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Shyn PB, Patel MD, Itani M, Gupta AC, Burgan CM, Planz V, Galgano SJ, Lamba R, Raman SS, Yoshikawa MH. Image-guided renal parenchymal biopsies- how we do it. Abdom Radiol (NY) 2025; 50:2595-2605. [PMID: 39585376 DOI: 10.1007/s00261-024-04690-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/26/2024]
Abstract
This paper is a multi-institutional review of image-guided renal parenchymal biopsies. Among the topics covered are indications, preprocedural considerations, biopsy technique, complications, and postprocedural management. Both native kidney and transplant kidney biopsies are considered in this review.
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Affiliation(s)
- Paul B Shyn
- Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
| | | | - Malak Itani
- Washington University in St. Louis, St Louis, USA
| | | | | | | | | | | | - Steven S Raman
- David Geffen School of Medicine at UCLA, Los Angeles, USA
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2
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Liu J, Cheng P, Xu C, Pu K. Molecular probes for in vivo optical imaging of immune cells. Nat Biomed Eng 2025; 9:618-637. [PMID: 39984703 DOI: 10.1038/s41551-024-01275-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/23/2024] [Indexed: 02/23/2025]
Abstract
Advancing the understanding of the various roles and components of the immune system requires sophisticated methods and technology for the detection of immune cells in their natural states. Recent advancements in the development of molecular probes for optical imaging have paved the way for non-invasive visualization and real-time monitoring of immune responses and functions. Here we discuss recent progress in the development of molecular probes for the selective imaging of specific immune cells. We emphasize the design principles of the probes and their comparative performance when using various optical modalities across disease contexts. We highlight molecular probes for imaging tumour-infiltrating immune cells, and their applications in drug screening and in the prediction of therapeutic outcomes of cancer immunotherapies. We also discuss the use of these probes in visualizing immune cells in atherosclerosis, lung inflammation, allograft rejection and other immune-related conditions, and the translational opportunities and challenges of using optical molecular probes for further understanding of the immune system and disease diagnosis and prognosis.
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Affiliation(s)
- Jing Liu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
| | - Penghui Cheng
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
| | - Cheng Xu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
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Expert Panel on Urological Imaging, Taffel MT, Khatri G, Purysko AS, Avery R, Caserta MP, Chang SD, De Leon AD, Ganeshan D, Gupta RT, Lew SQ, Lyshchik A, Nicola R, Piel C, Sener A, Smith AD, Nikolaidis P. ACR Appropriateness Criteria® Renal Transplant Dysfunction: 2024 Update. J Am Coll Radiol 2025; 22:S372-S395. [PMID: 40409889 DOI: 10.1016/j.jacr.2025.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 05/25/2025]
Abstract
Renal transplantation remains the treatment of choice in patients with end-stage renal disease as the 5-year survival rates for the graft in renal transplant patients range from 72% to 99%. Despite improvements in graft survival related to increased efficacy of immunosuppression drugs and improvements in surgical technique, various complications do occur. Ultrasound is the first-line imaging modality for the evaluation of renal transplants in the immediate postoperative period and for longitudinal follow-up. Various other imaging techniques serve as complementary examinations in specific clinical settings. Angiography remains the reference standard for arterial complications and is used for nonsurgical intervention, but noninvasive CT or MR angiography could be considered prior to an invasive procedure. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.
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Affiliation(s)
| | - Myles T Taffel
- New York University Langone Medical Center, New York, New York.
