \u0026ldquo;AR\u0026rdquo; \u003cem\u003evs.\u003c/em\u003e \u0026ldquo;borderline\u0026rdquo; groups. A positive correlation between mSUV\u003csub\u003emean\u003c/sub\u003e and the acute Banff score was found, with adjusted r\u0026sup2; of 0.41 (\u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). The area under the ROC curve reached 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). Of methodological note, the Youden index reached 2.073, with a sensitivity of 57.1% and a specificity of 96.8%.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eClinical and biological characteristics of the cohort\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCohort\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;86 events)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRecipent\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55 [43; 63]\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender (male/female; n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47/39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 [22; 30]\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDonor\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDonor type (n), DBD/DCD/LD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63/17/6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender (male/female; n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40/46\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTransplantation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRank 1st / 2nd or 3rd (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79/7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCIT (min)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e644\u0026thinsp;\u0026plusmn;\u0026thinsp;287\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHLA mismatches, A\u0026thinsp;+\u0026thinsp;B\u0026thinsp;+\u0026thinsp;DR/6 (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 [2; 4]\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEarly graft function, immediate/slow/DGF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51/26/9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eStatus at time of biopsy\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaintenance immunosuppression (n)\u003c/p\u003e\n\u003cp\u003eCNI, CsA/FK/none\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8/75/3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnti-metabolites (n)\u003c/p\u003e\n\u003cp\u003eMMF/MPA/Aza/none\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66/12/1/7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emTOR inhibitors: yes/no (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4/82\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSteroids: yes/stop (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70/16\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuration KTx at Biopsy (days)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e279 [28; 1923]\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDonor specific antibodies: yes/no (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14/72\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\"\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation ; median [interquartile range]. \u003cem\u003eAZA, azathioprine; BMI, body mass index; CIT, cold ischemia time; CNI, calcineurin inhibitors; CsA, cyclosporin A; DBD, donor after brain death; DCD, donor after circulatory death; DGF, delayed graft function; FK, tacrolimus; KTx, kidney transplantation; HLA, Human Leucocyte Antigen; LD, living donor; MMF, mycophenolate mofetyl; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin.\u003c/em\u003e\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eIn the present prospective validation cohort of 86 [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT performed in 79 KTRs presenting with AKI, the previously proposed mSUV\u003csub\u003emean\u003c/sub\u003e threshold of 1.6 significantly discriminated non-rejection, with a sensitivity of 100%\u003csup\u003e7\u003c/sup\u003e. The poor specificity of [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in detecting AR is most probably due to the radiotracer which accumulates in other inflammatory conditions. Still, the renal allografts with biopsy-proven AR were characterized by a significantly higher uptake of [\u003csup\u003e18\u003c/sup\u003eF]FDG compared to \u0026ldquo;normal/borderline\u0026rdquo; biopsies, with a Youden index of 2.073 corresponding to a specificity of 96.8%. From a clinical point of view, a high negative predictive value appears more appropriate in the management of KTR with AKI in order to certify that no diagnosis of AR is missed or delayed. The pathophysiological hypothesis of such a preferential accumulation of the radiotracer in case of AR relies on the increased metabolic activity of infiltrating inflammatory cells, as suggested by the significant correlation between renal mSUV\u003csub\u003emean\u003c/sub\u003e and the severity of leucocyte infiltrates as quantified by the acute Banff score\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The clinical significance and treatment of borderline changes remain highly debated, which prompts the ongoing development and validation of various biofluid-based biomarkers of clinically relevant AR\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. All cases with biopsy-proven polyoma-BK nephropathy were excluded from our analysis since the diagnostic procedure has been standardized \u003cem\u003evia\u003c/em\u003e polymerase chain reaction (PCR)-based screening for BK virus replication in urine and/or blood specimens\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eStricto sensu\u003c/em\u003e, a needle biopsy of the renal allograft should only be performed after negative PCR results. The median mSUV\u003csub\u003emean\u003c/sub\u003e of the allografts with biopsy-proven polyoma-BK nephropathy was 2.20 [1.96; 2.47].