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1
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Rafidi H, Rajan S, Urban K, Shatz-Binder W, Hui K, Ferl GZ, Kamath AV, Boswell CA. Effect of molecular size on interstitial pharmacokinetics and tissue catabolism of antibodies. MAbs 2022; 14:2085535. [PMID: 35867780 PMCID: PMC9311319 DOI: 10.1080/19420862.2022.2085535] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Advances in antibody engineering have enabled the construction of novel molecular formats in diverse shapes and sizes, providing new opportunities for biologic therapies and expanding the need to understand how various structural aspects affect their distribution properties. To assess the effect of antibody size on systemic pharmacokinetics (PK) and tissue distribution with or without neonatal Fc receptor (FcRn) binding, we evaluated a series of non-mouse-binding anti-glycoprotein D monoclonal antibody formats, including IgG [~150 kDa], one-armed IgG [~100 kDa], IgG-HAHQ (attenuated FcRn binding) [~150 kDa], F(ab')2 [~100 kDa], and F(ab) [~50 kDa]. Tissue-specific concentration-time profiles were corrected for blood content based on vascular volumes and normalized based on interstitial volumes to allow estimation of interstitial concentrations and interstitial:serum concentration ratios. Blood correction demonstrated that the contribution of circulating antibody on total uptake was greatest at early time points and for highly vascularized tissues. Tissue interstitial PK largely mirrored serum exposure profiles. Similar interstitial:serum ratios were obtained for the two FcRn-binding molecules, IgG and one-armed IgG, which reached pseudo-steady-state kinetics in most tissues. For non-FcRn-binding molecules, interstitial:serum ratios changed over time, suggesting that these molecules did not reach steady-state kinetics during the study. Furthermore, concentration-time profiles of both intact and catabolized molecule were measured by a dual tracer approach, enabling quantification of tissue catabolism and demonstrating that catabolism levels were highest for IgG-HAHQ. Overall, these data sets provide insight into factors affecting preclinical distribution and may be useful in estimating interstitial concentrations and/or catabolism in human tissues.
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Affiliation(s)
- Hanine Rafidi
- Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - Sharmila Rajan
- Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - Konnie Urban
- Safety Assessment, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - Whitney Shatz-Binder
- Protein Chemistry, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - Keliana Hui
- Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - Gregory Z Ferl
- Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA.,Biomedical Imaging, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - Amrita V Kamath
- Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
| | - C Andrew Boswell
- Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA.,Biomedical Imaging, Research and Early Development, Genentech, Inc, South San Francisco, CA, USA
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2
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Reuter S, Kentrup D, Grabner A, Köhler G, Buscher K, Edemir B. C4d Deposition after Allogeneic Renal Transplantation in Rats Is Involved in Initial Apoptotic Cell Clearance. Cells 2021; 10:3499. [PMID: 34944007 PMCID: PMC8700759 DOI: 10.3390/cells10123499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022] Open
Abstract
In the context of transplantation, complement activation is associated with poor prognosis and outcome. While complement activation in antibody-mediated rejection is well-known, less is known about complement activation in acute T cell-mediated rejection (TCMR). There is increasing evidence that complement contributes to the clearance of apoptotic debris and tissue repair. In this regard, we have analysed published human kidney biopsy transcriptome data clearly showing upregulated expression of complement factors in TCMR. To clarify whether and how the complement system is activated early during acute TCMR, experimental syngeneic and allogeneic renal transplantations were performed. Using an allogeneic rat renal transplant model, we also observed upregulation of complement factors in TCMR in contrast to healthy kidneys and isograft controls. While staining for C4d was positive, staining with a C3d antibody showed no C3d deposition. FACS analysis of blood showed the absence of alloantibodies that could have explained the C4d deposition. Gene expression pathway analysis showed upregulation of pro-apoptotic factors in TCMR, and apoptotic endothelial cells were detected by ultrastructural analysis. Monocytes/macrophages were found to bind to and phagocytise these apoptotic cells. Therefore, we conclude that early C4d deposition in TCMR may be relevant to the clearance of apoptotic cells.
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Affiliation(s)
- Stefan Reuter
- Department of Internal Medicine D, Experimental Nephrology, University Clinics Münster, 48143 Münster, Germany; (S.R.); (D.K.); (A.G.); (K.B.)
| | - Dominik Kentrup
- Department of Internal Medicine D, Experimental Nephrology, University Clinics Münster, 48143 Münster, Germany; (S.R.); (D.K.); (A.G.); (K.B.)
- Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Alexander Grabner
- Department of Internal Medicine D, Experimental Nephrology, University Clinics Münster, 48143 Münster, Germany; (S.R.); (D.K.); (A.G.); (K.B.)
- Department of Medicine, Division of Nephrology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Gabriele Köhler
- Gerhard Domagk Institute of Pathology, University Clinics Münster, 48143 Münster, Germany;
| | - Konrad Buscher
- Department of Internal Medicine D, Experimental Nephrology, University Clinics Münster, 48143 Münster, Germany; (S.R.); (D.K.); (A.G.); (K.B.)
| | - Bayram Edemir
- Department of Internal Medicine D, Experimental Nephrology, University Clinics Münster, 48143 Münster, Germany; (S.R.); (D.K.); (A.G.); (K.B.)
- Department of Medicine, Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
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3
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Lovinfosse P, Weekers L, Pottel H, Bouquegneau A, Bonvoisin C, Bovy C, Grosch S, Hustinx R, Jouret F. [ 18F]FDG PET/CT imaging disproves renal allograft acute rejection in kidney transplant recipients with acute kidney dysfunction: a validation cohort. Eur J Nucl Med Mol Imaging 2021; 49:331-335. [PMID: 34191101 DOI: 10.1007/s00259-021-05467-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/16/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE [18F]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 [18F]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 min after administration of 254.4 ± 30.4 MBq of [18F]FDG. The SUVmean 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] mSUVmean 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 mSUVmean 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 [18F]FDG PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.
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Affiliation(s)
- P Lovinfosse
- Division of Nuclear Medicine and Oncological Imaging, Department of Medical Physics, University Hospital of Liège, Liège, Belgium
| | - L Weekers
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - H Pottel
- Department of Public Health and Primary Care, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - A Bouquegneau
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - C Bonvoisin
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - C Bovy
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium
- Division of Renal Pathology, Unilab, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - S Grosch
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium
- Division of Renal Pathology, Unilab, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - R Hustinx
- Division of Nuclear Medicine and Oncological Imaging, Department of Medical Physics, University Hospital of Liège, Liège, Belgium
- GIGA CRC in Vivo Imaging, University of Liège, Liège, Belgium
| | - Francois Jouret
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium.
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.
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4
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The utilization of positron emission tomography in the evaluation of renal health and disease. Clin Transl Imaging 2021. [DOI: 10.1007/s40336-021-00469-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Abstract
Purpose
Positron emission tomography (PET) is a nuclear imaging technique that uses radiotracers to visualize metabolic processes of interest across different organs, to diagnose and manage diseases, and monitor therapeutic response. This systematic review aimed to characterize the value of PET for the assessment of renal metabolism and function in subjects with non-oncological metabolic disorders.
Methods
This review was conducted and reported in accordance with the PRISMA statement. Research articles reporting “kidney” or “renal” metabolism evaluated with PET imaging between 1980 and 2021 were systematically searched in Medline/PubMed, Science Direct, and the Cochrane Library. Search results were exported and stored in RefWorks, the duplicates were removed, and eligible studies were identified, evaluated, and summarized.
Results
Thirty reports met the inclusion criteria. The majority of the studies were prospective (73.33%, n = 22) in nature. The most utilized PET radiotracers were 15O-labeled radio water (H215O, n = 14) and 18F-fluorodeoxyglucose (18F-FDG, n = 8). Other radiotracers used in at least one study were 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid (18F-FTHA), 18F-Sodium Fluoride (18F-NaF), 11C-acetate, 68-Gallium (68Ga), 13N-ammonia (13N-NH3), Rubidium-82 (82Rb), radiolabeled cationic ferritin (RadioCF), 11C‐para-aminobenzoic acid (11C-PABA), Gallium-68 pentixafor (68Ga-Pentixafor), 2-deoxy-2-F-fluoro-d-sorbitol (F-FDS) and 55Co-ethylene diamine tetra acetic acid (55Co-EDTA).
Conclusion
PET imaging provides an effective modality for evaluating a range of metabolic functions including glucose and fatty acid uptake, oxygen consumption and renal perfusion. Multiple positron emitting radiolabeled racers can be used for renal imaging in clinical settings. PET imaging thus holds the potential to improve the diagnosis of renal disorders, and to monitor disease progression and treatment response.