| | - Gaurav Khatri
- Panel Chair, UT Southwestern Medical Center, Dallas, Texas
| | | | - Ryan Avery
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Commission on Nuclear Medicine and Molecular Imaging
| | | | - Silvia D Chang
- University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | - Rajan T Gupta
- Duke University Medical Center, Durham, North Carolina
| | - Susie Q Lew
- George Washington University, Washington, District of Columbia; American Society of Nephrology
| | - Andrej Lyshchik
- Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | - Refky Nicola
- SUNY Upstate Medical University, Syracuse, New York
| | - Carl Piel
- UT Southwestern Medical Center, Dallas, Texas; American College of Emergency Physicians
| | - Alp Sener
- Western University, London, Ontario, Canada; American Urological Association
| | - Andrew D Smith
- University of Alabama at Birmingham, Birmingham, Alabama
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Kawazoe T, Tanaka A, Furuhashi K, Hattori K, Onogi C, Owaki A, Kato A, Watanabe Y, Koshi-Ito E, Kato N, Kosugi T, Sano Y, Ishida S, Maruyama S. Urinary presepsin can efficiently detect T-cell-mediated rejection in patients who have undergone kidney transplantation. Clin Exp Nephrol 2025:10.1007/s10157-025-02672-1. [PMID: 40186650 DOI: 10.1007/s10157-025-02672-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Urinary presepsin (uPSEP) is a marker of tubular interstitial injury. For patients who have undergone kidney transplantation, the early diagnosis of rejection is important to early treatment and preservation of the transplanted kidney function. We investigated whether uPSEP is useful for predicting T-cell-mediated rejection (TCMR). Patients who underwent graft biopsy in 2020 and 2023 after kidney transplantation at our hospital were included. We excluded protocol biopsy samples obtained at 1 h. We measured uPSEP and divided the patients into groups based on the presence or absence of TCMR; then, group comparisons were performed. A total of 39 patients (17 female and 22 male patients) with a median age of 57 years (interquartile range [IQR], 46.5-63 years) at the time of biopsy were included. Thirty-one patients underwent protocol biopsies and eight underwent episode biopsies. TCMR occurred in three patients. The uPSEP value of the TCMR group was 6788.63 ng/gCr (IQR, 5374.57-9931.87 ng/gCr), and that of the non-TCMR group was 777.61 ng/gCr (IQR, 321.57-1299.63 ng/gCr) (P < 0.01). The receiver-operating characteristic curve for predicting TCMR had a cutoff value of 3961 ng/gCr and an area under the curve of 0.982 (95% confidence interval [CI], 0.942-1). The odds ratio of TCMR based on uPSEP (per 1000-ng/gCr increase in uPSEP) was 1.90 (95% CI, 1.10-3.28; P = 0.02). uPSEP levels may predict TCMR with high accuracy.
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Affiliation(s)
- Tomohiro Kawazoe
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Akihito Tanaka
- Department of Nephrology, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Kazuhiro Furuhashi
- Department of Nephrology, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan.
| | - Keita Hattori
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Chikao Onogi
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Akiko Owaki
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Akihisa Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Yu Watanabe
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Eri Koshi-Ito
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Noritoshi Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Yuta Sano
- Department of Urology, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Shohei Ishida
- Department of Urology, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya-City, Aichi, 466-8550, Japan
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Weidmann L, Harmacek D, Castrezana Lopez K, Helmchen BM, Gaspert A, Korach R, Bortel N, Schmid N, von Moos S, Rho E, Schachtner T. Limitations of biopsy-based transcript diagnostics to detect T-cell-mediated allograft rejection. Nephrol Dial Transplant 2025; 40:294-307. [PMID: 38925651 PMCID: PMC11852332 DOI: 10.1093/ndt/gfae147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Isolated tubulitis, borderline changes and isolated arteritis suspicious for histologic T-cell-mediated rejection (hTCMR) remain findings of uncertain significance. Although the Molecular Microscope Diagnostics System (MMDx) has not been trained on those lesions, it was suggested that MMDx might reclassify a subgroup to molecular TCMR (mTCMR). METHODS In this single-center cohort of 326 consecutive, unselected kidney allograft biopsies assessed by histology and MMDx, we analyzed 249 cases with isolated tubulitis (i0, t1-3, v0; n = 101), borderline changes (according to Banff 2022, v0; n = 9), isolated arteritis (no borderline, v1; n = 37), no