\u003c/p\u003e \u003cp\u003eThe limitations of our proposed non-invasive diagnostic approach based on [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in unstable KTR with AKI include (i) the somewhat restricted availability of PET/CT machine, (ii) the minor exposure to radiations originating from both PET and CT procedures, and (iii) the 3-hour delay between [\u003csup\u003e18\u003c/sup\u003eF]FDG injection and image acquisition. Still, the repeatability and reproducibility of the quantification of kidney allograft [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake has been reported as consistent\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The use of multiple independent VOI distributed right beneath the renal capsula in both upper and lower renal cortices aimed at (i) limiting the noise of the urinary [\u003csup\u003e18\u003c/sup\u003eF]FDG and (ii) averting sampling error, which also represents one of the main limitations of transplant biopsy\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Of technical note, no difference was statistically detected between the SUV\u003csub\u003emean\u003c/sub\u003e of the 4 VOI in the present 86-scan cohort, as previously reported\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Assessing the global [\u003csup\u003e18\u003c/sup\u003eF]FDG accumulation in the renal allograft by the means of image segmentation softwares (currently under development and validation) would further help to minimize the sampling error.\u003c/p\u003e \u003cp\u003eOn the basis of this validation cohort, we postulate that [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT as first-line examination may help save selected patients with AKI from undergoing renal transplant biopsy. Such an invasive procedure would have been avoided in 19 cases of our series, which were characterized by an mSUV\u003csub\u003emean\u003c/sub\u003e strictly inferior to the 1.6 threshold and normal histology. Further large prospective multicentric studies are needed to test whether the mSUV\u003csub\u003emean\u003c/sub\u003e threshold of [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT imaging, in combination with blood and urinary biomarkers\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, helps to pragmatically dictate the need for transplant biopsy in KTR presenting with AKI and suspected AR. Other tracers for inflammation may also be envisioned in this frequent clinical scenario, such as [\u003csup\u003e11\u003c/sup\u003eC]Methionine or [\u003csup\u003e68\u003c/sup\u003eGa]Pentixafor.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors cordially thank the surgeons (C. Coimbra Marques, A. De Roover, O. Detry, E. Hamoir, P. Honor\u0026eacute;, L. Kohnen, N. Meurisse and J-P Squifflet), the physicians (P. Erpicum, O. Hanssen, L. Vanovermeire and P. Xhignesse) and the members of the local transplant coordination center (M-H. Delbouille, J. Monard, S. Princen and A. Waromes), as well as the staff of the Division of Nuclear Medicine of the University of Li\u0026egrave;ge Hospital in Li\u0026egrave;ge, Belgium. FJ is a Fellow of the Fonds National de la Recherche Scientifique, and received support from the University of Li\u0026egrave;ge (Fonds Sp\u0026eacute;ciaux \u0026agrave; la Recherche) and from the Fondation L\u0026eacute;on Fredericq.\u003c/p\u003e\n\u003ch2\u003eConflict of interest:\u003c/h2\u003e\n\u003cp\u003enone.\u003c/p\u003e\n\u003ch2\u003eFunding.\u003c/h2\u003e\n\u003cp\u003eFJ is a Fellow of the Fonds National de la Recherche Scientifique, and received support from the University of Li\u0026egrave;ge (Fonds Sp\u0026eacute;ciaux \u0026agrave; la Recherche) and from the Fondation L\u0026eacute;on Fredericq.\u003c/p\u003e\n\u003ch2\u003eConflicts of interest/Competing interests.\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflict of interest\u003c/p\u003e\n\u003ch2\u003eAvailability of data and material.\u003c/h2\u003e\n\u003cp\u003eThe data will be made available on request.\u003c/p\u003e\n\u003ch2\u003eCode availability.\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003ch2\u003eAuthors' contributions.\u003c/h2\u003e\n\u003cp\u003eLP, LW, RH and FJ designed the study; RH and FJ secured the funding of the study; HP performed the statistical analyses; LW, AB, CB recruited the patients and filled the medical files; AB performed the kidney biopsies; CB and SG scored the biopsies; LP and RH scored the [\u003csup\u003e18\u003c/sup\u003eF]FDG\u003csup\u003e-\u003c/sup\u003ePET/CT images; LP and FJ wrote the manuscript; all authors approved the final version of the manuscript\u003c/p\u003e\n\u003ch2\u003eEthics approval.\u003c/h2\u003e\n\u003cp\u003eThe study was approved by the institutional review board of the ULi\u0026egrave;ge Academic Hospital (#B707201215598).\u003c/p\u003e\n\u003ch2\u003eConsent to participate.\u003c/h2\u003e\n\u003cp\u003eAfter written informed consent, adult KTRs undergoing a transplant biopsy for suspected AR were prospectively enrolled between March 2015 and December 2019.\u003cstrong\u003e\u003cbr /\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLoupy A, Haas M, Roufosse C, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant 2020;20:2318-31.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"2\"\u003e\n\u003cli\u003ePaquot F, Weekers L, Bonvoisin C, Pottel H, Jouret F. \"Acute kidney dysfunction with no rejection\" is associated with poor renal outcomes at 2 years post kidney transplantation. BMC Nephrol 2019;20:249.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"3\"\u003e\n\u003cli\u003eHanssen O, Erpicum P, Lovinfosse P, et al. Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients. Part I. In vivo imaging methods. Clin Kidney J 2017;10:97-105.