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5
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Klinkhammer BM, Lammers T, Mottaghy FM, Kiessling F, Floege J, Boor P. Non-invasive molecular imaging of kidney diseases. Nat Rev Nephrol 2021; 17:688-703. [PMID: 34188207 PMCID: PMC7612034 DOI: 10.1038/s41581-021-00440-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 02/05/2023]
Abstract
In nephrology, differential diagnosis or assessment of disease activity largely relies on the analysis of glomerular filtration rate, urinary sediment, proteinuria and tissue obtained through invasive kidney biopsies. However, currently available non-invasive functional parameters, and most serum and urine biomarkers, cannot capture intrarenal molecular disease processes specifically. Moreover, although histopathological analyses of kidney biopsy samples enable the visualization of pathological morphological and molecular alterations, they only provide information about a small part of the kidney and do not allow longitudinal monitoring. These limitations not only hinder understanding of the dynamics of specific disease processes in the kidney, but also limit the targeting of treatments to active phases of disease and the development of novel targeted therapies. Molecular imaging enables non-invasive and quantitative assessment of physiological or pathological processes by combining imaging technologies with specific molecular probes. Here, we discuss current preclinical and clinical molecular imaging approaches in nephrology. Non-invasive visualization of the kidneys through molecular imaging can be used to detect and longitudinally monitor disease activity and can therefore provide companion diagnostics to guide clinical trials, as well as the safe and effective use of drugs.
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Affiliation(s)
| | - Twan Lammers
- Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
- Department of Pharmaceutics, Utrecht University, Utrecht, Netherlands
- Department of Targeted Therapeutics, University of Twente, Enschede, Netherlands
| | - Felix M Mottaghy
- Department of Nuclear Medicine, University Hospital RWTH, Aachen, Germany
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Fabian Kiessling
- Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
- Fraunhofer Institute for Digital Medicine MEVIS, Bremen, Germany
| | - Jürgen Floege
- Department of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
- Department of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
- Electron Microscopy Facility, RWTH Aachen University Hospital, Aachen, Germany.
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6
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Hirai T, Mayer AT, Nobashi TW, Lin PY, Xiao Z, Udagawa T, Seo K, Simonetta F, Baker J, Cheng AG, Negrin RS, Gambhir SS. Imaging alloreactive T cells provides early warning of organ transplant rejection. JCI Insight 2021; 6:e145360. [PMID: 34236044 PMCID: PMC8410037 DOI: 10.1172/jci.insight.145360] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Diagnosis of organ transplant rejection relies upon biopsy approaches to confirm alloreactive T cell infiltration in the graft. Immune molecular monitoring is under investigation to screen for rejection, though these techniques have suffered from low specificity and lack of spatial information. ImmunoPET utilizing antibodies conjugated to radioisotopes has the potential to improve early and accurate detection of graft rejection. ImmunoPET is capable of noninvasively visualizing the dynamic distribution of cells expressing specific immune markers in the entire body over time. In this work, we identify and characterize OX40 as a surrogate biomarker for alloreactive T cells in organ transplant rejection and monitor its expression by utilizing immunoPET. In a dual murine heart transplant model that has both syngeneic and allogeneic hearts engrafted in bilateral ear pinna on the recipients, OX40 immunoPET clearly depicted alloreactive T cells in the allograft and draining lymph node that were not observed in their respective isograft counterparts. OX40 immunoPET signals also reflected the subject’s immunosuppression level with tacrolimus in this study. OX40 immunoPET is a promising approach that may bridge molecular monitoring and morphological assessment for improved transplant rejection diagnosis.
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Affiliation(s)
- Toshihito Hirai
- Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA.,Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Aaron T Mayer
- Department of Bioengineering.,Department of Radiology.,Molecular Imaging Program at Stanford, and.,BioX Program at Stanford, Stanford University, Stanford, California, USA
| | | | - Po-Yu Lin
- Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA
| | - Zunyu Xiao
- Department of Radiology.,Molecular Imaging Program at Stanford, and.,Molecular Imaging Research Center of Harbin Medical University, Harbin, China
| | | | | | - Federico Simonetta
- Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA
| | - Jeanette Baker
- Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA
| | - Alan G Cheng
- Department of Otolaryngology-Head and Neck Surgery
| | - Robert S Negrin
- Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA
| | - Sanjiv S Gambhir
- Department of Bioengineering.,Department of Radiology.,Molecular Imaging Program at Stanford, and.,BioX Program at Stanford, Stanford University, Stanford, California, USA.,Department of Materials Science and Engineering, and.,Canary Center at Stanford, Stanford University, Stanford, California, USA
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7
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Wareham NE, Nielsen SD, Sørensen SS, Fischer BM. FDG PET/CT for Detection of Infectious Complications Following Solid Organ Transplantation. Semin Nucl Med 2021; 51:321-334. [PMID: 33397588 DOI: 10.1053/j.semnuclmed.2020.12.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Infectious complications after solid organ transplantation (SOT) are often more severe and remain a diagnostic challenge due to vague and atypical clinical presentations. Diagnostic performance of conventional diagnostic tools is frequently inadequate which may lead to delayed diagnosis with the risk of poorer outcomes. This literature review aimed to investigate the current evidence on the use of 18F-fluoro-deoxy-glucose (FDG) Positron Emission Tomography (PET)/computer tomography (CT) in infectious complications after SOT. Based on search in PubMed, Medline, and Cochrane databases, 13 articles and 46 case reports were included. For inclusion, articles were to include data on patients with infectious complications after SOT, and where FDG PET/CT was part of the work-up. Final searches were conducted on 02 September 2020. Overall, in the absence of initial diagnostic clues, FDG PET/CT should be considered as the imaging technique of choice as it may guide further investigations and eventually reveal the diagnosis in most of the patients. However, the available literature of the role of FDG PET/CT in SOT recipients with infectious complications is scarce and well-designed prospective studies including control groups are warranted to establish the role of FDG PET/C/ in SOT recipients. The main drawback of FDG PET/CT is the lack of ability to differentiate between cancer and infectious diseases which are both highly prevalent in this patient group. Accordingly, the main reasons for "false" results of FDG PET/CT is the misdiagnosis of cancer in benign inflammatory or infectious processes, information which nonetheless can be useful.
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Affiliation(s)
- Neval E Wareham
- Department of Infectious Diseases, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
| | - Susanne Dam Nielsen
- Department of Infectious Diseases, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Søren Schwartz Sørensen
- Department of Nephrology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Barbara Malene Fischer
- The PET Centre, Guy's & St Thomas Hospital, School of Biomedical Engineering and Imaging Sciences, Kings College London, St Thomas' Hospital, London
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8
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Abstract
Although kidney oxygen tensions are heterogenous, and mostly below renal vein level, the nephron is highly dependent on aerobic metabolism for active tubular transport. This renders the kidney particularly susceptible to hypoxia, which is considered a main characteristic and driver of acute and chronic kidney injury, albeit the evidence supporting this assumption is not entirely conclusive. Kidney transplants are exposed to several conditions that may interfere with the balance between oxygen supply and consumption, and enhance hypoxia and hypoxic injury. These include conditions leading to and resulting from brain death of kidney donors, ischemia and reperfusion during organ donation, storage and transplantation, postoperative vascular complications, vasoconstriction induced by immunosuppression, and impaired perfusion resulting from interstitial edema, inflammation, and fibrosis. Acute graft injury, the immediate consequence of hypoxia and reperfusion, results in delayed graft function and increased risk of chronic graft failure. Although current strategies to alleviate hypoxic/ischemic graft injury focus on limiting injury (eg, by reducing cold and warm ischemia times), experimental evidence suggests that preconditioning through local or remote ischemia, or activation of the hypoxia-inducible factor pathway, can decrease hypoxic injury. In combination with ex vivo machine perfusion such approaches hold significant promise for improving transplantation outcomes.
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Affiliation(s)
- Christian Rosenberger
- Department of Nephrology and Medical Intensive Care, Charité Universitaetsmedizin Berlin, Berlin, Germany.