inflammation (i0, t0, v0; n = 67) and a positive control cohort (hTCMR, n = 27; mixed histologic rejection, n = 8; both according to Banff 2022; total n = 35). The first three groups were summarized as TCMR-suspicion (n = 147). Subcategorization included the presence and absence of microvascular inflammation (MVI); g+ptc ptc ≥2. Molecular rejection rates and differentiation were investigated. RESULTS Molecular rejection rates were 37/147 cases (25.2%; 32 with MVI) in TCMR-suspicion, 6/67 (9%; 4 with MVI) in no inflammation and 30/35 (85.7%; 19 with MVI) in the positive control cohort. Molecular antibody-mediated rejection (mAMR) was present in 39/73 (53.4%) of cases. The presence of donor-specific antibodies at the time of the biopsy was high (127/249, 51%). Only 3 mAMR/TCMR and 0 pure mTCMR cases were detected in TCMR-suspicion and no inflammation, compared with 12 mAMR/TCMR and 10 mTCMR cases in the positive control cohort (P < .001). Even though the TCMR-specific molecular (Classifier) score differentiated between TCMR-suspicion and no inflammation (P = 0.005), rejection phenotype scores (R2 and R3) did not (P = .157 and .121). CONCLUSIONS MMDx did not identify pure mTCMR among isolated tubulitis, borderline changes or isolated arteritis, likely due to low sensitivity for TCMR lesions. However, it identified mAMR or mAMR/TCMR, especially in cases with MVI. Subthreshold findings remain to be further studied.
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Affiliation(s)
- Lukas Weidmann
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | - Dusan Harmacek
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | | | - Birgit Maria Helmchen
- University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
| | - Ariana Gaspert
- University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
| | - Raphael Korach
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | - Nicola Bortel
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | - Nicolas Schmid
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | - Seraina von Moos
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | - Elena Rho
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
| | - Thomas Schachtner
- University Hospital Zurich, Department of Nephrology, Zurich, Switzerland
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Shao J, Zhao X, Tang P, Chen B, Xu B, Lu H, Qin Z, Wu C. Label-free investigation of infected acute pyelonephritis tissue by FTIR microspectroscopy with unsupervised and supervised analytical methods. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 321:124753. [PMID: 38963949 DOI: 10.1016/j.saa.2024.124753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/13/2024] [Accepted: 06/27/2024] [Indexed: 07/06/2024]
Abstract
Acute pyelonephritis (AP) is a severe urinary tract infection (UTI) syndrome with a large population of patients worldwide. Current approaches to confirming AP are limited to urinalysis, radiological imaging methods and histological assessment. Fourier transform infrared (FTIR) microspectroscopy is a promising label-free modality that can offer information about both morphological and molecular pathologic alterations from biological tissues. Here, FTIR microspectroscopy serves to investigate renal biological histology of a rat model with AP and classify normal cortex, normal medulla and infected acute pyelonephritis tissues. The spectra were experimentally collected by FTIR with an infrared Globar source through raster scanning procedure. Unsupervised analysis methods, including integrating, clustering and principal component analysis (PCA) were performed on such spectra data to form infrared histological maps of entire kidney section. In comparison to Hematoxylin & Eosin-stained results of the adjacent tissue sections, these infrared maps were proved to enable the differentiation of the renal tissue types. The results of both integration and clustering indicated that the concentration of amide II decreases in the infected acute pyelonephritis tissues, with an increased presence of nucleic acids and lipids. By means of PCA, the infected tissue was linearly separated from normal ones by plotting confident ellipses with the score values of the first and second principal components. Moreover, supervised analysis was performed based on the supported vector machines (SVM). Normal cortex, normal medulla and infected acute pyelonephritis tissues were classified by SVM models with the best accuracy of 96.11% in testing dataset. In addition, these analytical methods were further employed on synchrotron-based FTIR spectra data and successfully form high-resolution infrared histological maps of glomerulus and necrotic cell mass. This work demonstrates that FTIR microspectroscopy will be a powerful manner to investigate AP tissue and differentiate infected tissue from normal tissue in a renal infected model system.