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"4\"\u003e\n\u003cli\u003eErpicum P, Hanssen O, Weekers L, et al. Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients, part II: omics analyses of urine and blood samples. Clin Kidney J 2017;10:106-15.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"5\"\u003e\n\u003cli\u003eTinel C, Devresse A, Vermorel A, et al. Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection. Am J Transplant 2020;20:3462-76.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"6\"\u003e\n\u003cli\u003eReuter S, Schnockel U, Schroter R, et al. Non-invasive imaging of acute renal allograft rejection in rats using small animal F-FDG-PET. PLoS One 2009;4:e5296.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"7\"\u003e\n\u003cli\u003eLovinfosse P, Weekers L, Bonvoisin C, et al. Fluorodeoxyglucose F(18) Positron Emission Tomography Coupled With Computed Tomography in Suspected Acute Renal Allograft Rejection. Am J Transplant 2016;16:310-6.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"8\"\u003e\n\u003cli\u003eCosta C, Cavallo R. Polyomavirus-associated nephropathy. World journal of transplantation 2012;2:84-94.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"9\"\u003e\n\u003cli\u003eJadoul A, Lovinfosse P, Weekers L, et al. The Uptake of 18F-FDG by Renal Allograft in Kidney Transplant Recipients Is Not Influenced by Renal Function. Clin Nucl Med 2016;41:683-7.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"10\"\u003e\n\u003cli\u003eJadoul A, Lovinfosse P, Bouquegneau A, et al. Observer variability in the assessment of renal (18)F-FDG uptake in kidney transplant recipients. Sci Rep 2020;10:4617.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-nuclear-medicine-and-molecular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejnm","sideBox":"Learn more about [European Journal of Nuclear Medicine and Molecular Imaging](https://www.springer.com/journal/259)","snPcode":"259","submissionUrl":"https://submission.nature.com/new-submission/259/3","title":"European Journal of Nuclear Medicine and Molecular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"[18F]FDG-PET/CT, kidney transplant, acute rejection, diagnosis, Banff","lastPublishedDoi":"10.21203/rs.3.rs-434469/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-434469/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose. \u003c/strong\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG-PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. \u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods. \u003c/strong\u003eWe prospectively performed 86 [\u003csup\u003e18\u003c/sup\u003eF]FDG-PET/CT in 79 adult KTRs who underwent \u003cem\u003eper cause\u003c/em\u003e transplant biopsy for suspected AR. Biopsy-proven polyoma-BK nephropathies (n=7) were excluded. PET/CT was performed 192 ± 18 minutes after administration of 254.4 ± 30.4 MBq of [\u003csup\u003e18\u003c/sup\u003eF]FDG. The SUV\u003csub\u003emean\u003c/sub\u003e was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey’s studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate “AR” from non-pathological (“normal” + “borderline”) conditions. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m². Biopsies were categorized in 4 groups: “normal” (n=54), “borderline” (n=9), “AR” (n=14) or “others” (n=2). The median [min; max] mSUV\u003csub\u003emean\u003c/sub\u003e reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12] and 1.84 [1.57; 2.12] in “normal”, “borderline”, “AR” and “others” groups, respectively. ANOVA demonstrated a significant difference of mSUV\u003csub\u003emean\u003c/sub\u003e among groups (\u003cem\u003eF=13.25, p\u0026lt;0.0001\u003c/em\u003e). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion. \u003c/strong\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG\u003csup\u003e-\u003c/sup\u003ePET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.\u003c/p\u003e","manuscriptTitle":"[18F]FDG PET/CT Imaging Disproves Renal Allograft Acute Rejection in Kidney Transplant Recipients with Acute Kidney Dysfunction: A Validation Cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-27 21:54:51","doi":"10.21203/rs.3.rs-434469/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-05-03T00:00:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-04-24T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-04-19T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Nuclear Medicine and Molecular Imaging","date":"2021-04-16T10:29:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-nuclear-medicine-and-molecular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejnm","sideBox":"Learn more about [European Journal of Nuclear Medicine and Molecular Imaging](https://www.springer.com/journal/259)","snPcode":"259","submissionUrl":"https://submission.nature.com/new-submission/259/3","title":"European Journal of Nuclear Medicine and Molecular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"97ebd251-1849-48fd-ab6c-c9bb73b4b886","owner":[],"postedDate":"April 27th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":3929021,"name":"Nuclear Medicine \u0026 Medical Imaging"}],"tags":[],"updatedAt":"2021-12-27T06:09:25+00:00","versionOfRecord":{"articleIdentity":"rs-434469","link":"https://doi.org/10.1007/s00259-021-05467-0","journal":{"identity":"european-journal-of-nuclear-medicine-and-molecular-imaging","isVorOnly":false,"title":"European Journal of Nuclear Medicine and Molecular Imaging"},"publishedOn":"2021-06-30 06:09:25","publishedOnDateReadable":"June 30th, 2021"},"versionCreatedAt":"2021-04-27 21:54:51","video":"","vorDoi":"10.1007/s00259-021-05467-0","vorDoiUrl":"https://doi.org/10.1007/s00259-021-05467-0","workflowStages":[]},"version":"v1","identity":"rs-434469","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-434469","identity":"rs-434469","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}