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité Universitaetsmedizin Berlin, Berlin, Germany
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9
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Hanssen O, Weekers L, Lovinfosse P, Jadoul A, Bonvoisin C, Bouquegneau A, Grosch S, Huynen A, Anglicheau D, Hustinx R, Jouret F. Diagnostic yield of 18 F-FDG PET/CT imaging and urinary CXCL9/creatinine levels in kidney allograft subclinical rejection. Am J Transplant 2020; 20:1402-1409. [PMID: 31841263 DOI: 10.1111/ajt.15742] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/19/2019] [Accepted: 11/22/2019] [Indexed: 01/25/2023]
Abstract
Subclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient." SCR detection relies on surveillance biopsy. Noninvasive approaches may help avoid biopsy-associated complications. From November 2015 to January 2018, we prospectively performed positron emission tomography/computed tomography (PET/CT) after injection of F18 -fluorodeoxyglucose (18 F-FDG) in adult kidney transplant recipients with surveillance biopsy at ~3 months posttransplantation. The Banff-2017 classification was used. The ratio of the mean standard uptake value (mSUVR) between kidney cortex and psoas muscle was measured. Urinary levels of CXCL-9 were concomitantly quantified. Our 92-patient cohort was categorized upon histology: normal (n = 70), borderline (n = 16), and SCR (n = 6). No clinical or biological difference was observed between groups. The mSUVR reached 1.87 ± 0.55, 1.94 ± 0.35, and 2.41 ± 0.54 in normal, borderline, and SCR groups, respectively. A significant difference in mSUVR was found among groups. Furthermore, mSUVR was significantly higher in the SCR vs normal group. The area under the receiver operating characteristic curve (AUC) was 0.79, with 83% sensitivity using an mSUVR threshold of 2.4. The AUC of urinary CXCL-9/creatinine ratios comparatively reached 0.79. The mSUVR positively correlated with ti and acute composite Banff scores. 18 F-FDG-PET/CT helps noninvasively exclude SCR, with a negative predictive value of 98%. External validations are required.
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Affiliation(s)
- Oriane Hanssen
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
| | - Laurent Weekers
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
| | - Pierre Lovinfosse
- Division of Nuclear Medicine, Department of Medical Physics, University of Liège Hospital, Liège, Belgium
| | - Alexandre Jadoul
- Division of Nuclear Medicine, Department of Medical Physics, University of Liège Hospital, Liège, Belgium
| | - Catherine Bonvoisin
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
| | - Antoine Bouquegneau
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
| | - Stéphanie Grosch
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium.,Division of Renal Pathology, Unilab, University of Liège Hospital, Liège, Belgium
| | - Alexandre Huynen
- Structural Engineering Division, Faculty of Applied Sciences, University of Liège, Liège, Belgium
| | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, RTRS Centaure, LabEx Transplantex, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Roland Hustinx
- Division of Nuclear Medicine, Department of Medical Physics, University of Liège Hospital, Liège, Belgium
| | - Francois Jouret
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium.,Groupe Interdisciplinaire de Géno-protéomique Appliquée, Cardiovascular Sciences, University of Liège, Liège, Belgium
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10
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Hanssen O, Lovinfosse P, Weekers L, Hustinx R, Jouret F. [ 18F-FDG positron emission tomography in non-oncological renal pathology: Current indications and perspectives]. Nephrol Ther 2019; 15:430-438. [PMID: 30982747 DOI: 10.1016/j.nephro.2018.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 11/28/2018] [Indexed: 12/26/2022]
Abstract
Positron emission tomography combined with computed tomography (PET/CT) is a nuclear imaging technique which provides anatomical and functional information. PET/CT is increasingly used in non-oncological nephrology since conventional radiological approaches after injection of contrast agents are relatively contra-indicated in patients with chronic kidney disease (CKD). PET/CT after i.v. injection of 18F-fluoro-deoxy-glucose (FDG) is not toxic and is characterized by a high sensitivity. The level of irradiation (∼5mSv) is acceptable. CKD does not significantly influence tissue uptake of 18F-FDG. The purpose of the present review aims at detailing the non-oncological indications of 18F-FDG PET/CT in general nephrology and after kidney transplantation. Particularly, 18F-FDG PET/CT appears useful in the diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease, as well as in the characterization of retroperitoneal fibrosis. In kidney transplant recipients, 18F-FDG PET/CT may help in the diagnostic work-up of suspected acute rejection, thereby eventually avoiding unnecessary kidney transplant biopsy. Perspectives in 18F-FDG PET/CT imaging are discussed, including innovative approaches of image analysis.
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Affiliation(s)
- Oriane Hanssen
- Service de néphrologie, centre hospitalier universitaire de Liège, avenue Hippocrate 13, 4000 Liège, Belgique
| | - Pierre Lovinfosse
- Service de médecine nucléaire et imagerie oncologique, centre hospitalier universitaire de Liège, avenue Hippocrate 13, 4000 Liège, Belgique
| | - Laurent Weekers
- Service de médecine nucléaire et imagerie oncologique, centre hospitalier universitaire de Liège, avenue Hippocrate 13, 4000 Liège, Belgique
| | - Roland Hustinx
- Service de médecine nucléaire et imagerie oncologique, centre hospitalier universitaire de Liège, avenue Hippocrate 13, 4000 Liège, Belgique
| | - François Jouret
- Service de néphrologie, centre hospitalier universitaire de Liège, avenue Hippocrate 13, 4000 Liège, Belgique; Groupe interdisciplinaire de géno-protéomique appliquée (GIGA), sciences cardiovasculaires, université de Liège, Liège, Belgique.
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11
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Köhnke R, Kentrup D, Schütte-Nütgen K, Schäfers M, Schnöckel U, Hoerr V, Reuter S. Update on imaging-based diagnosis of acute renal allograft rejection. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2019; 9:110-126. [PMID: 31139495 PMCID: PMC6526365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 04/12/2019] [Indexed: 06/09/2023]
Abstract
Kidney transplantation is the preferred treatment for patients with end-stage renal disease. Despite effective immunosuppressants, acute allograft rejections pose a major threat to graft survival. In early stages, acute rejections are still potentially reversible, and early detection is crucial to initiate the necessary treatment options and to prevent further graft dysfunction or even loss of the complete graft. Currently, invasive core needle biopsy is the reference standard to diagnose acute rejection. However, biopsies carry the risk of graft injuries and cannot be immediately performed on patients receiving anticoagulation drugs. Therefore, non-invasive assessment of the whole organ for specific and rapid detection of acute allograft rejection is desirable. We herein provide a review summarizing current imaging-based approaches for non-invasive diagnosis of acute renal allograft rejection.
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Affiliation(s)
- Richard Köhnke
- Department of Medicine, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Muenster48149 Muenster, Germany
| | - Dominik Kentrup
- Department of Medicine, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Muenster48149 Muenster, Germany
- Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham (UAB)35294 Birmingham Alabama, US
| | - Katharina Schütte-Nütgen
- Department of Medicine, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Muenster48149 Muenster, Germany
| | - Michael Schäfers
- Department of Nuclear Medicine, University Hospital of Muenster48149 Muenster, Germany
- European Institute for Molecular Imaging, University of Muenster48140 Muenster, Germany
| | - Uta Schnöckel
- Department of Nuclear Medicine, University Hospital of Muenster48149 Muenster, Germany
| | - Verena Hoerr
- Department of Clinical Radiology, University Hospital of Muenster48149 Muenster, Germany
- Institute of Medical Microbiology, Jena University HospitalAm Klinikum 1, 07747 Jena, Germany
| | - Stefan Reuter
- Department of Medicine, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Muenster48149 Muenster, Germany
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Using functional magnetic resonance imaging to evaluate an acute allograft rejection model in rats. Magn Reson Imaging 2019; 58:24-31. [PMID: 30630071 DOI: 10.1016/j.mri.2019.01.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/03/2018] [Accepted: 01/06/2019] [Indexed: 12/30/2022]
Abstract
PURPOSE To assess the longitudinal changes of allograft pathophysiology by intravoxel incoherent motion (IVIM) and blood oxygen level-dependent (BOLD) MRI in a rat model of acute renal allograft rejection. MATERIALS AND METHODS Acute rejection (AR) was induced by transplantation of Dark Agouti donor kidneys into Lewis recipients (n = 18). A Lewis-Lewis rat syngeneically transplanted (sTX) model served as the control (n = 6). Acute tubular necrosis (n = 6) and acute calcineurin inhibitor toxicity (n = 6) groups were established using Lewis rats. MRI was performed on postoperative day (POD) 1, 4 and 7 in the allogeneically transplanted (aTX) group and on POD4 in the other groups. Histological evaluation and PCR were performed. RESULTS After the allogenic transplantation, all MRI parameters of allograft further decreased until POD7, and the D and ADC values in the cortex were significantly lower than that in the sTX group (1.03 ± 0.09 vs 1.52 ± 0.09 × 10-3 mm2/s, Padj < 0.05; 1.21 ± 0.03 vs 1.78 ± 0.07 × 10-3 mm2/s, Padj < 0.05). The D*, f and R2* values of the aTX group in the cortex and medulla were significantly lower than those in the sTX group on POD7 (cortex, D*: 25.60 ± 4.78 vs 69.32 ± 9.79 × 10-3 mm2/s, Padj < 0.05; f: 7.84 ± 1.83 vs 20.34 ± 3.08%, Padj < 0.05; R2*: 16.61 ± 4.18 vs 31.48 ± 6.43 1/s, Padj < 0.05; medulla, D*: 13.59 ± 6.08 vs 62.75 ± 9.20 × 10-3 mm2/s, Padj < 0.05; f: 7.46 ± 1.62 vs 14.68 ± 2.05%, Padj < 0.05; R2*: 21.59 ± 3.45 vs 39.53 ± 4.34 1/s, Padj < 0.05). AR grafts presented serve interstitial inflammation, tubulitis and infiltration of T-lymphocytes and macrophages. The MRI parameters, including D, ADC, D*, f and R2*, were significantly correlated with the histological changes, cell infiltration and inflammatory cytokine mRNA levels. CONCLUSIONS IVIM coupled with BOLD MRI allows longitudinal assessment of allograft diffusion, perfusion and oxygen consumption impairment caused by acute renal allograft rejection in rat model.