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Affiliation(s)
- Jingzhu Shao
- Center for Biophotonics, Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangyu Zhao
- Center for Biophotonics, Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Ping Tang
- Center for Biophotonics, Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Bo Chen
- Center for Biophotonics, Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Borui Xu
- Center for Biophotonics, Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Han Lu
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen Qin
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Chongzhao Wu
- Center for Biophotonics, Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Wuhan National Laboratory for Optoelectronics, Hubei, China.
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Lee S, Kim JM, Lee K, Cho H, Shin S, Kim JK. Diagnosis and classification of kidney transplant rejection using machine learning-assisted surface-enhanced Raman spectroscopy using a single drop of serum. Biosens Bioelectron 2024; 261:116523. [PMID: 38924813 DOI: 10.1016/j.bios.2024.116523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/13/2024] [Accepted: 06/23/2024] [Indexed: 06/28/2024]
Abstract
The quest to reduce kidney transplant rejection has emphasized the urgent requirement for the development of non-invasive, precise diagnostic technologies. These technologies aim to detect antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR), which are asymptomatic and pose a risk of potential kidney damage. The protocols for managing rejection caused by ABMR and TCMR differ, and diagnosis has traditionally relied on invasive biopsy procedures. Therefore, a convergence system using a nano-sensing chip, Raman spectroscopy, and AI technology was introduced to facilitate diagnosis using serum samples obtained from patients with no major abnormality, ABMR, and TCMR after kidney transplantation. Tissue biopsy and Banff score analysis were performed across the groups for validation, and 5 μL of serum obtained at the same time was added onto the Au-ZnO nanorod-based Surface-Enhanced Raman Scattering sensing chip to obtain Raman spectroscopy signals. The accuracy of machine learning algorithms for principal component-linear discriminant analysis and principal component-partial least squares discriminant analysis was 93.53% and 98.82%, respectively. The collagen (an indicative of kidney injury), creatinine, and amino acid-derived signals (markers of kidney function) contributed to this accuracy; however, the high accuracy was primarily due to the ability of the system to analyze a broad spectrum of various biomarkers.
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Affiliation(s)
- Sanghwa Lee
- Department of Convergence Medicine, Asan Institute for Life Science, Asan Medical Center, Seoul, 05505, South Korea
| | - Jin-Myung Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Kwanhee Lee
- Department of Biomedical Engineering, Brain Korea 21 Project, University of Ulsan, College of Medicine, Seoul, 05505, South Korea
| | - Haeyon Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Sung Shin
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
| | - Jun Ki Kim
- Department of Convergence Medicine, Asan Institute for Life Science, Asan Medical Center, Seoul, 05505, South Korea; Department of Biomedical Engineering, Brain Korea 21 Project, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
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Wiśnicki K, Donizy P, Kuriata-Kordek M, Uchmanowicz I, Zachciał J, Hałoń A, Janczak D, Banasik M. Interstitial Foci Expression of Indoleamine 2,3-Dioxygenase 1: A Potential Biomarker for Kidney Transplant Rejection. J Clin Med 2024; 13:4265. [PMID: 39064305 PMCID: PMC11277928 DOI: 10.3390/jcm13144265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/17/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
(1) Background: Kidney transplantation is the best therapy for patients with end-stage renal disease, but the risk of rejection complicates it. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme involved in immune response modulation, has been suggested to play a role in transplant immunological injury. The aim of the study was to explore the expression of IDO1 in the interstitial foci of transplanted kidneys and its potential association with rejection episodes. (2) Methods: This retrospective study analysed kidney transplant biopsies from 121 patients, focusing on IDO1 expression in interstitial foci. Immunohistochemistry was used to detect IDO1, and patients were categorised based on IDO1 presence (IDO1-IF positive or negative). The incidence of rejection was compared between these groups. (3) Results: Patients with IDO1 expression in interstitial foci (IDO1-IF(+)) exhibited higher incidences of rejection 46/80 (57.5%) vs. 10/41 (24.34%) patients compared to IDO1-IF(-) patients, which was statistically significant with p = 0.0005. The analysis of antibody-mediated rejection showed that IDO1-IF(+) patients developed AMR at 12/80 (15%), while only 1 IDO1-IF(-) negative patient did (2,44%), with p = 0.035. T-cell-mediated rejection was also more common in IDO1-IF(+) patients 43/80 (53.75%) than in IDO1-IF(-) patients 7/41 (17.07%), with p = 0.0001. (4) Conclusions: IDO1 expression in interstitial foci of renal transplant biopsies is associated with a higher incidence of rejection, suggesting that IDO1 could serve as a potential biomarker for transplant rejection. These findings highlight the importance of IDO1 in immune regulation and its potential utility in improving the management of kidney transplant recipients.