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Zheng L, Wang J, Gao W, Hu C, Wang S, Rong R, Guo Y, Zhu T, Zhu D. GC/MS-based urine metabolomics analysis of renal allograft recipients with acute rejection. J Transl Med 2018; 16:202. [PMID: 30029606 PMCID: PMC6053779 DOI: 10.1186/s12967-018-1584-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 07/17/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Acute renal allograft rejection is a common complication after renal transplantation that often leads to chronic rejection and ultimate graft loss. While renal allograft biopsy remains the gold standard for diagnosis of acute rejection, the possibility of biopsy-associated complications cannot be overlooked. The development of noninvasive methods for accurate detection of acute renal allograft rejection is thus of significant clinical importance. METHODS Gas chromatography-mass spectrometry (GC/MS) was employed for analysis of urine metabolites in 15 renal allograft recipients with acute rejection and 15 stable renal transplant recipients. Partial least squares (PLS) regression and leave-one-out analyses were performed to ascertain whether the metabolites identified could be exploited to distinguish acute rejection from stable groups as well as their sensitivity and specificity. RESULTS Overall, 14 metabolites were significantly altered in the acute rejection group (11 and 3 metabolites displayed higher and lower levels, respectively) relative to the stable transplant group. Data from PLS and leave-one-out analyses revealed that the differential metabolites identified not only distinguished acute rejection from stable transplant recipients but also showed high sensitivity and specificity for diagnosis of renal allograft recipients with acute rejection. CONCLUSION Urine metabolites identified with GC/MS can effectively distinguish acute rejection from stable transplant recipients, supporting the potential utility of metabolome analysis in non-invasive diagnosis of acute rejection.
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Affiliation(s)
- Long Zheng
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China
| | - Jina Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China
| | - Wenjun Gao
- Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China
| | - Chao Hu
- Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China
| | - Shuo Wang
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250000, Shandong, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Department of Blood Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yinlong Guo
- National Center for Organic Mass Spectrometry in Shanghai, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China.
| | - Dong Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China.
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14
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Renal scintigraphy for post-transplant monitoring after kidney transplantation. Transplant Rev (Orlando) 2018; 32:102-109. [DOI: 10.1016/j.trre.2017.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/30/2017] [Accepted: 12/18/2017] [Indexed: 01/22/2023]
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Abstract
KEY POINTS • The number of publications on imaging and kidney transplantation is low. • These publications are poorly cited, as compared with other fields of imaging. • Conversely, there is a clinical need for evidence-based recommendations. • Innovative advances for the use of imaging and kidney transplantation are essential. • An increased focus and adequate research funding are highly anticipated by clinicians.
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16
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Kentrup D, Bovenkamp P, Busch A, Schuette-Nuetgen K, Pawelski H, Pavenstädt H, Schlatter E, Herrmann KH, Reichenbach JR, Löffler B, Heitplatz B, Van Marck V, Yadav NN, Liu G, van Zijl PCM, Reuter S, Hoerr V. GlucoCEST magnetic resonance imaging in vivo may be diagnostic of acute renal allograft rejection. Kidney Int 2017; 92:757-764. [PMID: 28709641 DOI: 10.1016/j.kint.2017.04.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 03/20/2017] [Accepted: 04/06/2017] [Indexed: 11/29/2022]
Abstract
Acute cellular renal allograft rejection (AR) frequently occurs after kidney transplantations. It is a sterile T-cell mediated inflammation leading to increased local glucose metabolism. Here we demonstrate in an allogeneic model of Brown Norway rat kidneys transplanted into uninephrectomized Lewis rats the successful implementation of the recently developed glucose chemical exchange saturation transfer (glucoCEST) magnetic resonance imaging. This technique is a novel method to assess and differentiate AR. Renal allografts undergoing AR showed significantly increased glucoCEST contrast ratios of cortex to medulla of 1.61 compared to healthy controls (1.02), syngeneic Lewis kidney to Lewis rat transplants without rejection (0.92), kidneys with ischemia reperfusion injury (0.99) and kidneys affected by cyclosporine A toxicity (1.10). Receiver operating characteristic curve analysis showed an area under the curve value of 0.92, and the glucoCEST contrast ratio predicted AR with a sensitivity of 100% and a specificity of 69% at a threshold level over 1.08. In defined animal models of kidney injuries, the glucoCEST contrast ratios of cortex to medulla correlated positively with mRNA expression levels of T-cell markers (CD3, CD4, CD8a/b), but did not correlate to impaired renal perfusion. Thus, the glucoCEST parameter may be valuable for the assessment and follow up treatment of AR.
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Affiliation(s)
- Dominik Kentrup
- Medical Clinic D, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Philipp Bovenkamp
- Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Annika Busch
- Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | | | - Helga Pawelski
- Medical Clinic D, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Hermann Pavenstädt
- Medical Clinic D, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Eberhard Schlatter
- Medical Clinic D, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Karl-Heinz Herrmann
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller-University Jena, Philosophenweg 3, 07743 Jena, Germany
| | - Jürgen R Reichenbach
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller-University Jena, Philosophenweg 3, 07743 Jena, Germany
| | - Bettina Löffler
- Institute of Medical Microbiology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany
| | - Barbara Heitplatz
- Department of Pathology, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Veerle Van Marck
- Department of Pathology, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany
| | - Nirbhay N Yadav
- Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, Maryland 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, Maryland 21205, USA
| | - Guanshu Liu
- Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, Maryland 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, Maryland 21205, USA
| | - Peter C M van Zijl
- Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, Maryland 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, Maryland 21205, USA
| | - Stefan Reuter
- Medical Clinic D, University of Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany.
| | - Verena Hoerr
- Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer Campus 1, 48149 Muenster, Germany; Institute of Medical Microbiology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.
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17
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Hanssen O, Erpicum P, Lovinfosse P, Meunier P, Weekers L, Tshibanda L, Krzesinski JM, Hustinx R, Jouret F. 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. [PMID: 28643821 PMCID: PMC5469561 DOI: 10.1093/ckj/sfw062] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 06/02/2016] [Indexed: 12/18/2022] Open
Abstract
Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene expression profiling and omics analyses of blood and urine samples. Most imaging techniques, like contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leukocytes may be detectable by 18F-fluoro-deoxy-glucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3ε, IP-10 and 18S RNA levels, have been identified. None of these approaches has been adopted yet in the clinical follow-up of KTRs, but standardization of procedures may help assess reproducibility and compare diagnostic yields in large prospective multicentric trials.
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Affiliation(s)
- Oriane Hanssen
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), Avenue Hippocrate, 13, B-4000 Liège, Belgium
| | - Pauline Erpicum
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), Avenue Hippocrate, 13, B-4000 Liège, Belgium
- GIGA Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Pierre Lovinfosse
- Division of Nuclear Medicine, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - Paul Meunier
- Division of Radiology, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - Laurent Weekers
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), Avenue Hippocrate, 13, B-4000 Liège, Belgium
| | - Luaba Tshibanda
- Division of Radiology, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - Jean-Marie Krzesinski
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), Avenue Hippocrate, 13, B-4000 Liège, Belgium
- GIGA Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Roland Hustinx
- Division of Nuclear Medicine, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - François Jouret
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), Avenue Hippocrate, 13, B-4000 Liège, Belgium
- GIGA Cardiovascular Sciences, University of Liège, Liège, Belgium
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18
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The Uptake of 18F-FDG by Renal Allograft in Kidney Transplant Recipients Is Not Influenced by Renal Function. Clin Nucl Med 2017; 41:683-7. [PMID: 27405040 DOI: 10.1097/rlu.0000000000001298] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF THE REPORT F-FDG PET/CT has been recently proposed as a noninvasive tool for the diagnosis of renal allograft acute rejection (AR) in kidney transplant recipients (KTRs). Still, the influence of kidney function on F-FDG uptake by renal grafts remains unknown. PATIENTS AND METHODS We retrospectively identified all KTRs who underwent at least one F-FDG PET/CT. Kidney transplant recipients with documented pyelonephritis or AR were excluded. Estimated glomerular filtration rate (eGFR) was assessed using chronic kidney disease (CKD)-EPI equation. Mean standardized uptake values (SUVmean) of renal graft cortex and aorta were measured in 4 and 1 volumes of interest, respectively. Spearman rank correlation coefficient (ρ) and analysis of variance (ANOVA) were performed. RESULTS Eighty-two KTRs underwent F-FDG PET/CT for tumor staging (n = 46), suspected infection (n = 11), or fever of unknown origin (n = 25). Mean eGFR was 50 ± 19 mL/min per 1.73 m, including CKD stage 1 (n = 3), stage 2 (n = 21), stage 3a (n = 20), stage 3b (n = 29), and stage 4 (n = 9). Mean kidney and aorta SUVmean were 1.8 ± 0.2 and 1.7 ± 0.3, respectively. No significant correlation was observed between eGFR and kidney SUVmean (ρ, 0.119; P, 0.28) or aorta SUVmean (ρ, -0.144; P, 0.20). ANOVA showed no difference of kidney (P, 0.62) and aorta (P, 0.85) SUVmean between CKD groups. Mean coefficient of variation (on the basis of kidney SUVmean of >3 consecutive F-FDG PET/CT in 15 patients with no significant change of eGFR) reached 13.1%. CONCLUSIONS The uptake of F-FDG by renal allografts within an hour postinjection is not significantly impacted by CKD.
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19
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Grabner A, Kentrup D, Pawelski H, Mühlmeister M, Biermann C, Edemir B, Heitplatz B, Van Marck V, Bettinger T, Pavenstädt H, Schlatter E, Stypmann J, Tiemann K, Reuter S. Renal Contrast-Enhanced Sonography Findings in a Model of Acute Cellular Allograft Rejection. Am J Transplant 2016; 16:1612-9. [PMID: 26613381 DOI: 10.1111/ajt.13648] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 11/22/2015] [Indexed: 01/25/2023]
Abstract
Noninvasive methods to diagnose and differentiate acute cellular rejection from acute tubular necrosis or acute calcineurin inhibitor toxicity are still missing. Because T lymphocytes play a decisive role in early states of rejection, we investigated the suitability and feasibility of antibody-mediated contrast-enhanced ultrasound by using microbubbles targeted to CD3(+) , CD4(+) , or CD8(+) T cells in different models of renal disease. In an established rat renal transplantation model, CD3-mediated ultrasound allows the detection of acute rejection as early as on postoperative day 2. Ultrasound signal intensities increased with the severity of inflammation. Further, an early response to therapy could be monitored by using contrast-enhanced sonography. Notably, acute tubular necrosis occurring after ischemia-reperfusion injury as well as acute calcineurin inhibitor toxicity could easily be differentiated. Finally, the quantified ultrasound signal correlated significantly with the number of infiltrating T cells obtained by histology and with CD3 mRNA levels, as well as with chemokine CXCL9, CXCL11, and CCL19 mRNA but not with KIM-1 mRNA expression, thereby representing the severity of graft inflammation but not the degree of kidney injury. In summary, we demonstrate that antibody-mediated contrast-enhanced ultrasound targeting T lymphocytes could be a promising tool for an easy and reproducible assessment of acute rejection after renal transplantation.
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Affiliation(s)
- A Grabner
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - D Kentrup
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - H Pawelski
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - M Mühlmeister
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - C Biermann
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - B Edemir
- Department of Medicine, Hematology and Oncology, University of Halle, Halle, Germany
| | - B Heitplatz
- Department of Pathology, University of Münster, Münster, Germany
| | - V Van Marck
- Department of Pathology, University of Münster, Münster, Germany
| | | | - H Pavenstädt
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - E Schlatter
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - J Stypmann
- Department of Cardiovascular Medicine, University of Münster, Münster, Germany
| | - K Tiemann
- Department of Cardiology, Otypka Heart Center and Department of Nuclear Medicine, Technical University Munich, Munich, Germany
| | - S Reuter
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
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20
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Thölking G, Schuette-Nuetgen K, Kentrup D, Pawelski H, Reuter S. Imaging-based diagnosis of acute renal allograft rejection. World J Transplant 2016; 6:174-182. [PMID: 27011915 PMCID: PMC4801793 DOI: 10.5500/wjt.v6.i1.174] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 11/13/2015] [Accepted: 12/01/2015] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the "gold-standard". However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasound-based methods.
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21
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Hato T, Friedman AN, Mang H, Plotkin Z, Dube S, Hutchins GD, Territo PR, McCarthy BP, Riley AA, Pichumani K, Malloy CR, Harris RA, Dagher PC, Sutton TA. Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney. Am J Physiol Renal Physiol 2016; 310:F717-F725. [PMID: 26764206 DOI: 10.1152/ajprenal.00535.2015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 01/12/2016] [Indexed: 12/14/2022] Open
Abstract
The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-18fluoro-2-deoxyglucose (18F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals. Given emerging literature that the tumor suppressor protein p53 is an important regulator of cellular metabolism, we demonstrated that PET imaging was able to discern a threefold increase in cortical 18F-FDG uptake following the pharmacological inhibition of p53 in animals. Intravital MPM with the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) provided increased resolution and corroborated these findings at the level of the proximal tubule. Extending our observation of p53 inhibition on proximal tubule glucose tracer uptake, we demonstrated by intravital MPM that pharmacological inhibition of p53 diminishes mitochondrial potential difference. We provide additional evidence that inhibition of p53 alters key metabolic enzymes regulating glycolysis and increases intermediates of glycolysis. In summary, we provide evidence that PET is a valuable tool for examining kidney metabolism in preclinical and clinical studies, intravital MPM is a powerful adjunct to PET in preclinical studies of metabolism, and p53 inhibition alters basal kidney metabolism.
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Affiliation(s)
- Takashi Hato
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Allon N Friedman
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Henry Mang
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Zoya Plotkin
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Shataakshi Dube
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Gary D Hutchins
- Department of Radiology and Imaging Sciences and the Indiana Institute for Biomedical Imaging Sciences, Indiana University, Indianapolis, Indiana
| | - Paul R Territo
- Department of Radiology and Imaging Sciences and the Indiana Institute for Biomedical Imaging Sciences, Indiana University, Indianapolis, Indiana
| | - Brian P McCarthy
- Department of Radiology and Imaging Sciences and the Indiana Institute for Biomedical Imaging Sciences, Indiana University, Indianapolis, Indiana
| | - Amanda A Riley
- Department of Radiology and Imaging Sciences and the Indiana Institute for Biomedical Imaging Sciences, Indiana University, Indianapolis, Indiana
| | - Kumar Pichumani
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
| | - Craig R Malloy
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.,Departments of Internal Medicine and Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.,Veterans Affairs North Texas Health Care System, Dallas, Texas; and
| | - Robert A Harris
- Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana
| | - Pierre C Dagher
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Timothy A Sutton
- Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana;
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22
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Lovinfosse P, Weekers L, Bonvoisin C, Bovy C, Grosch S, Krzesinski JM, Hustinx R, Jouret F. Fluorodeoxyglucose F(18) Positron Emission Tomography Coupled With Computed Tomography in Suspected Acute Renal Allograft Rejection. Am J Transplant 2016; 16:310-6. [PMID: 26302136 DOI: 10.1111/ajt.13429] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Revised: 06/10/2015] [Accepted: 06/21/2015] [Indexed: 01/25/2023]
Abstract
Management of kidney transplant recipients (KTRs) with suspected acute rejection (AR) ultimately relies on kidney biopsy; however, noninvasive tests predicting nonrejection would help avoid unnecessary biopsy. AR involves recruitment of leukocytes avid for fluorodeoxyglucose F(18) ((18) F-FDG), thus (18) F-FDG positron emission tomography (PET) coupled with computed tomography (CT) may noninvasively distinguish nonrejection from AR. From January 2013 to February 2015, we prospectively performed 32 (18) F-FDG PET/CT scans in 31 adult KTRs with suspected AR who underwent transplant biopsy. Biopsies were categorized into four groups: normal (n = 8), borderline (n = 10), AR (n = 8), or other (n = 6, including 3 with polyoma BK nephropathy). Estimated GFR was comparable in all groups. PET/CT was performed 201 ± 18 minutes after administration of 3.2 ± 0.2 MBq/kg of (18) F-FDG, before any immunosuppression change. Mean standard uptake values (SUVs) of both upper and lower renal poles were measured. Mean SUVs reached 1.5 ± 0.2, 1.6 ± 0.3, 2.9 ± 0.8, and 2.2 ± 1.2 for the normal, borderline, AR, and other groups, respectively. One-way analysis of variance demonstrated a significant difference of mean SUVs among groups. A positive correlation between mean SUV and acute composite Banff score was found, with r(2) = 0.49. The area under the receiver operating characteristic curve was 0.93, with 100% sensitivity and 50% specificity using a mean SUV threshold of 1.6. In conclusion, (18) F-FDG PET/CT may help noninvasively prevent avoidable transplant biopsies in KTRs with suspected AR.