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Affiliation(s)
- Krzysztof Wiśnicki
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Piotr Donizy
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.D.); (A.H.)
| | - Magdalena Kuriata-Kordek
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Izabella Uchmanowicz
- Department of Nursing and Obstetrics, Wroclaw Medical University, 50-367 Wroclaw, Poland; (I.U.); (J.Z.)
| | - Justyna Zachciał
- Department of Nursing and Obstetrics, Wroclaw Medical University, 50-367 Wroclaw, Poland; (I.U.); (J.Z.)
| | - Agnieszka Hałoń
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.D.); (A.H.)
| | - Dariusz Janczak
- Department of Vascular, General and Transplantation Surgery, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland;
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Filipov T, Teutsch B, Szabó A, Forintos A, Ács J, Váradi A, Hegyi P, Szarvas T, Ács N, Nyirády P, Deák PÁ. Investigating the role of ultrasound-based shear wave elastography in kidney transplanted patients: correlation between non-invasive fibrosis detection, kidney dysfunction and biopsy results-a systematic review and meta-analysis. J Nephrol 2024; 37:1509-1522. [PMID: 38427308 PMCID: PMC11473454 DOI: 10.1007/s40620-023-01856-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/28/2023] [Indexed: 03/02/2024]
Abstract
INTRODUCTION Interstitial fibrosis and tubular atrophy are leading causes of renal allograft failure. Shear wave elastography could be a promising noninvasive method for providing information on the state of the kidney, with specific regard to fibrosis but currently available data in the literature are controversial. Our study aimed to analyze the correlation between shear wave elastography and various kidney dysfunction measures. METHODS This review was registered on PROSPERO (CRD42021283152). We systematically searched three major databases (MEDLINE, Embase, and CENTRAL) for articles concerning renal transplant recipients, shear wave elastography, fibrosis, and kidney dysfunction. Meta-analytical calculations for pooled Pearson and Spearman correlation coefficients (r) were interpreted with 95% confidence intervals (CIs). Heterogeneity was tested with Cochran's Q test. I2 statistic and 95% CI were reported as a measurement of between-study heterogeneity. Study quality was assessed with the QUADAS2 tool. RESULTS In total, 16 studies were included in our meta-analysis. Results showed a moderate correlation between kidney stiffness and interstitial fibrosis and tubular atrophy, graded according to BANFF classification, on biopsy findings for pooled Pearson (r = 0.48; CI: 0.20, 0.69; I2 = 84%) and Spearman correlations (r = 0.57; CI: 0.35, 0.72; I2 = 74%). When compared to kidney dysfunction parameters, we found a moderate correlation between shear wave elastography and resistive index (r = 0.34 CI: 0.13, 0.51; I2 = 67%) and between shear wave elastography and estimated Glomerular Filtration Rate (eGFR) (r = -0.65; CI: - 0.81, - 0.40; I2 = 73%). All our outcomes had marked heterogeneity. CONCLUSION Our results showed a moderate correlation between kidney stiffness measured by shear wave elastography and biopsy results. While noninvasive assessment of kidney fibrosis after transplantation is an important clinical goal, there is insufficient evidence to support the use of elastography over the performance of a kidney biopsy.