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Affiliation(s)
- P Lovinfosse
- Division of Nuclear Medicine, Department of Medical Physics, University of Liège Hospital, Liège, Belgium
| | - L Weekers
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
| | - C Bonvoisin
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
| | - C Bovy
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium.,Division of Renal Pathology, Unilab, University of Liège Hospital, Liège, Belgium
| | - S Grosch
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium.,Division of Renal Pathology, Unilab, University of Liège Hospital, Liège, Belgium
| | - J-M Krzesinski
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium.,Groupe Interdisciplinaire de Génoprotéomique Appliquée, Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - R Hustinx
- Division of Nuclear Medicine, Department of Medical Physics, University of Liège Hospital, Liège, Belgium
| | - F Jouret
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium.,Groupe Interdisciplinaire de Génoprotéomique Appliquée, Cardiovascular Sciences, University of Liège, Liège, Belgium
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23
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Khor YM, Lam WWC, Wong WY, Whatt Goh AS. Role of nuclear medicine imaging in evaluation of complications following renal transplant. PROCEEDINGS OF SINGAPORE HEALTHCARE 2015. [DOI: 10.1177/2010105815611813] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Evaluation of a failing renal allograft is a complex and challenging diagnostic problem. While ultrasonography with colour Doppler is usually the first approach for evaluation of graft dysfunction, radionuclide imaging is an excellent modality which provides complementary information regarding the perfusion and function of the allograft without any deleterious effect on the precious allograft. In this article, we review the imaging techniques of the nuclear medicine studies most commonly performed after renal transplant, discuss their roles and limitations in different clinical settings and illustrate with cases from our institution. Lastly, we will explore future development in the arena of nuclear imaging for renal transplant related complications.
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Affiliation(s)
- Yiu Ming Khor
- Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore
| | | | - Wai Yin Wong
- Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore
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24
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Hou J, Fujino M, Cai S, Ding Q, Li XK. Noninvasive monitoring of mouse renal allograft rejection using micro-CT. Ann Surg Treat Res 2015; 88:276-80. [PMID: 25960991 PMCID: PMC4422881 DOI: 10.4174/astr.2015.88.5.276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 10/27/2014] [Accepted: 10/28/2014] [Indexed: 11/30/2022] Open
Abstract
Purpose Acute renal graft rejection can only be definitively diagnosed by renal biopsy. However, biopsies carry a risk of renal transplant injury and loss. Micro-CT is widely used in preclinical studies of small animals. Here, we propose micro-CT could noninvasively monitor and evaluate renal location and function in a mouse kidney transplant model. Methods Orthotopic kidney transplantation was performed in a BALB/c -to- C57BL/6j or C57BL/6j-to- C57BL/6j mouse model. After optimizing imaging techniques, five mice were imaged with micro-CT and the findings were verified histologically. Results Micro-CT can monitor and evaluate renal location and function after orthotopic kidney transplantation. There were no mice deaths while renal transplants were failure. Conclusion We propose that graft micro-CT imaging is a new option that is noninvasive and specific, and can aid in early detection and follow-up of acute renal rejection. This method is potentially useful to improve posttransplant rejection monitoring.
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Affiliation(s)
- Jiangang Hou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China. ; Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Masayuki Fujino
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan. ; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Songjie Cai
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Qiang Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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25
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SPECT- and PET-based approaches for noninvasive diagnosis of acute renal allograft rejection. BIOMED RESEARCH INTERNATIONAL 2014; 2014:874785. [PMID: 24804257 PMCID: PMC3988725 DOI: 10.1155/2014/874785] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 03/04/2014] [Indexed: 11/18/2022]
Abstract
Molecular imaging techniques such as single
photon emission computed tomography (SPECT) or positron emission tomography are promising tools for noninvasive diagnosis of acute allograft rejection (AR). Given the importance of renal transplantation and the limitation of available donors, detailed analysis of factors that affect transplant survival is important. Episodes of acute allograft rejection are a negative prognostic factor for long-term graft survival. Invasive core needle biopsies are still the “goldstandard” in rejection diagnostics. Nevertheless, they are cumbersome to the patient and carry the risk of significant graft injury. Notably, they cannot be performed on patients taking anticoagulant drugs. Therefore, a noninvasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review SPECT- and PET-based approaches for noninvasive molecular imaging-based diagnostics of acute transplant rejection.
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Zöllner FG, Zimmer F, Klotz S, Hoeger S, Schad LR. Functional imaging of acute kidney injury at 3 Tesla: investigating multiple parameters using DCE-MRI and a two-compartment filtration model. Z Med Phys 2014; 25:58-65. [PMID: 24629306 DOI: 10.1016/j.zemedi.2014.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 01/10/2014] [Accepted: 01/10/2014] [Indexed: 11/28/2022]
Abstract
OBJECT To investigate how MR-based parameters reflect functional changes in kidneys with acute kidney injury (AKI) using dynamic contrast enhanced MRI and a two-compartment renal filtration model. MATERIALS AND METHODS MRI data of eight male Lewis rats were analyzed retrospectively. Five animals were subjected to AKI, three native rats served as control. All animals underwent perfusion imaging by dynamic contrast-enhanced MRI. Renal blood volume, glomerular filtration rate (GFR) as well as plasma and tubular mean transit times were estimated from regions-of-interest drawn in the renal cortex. Differences between healthy kidneys and kidneys subjected to AKI were analyzed using a paired t-test. RESULTS Significant differences between ischemic and healthy kidneys could only be detected for the glomerular filtration rate. For all other calculated parameters, differences were present, however not significant. In rats with AKI, average single kidney GFR was 0.66 ± 0.37 ml/min for contralateral and 0.26 ± 0.12 ml/ min for diseased kidneys (P = 0.0254). For the healthy control group, the average GFR was 0.39 ± 0.06 ml/min and 0.41 ± 0.11 ml/min, respectively. Differences between diseased kidneys of AKI rats and ipsilateral kidneys of the healthy control group were significant (P = 0.0381). CONCLUSION Significant differences of functional parameters reflecting damage of the renal tissue of kidneys with AKI compared to the contralateral, healthy kidneys could only be detected by GFR. GFR might be a useful parameter that allows for a spatially resolved detection of abnormal changes of renal tissue by AKI.
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Affiliation(s)
- Frank G Zöllner
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - Fabian Zimmer
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sarah Klotz
- Department of Medicine V, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Simone Hoeger
- Department of Medicine V, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Lothar R Schad
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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27
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Zöllner FG, Schock-Kusch D, Bäcker S, Neudecker S, Gretz N, Schad LR. Simultaneous measurement of kidney function by dynamic contrast enhanced MRI and FITC-sinistrin clearance in rats at 3 tesla: initial results. PLoS One 2013; 8:e79992. [PMID: 24260332 PMCID: PMC3832374 DOI: 10.1371/journal.pone.0079992] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 10/02/2013] [Indexed: 11/19/2022] Open
Abstract
Glomerular filtration rate (GFR) is an essential parameter of kidney function which can be measured by dynamic contrast enhanced magnetic resonance imaging (MRI-GFR) and transcutaneous approaches based on fluorescent tracer molecules (optical-GFR). In an initial study comparing both techniques in separate measurements on the same animal, the correlation of the obtained GFR was poor. The goal of this study was to investigate if a simultaneous measurement was feasible and if thereby, the discrepancies in MRI-GFR and optical-GFR could be reduced. For the experiments healthy and unilateral nephrectomised (UNX) Sprague Dawley (SD) rats were used. The miniaturized fluorescent sensor was fixed on the depilated back of an anesthetized rat. A bolus of 5 mg/100 g b.w. of FITC-sinistrin was intravenously injected. For dynamic contrast enhanced perfusion imaging (DCE-MRI) a 3D time-resolved angiography with stochastic trajectories (TWIST) sequence was used. By means of a one compartment model the excretion half-life (t1/2) of FITC-sinistrin was calculated and converted into GFR. GFR from DCE-MRI was calculated by fitting pixel-wise a two compartment renal filtration model. Mean cortical GFR and GFR by FITC-sinistrin were compared by Bland-Altman plots and pair-wise t-test. Results show that a simultaneous GFR measurement using both techniques is feasible. Mean optical-GFR was 4.34 ± 2.22 ml/min (healthy SD rats) and 2.34 ± 0.90 ml/min (UNX rats) whereas MRI-GFR was 2.10 ± 0.64 ml/min (SD rats) and 1.17 ± 0.38 ml/min (UNX rats). Differences between healthy and UNX rats were significant (p<0.05) and almost equal percentage difference (46.1% and 44.3%) in mean GFR were assessed with both techniques. Overall mean optical-GFR values were approximately twice as high compared to MRI-GFR values. However, compared to a previous study, our results showed a higher agreement. In conclusion, the possibility to use the transcutaneous method in MRI may have a huge impact in improving and validating MRI methods for GFR assessment in animal models.
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Affiliation(s)
- Frank G. Zöllner
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- * E-mail:
| | - Daniel Schock-Kusch
- Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sandra Bäcker
- Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sabine Neudecker
- Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Norbert Gretz
- Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lothar R. Schad
- Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Abstract
Kidney transplantation can be associated with various complications that vary from vascular complications to urologic disorders to immunologic adverse effects. In evaluating the recipient with graft dysfunction, clinicians can choose among several imaging modalities, including ultrasonography, nuclear medicine studies, computed tomography, and magnetic resonance imaging. This review discusses the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality. A kidney biopsy is often required as a gold standard for diagnostic purposes. However, because of the inherent risks of a kidney biopsy, noninvasive imaging in diagnosing causes of graft dysfunction is a highly desired tool used and needed by the transplant community. Because the diagnostic accuracy varies depending on the time course and nature of the transplant-related complication, this review also addresses the advantages and limitations of each modality. The recent advances in kidney transplant imaging techniques and their clinical implications are also discussed.
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Affiliation(s)
- Asif Sharfuddin
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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29
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Grabner A, Kentrup D, Edemir B, Sirin Y, Pavenstädt H, Schlatter E, Schober O, Schäfers M, Schnöckel U, Reuter S. PET with 18F-FDG-labeled T lymphocytes for diagnosis of acute rat renal allograft rejection. J Nucl Med 2013; 54:1147-53. [PMID: 23670903 DOI: 10.2967/jnumed.112.109231] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
UNLABELLED We proposed small-animal PET with (18)F-FDG-labeled T lymphocytes as a new method for image-based diagnosis of acute allogeneic renal transplant rejection (AR) established in a rat model. METHODS One and 2 h after tail vein injection of 30 × 10(6) ex vivo (18)F-FDG-labeled human T cells into male 10-wk-old uninephrectomized, allogeneically transplanted rats (aTX; Lewis-brown Norway [LBN] to Lewis), whole-body radioactivity distribution was assessed in vivo by small-animal PET (postoperative day 4), and percentage injected dose (%ID) as a parameter of T-cell infiltration was assessed and compared between graft and native kidney. In vivo results were confirmed by autoradiography and staining of human CD3 after postmortem dissection. Syngeneically transplanted rats (sTX) (LBN to LBN), rats with ischemia-reperfusion injury (IRI) (45-min warm ischemia), and rats subjected to acute cyclosporine A (CSA) toxicity (50 mg/kg for 2 d intraperitoneally) served as controls. RESULTS The accumulation of labeled cells was significantly elevated in allografts with AR (1.07 ± 0.28 %ID), compared with native control kidneys (0.49 ± 0.18 %ID) (P < 0.0001). No differences were found among native controls, sTX, CSA toxicity, and kidneys with IRI. In vivo uptake of (18)F-FDG cells measured in the PET scanner correlated with results obtained by autoradiography, histologic evaluation, and polymerase chain reaction. CONCLUSION We proposed graft PET imaging using (18)F-FDG-labeled T cells as a new option to detect rat renal AR with a low dose of (18)F-FDG in a noninvasive, fast, and specific manner in rats.
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Affiliation(s)
- Alexander Grabner
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
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Okusa MD, Jaber BL, Doran P, Duranteau J, Yang L, Murray PT, Mehta RL, Ince C. Physiological biomarkers of acute kidney injury: a conceptual approach to improving outcomes. CONTRIBUTIONS TO NEPHROLOGY 2013; 182:65-81. [PMID: 23689656 DOI: 10.1159/000349967] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The past 5-10 years have brought significant advances in the identification and validation of novel biochemical biomarkers in the prevention and treatment of acute kidney injury (AKI). These biochemical biomarkers remain research tools but we anticipate that soon they will be employed in clinical practice. A Consensus Conference held by the Acute Dialysis Quality Initiative (ADQI) recently reviewed the evidence, and identified gaps and a research agenda. Furthermore, at this meeting was the birth of an initiative to comprehensively identify new opportunities to characterize the physiological changes during the course of AKI based upon a conceptual framework for the detection and monitoring of renal ischemia-reperfusion injury. This framework includes a transition from monitoring physiological biomarkers of adequate renal perfusion, to pathophysiologic biomarkers of renal hypoperfusion, and finally biomarkers of kidney cell structural injury/damage. Techniques to measure physiological changes in AKI include several physiological variables that might be used in an interactive way to supplement clinical information and biochemical damage biomarkers in the diagnosis and management of AKI. This review summarizes the spectrum of physiological parameters and potential new physiological methods that enable identification of high-risk patients for AKI, facilitate early diagnosis, and differential diagnosis to guide therapeutic management and prognostication. Finally, we propose a research agenda for the next 5 years to facilitate the development and validation of physiological biomarkers in AKI.
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Affiliation(s)
- Mark D Okusa
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Va., USA.
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Bettenworth D, Reuter S, Hermann S, Weckesser M, Kerstiens L, Stratis A, Nowacki TM, Ross M, Lenze F, Edemir B, Maaser C, Pap T, Koschmieder S, Heidemann J, Schäfers M, Lügering A. Translational 18F-FDG PET/CT imaging to monitor lesion activity in intestinal inflammation. J Nucl Med 2013; 54:748-755. [PMID: 23516311 DOI: 10.2967/jnumed.112.112623] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
UNLABELLED In patients with inflammatory bowel disease (IBD) and in murine IBD models, mucosal disease activity is routinely assessed by endoscopy and histologic evaluation. This information is valuable for monitoring treatment response, with mucosal healing being a major treatment goal. The aim of this study was to evaluate the translational potential of noninvasive (18)F-FDG PET/CT for the assessment of mucosal damage in murine dextran sodium sulfate (DSS) colitis and human IBD. METHODS After induction of DSS colitis, (18)F-FDG uptake was serially assessed from colonic volumes of interest defined on PET/CT scans and intraindividually correlated to histologic findings and to infiltrating cell types. In addition, (18)F-FDG PET/CT scans of 25 Crohn disease patients were analyzed, and colonic (18)F-FDG uptake was correlated to endoscopically assessed damage. RESULTS At days 4 and 7 after DSS induction, colonic (18)F-FDG uptake was significantly increased, with a distinct peak in the medial colon. (18)F-FDG uptake strongly correlated with histologic epithelial damage. Additionally, (18)F-FDG uptake increased in the bone marrow in the course of the disease, correlating with an increase in intestinal (18)F-FDG uptake. Histology and fluorescence-activated cell sorting analysis of the bone marrow of DSS mice revealed an increased number of immature neutrophils, whereas mucosal polymerase chain reaction suggested a correlation of (18)F-FDG uptake to T cell infiltration. In accordance with the results of (18)F-FDG PET/CT in DSS colitis, an increased (18)F-FDG uptake was found in 87% of deep mucosal ulcerations in IBD patients, whereas mild endoscopic lesions were detected only by (18)F-FDG PET/CT in about 50% of patients assessed. CONCLUSION (18)F-FDG PET/CT is a noninvasive method for evaluation of both experimental colitis and Crohn disease patients and thereby offers promising translational potential.
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Grabner A, Kentrup D, Schnöckel U, Gabriëls G, Schröter R, Pavenstädt H, Schober O, Schlatter E, Schäfers M, Reuter S. Non-invasive imaging of acute allograft rejection after rat renal transplantation using 18F-FDG PET. J Vis Exp 2013:e4240. [PMID: 23644348 DOI: 10.3791/4240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The number of patients with end-stage renal disease, and the number of kidney allograft recipients continuously increases. Episodes of acute cellular allograft rejection (AR) are a negative prognostic factor for long-term allograft survival, and its timely diagnosis is crucial for allograft function (1). At present, AR can only be definitely diagnosed by core-needle biopsy, which, as an invasive method, bares significant risk of graft injury or even loss. Moreover, biopsies are not feasible in patients taking anticoagulant drugs and the limited sampling site of this technique may result in false negative results if the AR is focal or patchy. As a consequence, this gave rise to an ongoing search for new AR detection methods, which often has to be done in animals including the use of various transplantation models. Since the early 60s rat renal transplantation is a well-established experimental method for the examination and analysis of AR (2). We herein present in addition small animal positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) to assess AR in an allogeneic uninephrectomized rat renal transplantation model and propose graft FDG-PET imaging as a new option for a non-invasive, specific and early diagnosis of AR also for the human situation (3). Further, this method can be applied for follow-up to improve monitoring of transplant rejection (4).