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Affiliation(s)
- Teodóra Filipov
- Department of Interventional Radiology, Heart and Vascular Center, Faculty of Medicine, Semmelweis University, Határőr ut 18, 1122, Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Brigitta Teutsch
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School University of Pécs, Pécs, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
| | - Anett Szabó
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Urology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Attila Forintos
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Júlia Ács
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Urology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Alex Váradi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary
- Department of Metagenomics, University of Debrecen, Debrecen, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School University of Pécs, Pécs, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
| | - Tibor Szarvas
- Department of Urology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Department of Urology, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
| | - Nándor Ács
- Department of Obstetrics and Gynecology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Péter Nyirády
- Department of Urology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Pál Ákos Deák
- Department of Interventional Radiology, Heart and Vascular Center, Faculty of Medicine, Semmelweis University, Határőr ut 18, 1122, Budapest, Hungary.
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10
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Wang W, Yu Y, Li X, Chen J, Zhang L, Wen J. Significance of Arterial Spin Labeling for Reducing Biopsies in Patients With Kidney Allograft Dysfunction. J Magn Reson Imaging 2024; 59:1777-1784. [PMID: 37515309 DOI: 10.1002/jmri.28926] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Although biopsy is often entailed for managing patients with kidney allograft dysfunction, it is associated with potential complications of severe hemorrhage. Arterial spin labeling (ASL) is a non-invasive technique that assesses tissue perfusion. PURPOSE To assess the utility of ASL for the discrimination of patients with post-transplant allograft dysfunction who do not need biopsy from those who need. STUDY TYPE Prospective. SUBJECTS Forty-six patients (34 males/12 females, aged 38.8 ± 9.5 years) with kidney allograft dysfunction, including 31 in which biopsy directly lead to changes in management (NECESSARY group) and 15 in which clinical management did not alter after biopsy (UNNECESSARY group). FIELD STRENGTH/SEQUENCE 3.0 T and 3D fast-spin echo sequence. ASSESSMENT All patients underwent both ASL scan and biopsies. The serum creatinine, proteinuria, pathologic results, and cortical ASL readings were obtained and compared between the two groups. STATISTICAL ANALYSES Chi-square test, independent student t-test, Mann-Whitney U test, receiver-operating characteristic curve. A two-tailed P < 0.05 denoted statistical significance. RESULTS The NECESSARY group presented with significantly elevated serum creatinine as compared with the UNNECESSARY group (1.87 ± 0.56 mg/dL vs. 1.31 ± 0.37 mg/dL). The acute composite score was significantly higher in the NECESSARY group than that in the UNNECESSARY group (7 [4-8] vs. 1 [0-2]). Cortical ASL in the NECESSARY group was significantly decreased as compared with the UNNECESSARY group (108.06 [69.96-134.92] mL/min/100 g vs. 153.48 [113.19-160.37] mL/min/100 g). Serum creatinine differentiated UNNCESSARY group from the NECESSARY group with an area under the curve (AUC) and specificity of 0.79 and 54.84%, respectively. By comparison, the cortical ASL yielded an AUC of 0.75 and a specificity of 70.97%. Notably, the specificity was increased to 90.30% by combined use of serum creatinine and cortical ASL. DATA CONCLUSION The combined use of ASL and serum creatinine yielded a high specificity for selecting patients who may not need allograft biopsy. LEVEL OF EVIDENCE 2 TECHNICAL EFFICACY: Stage 3.
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Affiliation(s)
- Wei Wang
- National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Shanghai Tenth People's Hospital, Shanghai, China
| | - Yuanmeng Yu
- Department of Medical Imaging, Jinling Hospital, Clinical School of Southern University, Nanjing, China
- Department of MRI, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xue Li
- National Clinical Research Center of Kidney Disease, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jinsong Chen
- National Clinical Research Center of Kidney Disease, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Longjiang Zhang
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jiqiu Wen
- National Clinical Research Center of Kidney Disease, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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11
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Matarneh AS, Salameh O, Sardar S, Karasinski A, Channapragada T, Abdulbasit M, Washburn E, Ghahramani N. A rare case of non-lupus full house nephropathy in a transplanted kidney, case report. Clin Case Rep 2024; 12:e8886. [PMID: 38707603 PMCID: PMC11066189 DOI: 10.1002/ccr3.8886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 05/07/2024] Open
Abstract
Key Clinical Message Non-lupus full house nephropathy is a rare entity that is still poorly understood. It can complicate post-transplant kidneys and result in a de novo process. Treatment is difficult but can be possibly achieved with optimization of immune suppression. Abstract Non-lupus full house nephropathy is a rare entity with an unclear incidence. It describes the kidney biopsy findings of positive deposits for IgG, IgA, IgM, C3, and C1q on immunofluorescence in the absence of the classical diagnostic features of systemic lupus nephritis. This disease entity is becoming more recognized but further studies are still needed to evaluate the incidence, etiologies, and management of this condition. Transplant glomerulopathy is a major cause for renal graft loss. It can present with a wide variety of manifestations; it can cause AKI, CKD, or glomerular inflammations through an immune complex or autoimmune-mediated damage.
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Affiliation(s)
- Ahmad Samir Matarneh
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Omar Salameh
- Department of Internal MedicinePenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Sundus Sardar
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Amanda Karasinski
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Theja Channapragada
- Department of Internal MedicinePenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Muhammad Abdulbasit
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Erik Washburn
- Department of PathologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
| | - Nasrollah Ghahramani
- Department of NephrologyPenn State Milton S Hershey Medical CenterHersheyPennsylvaniaUSA
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12
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Zhou T, Dong Y, Wang X, Liu R, Cheng R, Pan J, Zhang X, Sun SK. Highly Sensitive Early Diagnosis of Kidney Damage Using Renal Clearable Zwitterion-Coated Ferrite Nanoprobe via Magnetic Resonance Imaging In Vivo. Adv Healthc Mater 2024; 13:e2304577. [PMID: 38278515 DOI: 10.1002/adhm.202304577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Indexed: 01/28/2024]
Abstract
Iron oxide nanoprobes exhibit substantial potential in magnetic resonance imaging (MRI) of kidney diseases and can eliminate the nephrotoxicity of gadolinium-based contrast agents (GBCAs). Nevertheless, there is an extreme shortage of highly sensitive and renal clearable iron oxide nanoprobes suitable for early kidney damage detection through MRI. Herein, a renal clearable ultra-small ferrite nanoprobe (UMFNPs@ZDS) is proposed for highly sensitive early diagnosis of kidney damage via structural and functional MRI in vivo for the first time. The nanoprobe comprises a ferrite core coated with a zwitterionic layer, and possesses a high T1 relaxivity (12.52 mm-1s-1), a small hydrodynamic size (6.43 nm), remarkable water solubility, excellent biocompatibility, and impressive renal clearable ability. In a rat model of unilateral ureteral obstruction (UUO), the nanoprobe-based MRI can not only accurately visualize the locations of renal injury, but also provide comprehensive functional data including peak value, peak time, relative renal function (RRF), and clearance percentage via MRI. The findings prove the immense potential of ferrite nanoprobes as a superior alternative to GBCAs for the early diagnosis of kidney damage.