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Affiliation(s)
- Alexander Grabner
- Department of Internal Medicine D, Experimental Nephrology, University of Münster.
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Abstract
Renal transplantation is nowadays accepted as the treatment of choice for patients with end-stage renal disease. However, despite progress in immunosuppression and surgical techniques, various complications still can occur. Complications vary from vascular disorders and urologic diseases to parenchymal and immunologically related complications. The clinician evaluating the recipient with graft dysfunction has the option of choosing among a variety of imaging modalities including ultrasonography, nuclear medicine, computed tomography, and magnetic resonance imaging to start or continue the diagnostic work-up. In this article, we discuss the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality.
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Affiliation(s)
- Asif Sharfuddin
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Kentrup D, Reuter S, Schnöckel U, Grabner A, Edemir B, Pavenstädt H, Schober O, Schäfers M, Schlatter E, Büssemaker E. Hydroxyfasudil-mediated inhibition of ROCK1 and ROCK2 improves kidney function in rat renal acute ischemia-reperfusion injury. PLoS One 2011; 6:e26419. [PMID: 22031832 PMCID: PMC3198766 DOI: 10.1371/journal.pone.0026419] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 09/26/2011] [Indexed: 11/18/2022] Open
Abstract
Renal ischemia-reperfusion (IR) injury (IRI) is a common and important trigger of acute renal injury (AKI). It is inevitably linked to transplantation. Involving both, the innate and the adaptive immune response, IRI causes subsequent sterile inflammation. Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity. Considering the important role of cytoskeletal reorganization, mainly regulated by RhoGTPases, in the development of IRI we hypothesized that a preventive, selective inhibition of the Rho effector Rho-associated coiled coil containing protein kinase (ROCK) by hydroxyfasudil may improve renal IRI outcome. Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals. In addition, renal perfusion (as assessed by 18F-fluoride Positron Emission Tomography (PET)), creatinine- and urea-clearances improved significantly. Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, 18F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis. We conclude from our study that ROCK-inhibition by hydroxyfasudil significantly improves kidney function in a rat model of acute renal IRI and is therefore a potential new therapeutic option in humans.
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Affiliation(s)
- Dominik Kentrup
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - Stefan Reuter
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - Uta Schnöckel
- Department of Nuclear Medicine, University of Münster, Münster, Germany
| | - Alexander Grabner
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - Bayram Edemir
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - Hermann Pavenstädt
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - Otmar Schober
- Department of Nuclear Medicine, University of Münster, Münster, Germany
| | - Michael Schäfers
- European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Eberhard Schlatter
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - Eckhart Büssemaker
- Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
- Dialysis Unit Hamm, Hamm, Germany
- * E-mail:
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Lisanti MP, Martinez-Outschoorn UE, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs "fertilizer". Cell Cycle 2011; 10:2440-9. [PMID: 21734470 PMCID: PMC3180186 DOI: 10.4161/cc.10.15.16870] [Citation(s) in RCA: 173] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 06/18/2011] [Indexed: 01/13/2023] Open
Abstract
In 1889, Dr. Stephen Paget proposed the "seed and soil" hypothesis, which states that cancer cells (the seeds) need the proper microenvironment (the soil) for them to grow, spread and metastasize systemically. In this hypothesis, Dr. Paget rightfully recognized that the tumor microenvironment has an important role to play in cancer progression and metastasis. In this regard, a series of recent studies have elegantly shown that the production of hydrogen peroxide, by both cancer cells and cancer-associated fibroblasts, may provide the necessary "fertilizer," by driving accelerated aging, DNA damage, inflammation and cancer metabolism, in the tumor microenvironment. By secreting hydrogen peroxide, cancer cells and fibroblasts are mimicking the behavior of immune cells (macrophages/neutrophils), driving local and systemic inflammation, via the innate immune response (NFκB). Thus, we should consider using various therapeutic strategies (such as catalase and/or other anti-oxidants) to neutralize the production of cancer-associated hydrogen peroxide, thereby preventing tumor-stroma co-evolution and metastasis. The implications of these findings for overcoming chemo-resistance in cancer cells are also discussed in the context of hydrogen peroxide production and cancer metabolism.
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Affiliation(s)
- Michael P Lisanti
- The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
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Martinez-Outschoorn UE, Lin Z, Trimmer C, Flomenberg N, Wang C, Pavlides S, Pestell RG, Howell A, Sotgia F, Lisanti MP. Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle 2011; 10:2504-20. [PMID: 21778829 DOI: 10.4161/cc.10.15.16585] [Citation(s) in RCA: 259] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Previously, we proposed that cancer cells behave as metabolic parasites, as they use targeted oxidative stress as a "weapon" to extract recycled nutrients from adjacent stromal cells. Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis, and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the "reverse Warburg effect." To further test the validity of this hypothesis, here we used an in vitro MCF7-fibroblast co-culture system, and quantitatively measured a variety of metabolic parameters by FACS analysis (analogous to laser-capture micro-dissection). Mitochondrial activity, glucose uptake, and ROS production were measured with highly-sensitive fluorescent probes (MitoTracker, NBD-2-deoxy-glucose, and DCF-DA). Interestingly, using this approach, we directly show that cancer cells initially secrete hydrogen peroxide that then triggers oxidative stress in neighboring fibroblasts. Thus, oxidative stress is contagious (spreads like a virus) and is propagated laterally and vectorially from cancer cells to adjacent fibroblasts. Experimentally, we show that oxidative stress in cancer-associated fibroblasts quantitatively reduces mitochondrial activity, and increases glucose uptake, as the fibroblasts become more dependent on aerobic glycolysis. Conversely, co-cultured cancer cells show significant increases in mitochondrial activity, and corresponding reductions in both glucose uptake and GLUT1 expression. Pre-treatment of co-cultures with extracellular catalase (an anti-oxidant enzyme that detoxifies hydrogen peroxide) blocks the onset of oxidative stress, and potently induces the death of cancer cells, likely via starvation. Given that cancer-associated fibroblasts show the largest increases in glucose uptake, we suggest that PET imaging of human tumors, with Fluoro-2-deoxy-D-glucose (F-2-DG), may be specifically detecting the tumor stroma, rather than epithelial cancer cells.
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Affiliation(s)
- Ubaldo E Martinez-Outschoorn
- The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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Reuter S, Schnöckel U, Edemir B, Schröter R, Kentrup D, Pavenstädt H, Schober O, Schlatter E, Gabriëls G, Schäfers M. Potential of noninvasive serial assessment of acute renal allograft rejection by 18F-FDG PET to monitor treatment efficiency. J Nucl Med 2010; 51:1644-52. [PMID: 20847180 DOI: 10.2967/jnumed.110.078550] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED We propose (18)F-FDG PET as a method to monitor acute rejection of allogeneic renal transplants in a rat model. METHODS Allogeneically transplanted (aTX) rats (binephrectomized Lewis-brown Norway to Lewis) served as the renal transplant model. aTX rats treated with cyclosporine A (CSA) served as a therapy monitoring group. Healthy control rats, rats with acute CSA nephrotoxicity, rats with acute tubular necrosis, syngeneically transplanted (sTX) rats, and aTX rats treated with CSA since postoperative day 0 served as controls. After surgery, renal glucose metabolism was assessed in vivo serially up to postoperative day 7 by performing small-animal PET 3 h after intravenous injection of 30 MBq of (18)F-FDG. Mean radioactivity (cps/mm(3) of tissue) was measured and the percentage injected dose calculated. Results were confirmed by histologic, functional, and autoradiographic analysis. RESULTS Renal (18)F-FDG uptake was significantly elevated at postoperative day 4 in aTX rats, when compared with control, sTX, acute tubular necrosis, or CSA-treated rats (P < 0.05). In vivo (18)F-FDG uptake correlated with the results of autoradiography and with inflammatory infiltrates observed on histologic examination. Notably, (18)F-FDG PET assessed the response to therapy 48 h earlier than the time at which serum creatinine decreased and when histologic examination still showed signs of allograft rejection. In aTX rats, the CSA-susceptible graft infiltrate was dominated by activated cytotoxic T cells and monocytes/macrophages. CONCLUSION (18)F-FDG PET is an option to noninvasively assess early response to therapy in rat renal allograft rejection.
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Affiliation(s)
- Stefan Reuter
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany.
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