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Affiliation(s)
- Ting Zhou
- School of Medical Imaging, Tianjin Medical University, Tianjin, 300203, China
| | - Yanzhi Dong
- School of Medical Imaging, Tianjin Medical University, Tianjin, 300203, China
| | - Xiaoyi Wang
- Department of Radiology and Ultrasound, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Ruxia Liu
- Department of Rehabilitation, School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China
| | - Ran Cheng
- School of Medical Imaging, Tianjin Medical University, Tianjin, 300203, China
| | - Jinbin Pan
- Department of Radiology, Tianjin Key Laboratory of Functional Imaging, Tianjin Medical, University General Hospital, Tianjin, 300052, China
| | - Xuejun Zhang
- School of Medical Imaging, Tianjin Medical University, Tianjin, 300203, China
| | - Shao-Kai Sun
- School of Medical Imaging, Tianjin Medical University, Tianjin, 300203, China
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13
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Augulis R, Rasmusson A, Laurinaviciene A, Jen KY, Laurinavicius A. Computational pathology model to assess acute and chronic transformations of the tubulointerstitial compartment in renal allograft biopsies. Sci Rep 2024; 14:5345. [PMID: 38438513 PMCID: PMC10912734 DOI: 10.1038/s41598-024-55936-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/29/2024] [Indexed: 03/06/2024] Open
Abstract
Managing patients with kidney allografts largely depends on biopsy diagnosis which is based on semiquantitative assessments of rejection features and extent of acute and chronic changes within the renal parenchyma. Current methods lack reproducibility while digital image data-driven computational models enable comprehensive and quantitative assays. In this study we aimed to develop a computational method for automated assessment of histopathology transformations within the tubulointerstitial compartment of the renal cortex. Whole slide images of modified Picrosirius red-stained biopsy slides were used for the training (n = 852) and both internal (n = 172) and external (n = 94) tests datasets. The pipeline utilizes deep learning segmentations of renal tubules, interstitium, and peritubular capillaries from which morphometry features were extracted. Seven indicators were selected for exploring the intrinsic spatial interactions within the tubulointerstitial compartment. A principal component analysis revealed two independent factors which can be interpreted as representing chronic and acute tubulointerstitial injury. A K-means clustering classified biopsies according to potential phenotypes of combined acute and chronic transformations of various degrees. We conclude that multivariate analyses of tubulointerstitial morphometry transformations enable extraction of and quantification of acute and chronic components of injury. The method is developed for renal allograft biopsies; however, the principle can be applied more broadly for kidney pathology assessment.
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Affiliation(s)
- Renaldas Augulis
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences of the Faculty of Medicine, Vilnius University, M. K. Ciurlionio Str. 21, 03101, Vilnius, Lithuania.
- National Centre of Pathology, Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania.
| | - Allan Rasmusson
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences of the Faculty of Medicine, Vilnius University, M. K. Ciurlionio Str. 21, 03101, Vilnius, Lithuania
- National Centre of Pathology, Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania
| | - Aida Laurinaviciene
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences of the Faculty of Medicine, Vilnius University, M. K. Ciurlionio Str. 21, 03101, Vilnius, Lithuania
- National Centre of Pathology, Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania
| | - Kuang-Yu Jen
- Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA
| | - Arvydas Laurinavicius
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences of the Faculty of Medicine, Vilnius University, M. K. Ciurlionio Str. 21, 03101, Vilnius, Lithuania
- National Centre of Pathology, Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania
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14
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Yang Z, Zhang M, Li X, Xu Z, Chen Y, Xu X, Chen D, Meng L, Si X, Wang J. Fluorescence spectroscopic profiling of urine samples for predicting kidney transplant rejection. Photodiagnosis Photodyn Ther 2024; 45:103984. [PMID: 38244654 DOI: 10.1016/j.pdpdt.2024.103984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 01/08/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
Rejection is the primary factor affecting the functionality of a kidney post-transplant, where its prompt prediction of risk significantly influences therapeutic strategies and clinical outcomes. Current graft health assessment methods, including serum creatinine measurements and transplant kidney puncture biopsies, possess considerable limitations. In contrast, urine serves as a direct indicator of the graft's degenerative stage and provides a more accurate measure than peripheral blood analysis, given its non-invasive collection of kidney-specific metabolite. This research entailed collecting fluorescent fingerprint data from 120 urine samples of post-renal transplant patients using hyperspectral imaging, followed by the development of a learning model to detect various forms of immunological rejection. The model successfully identified multiple rejection types with an average diagnostic accuracy of 95.56 %.Beyond proposing an innovative approach for predicting the risk of complications post-kidney transplantation, this study heralds the potential introduction of a non-invasive, rapid, and accurate supplementary method for risk assessment in clinical practice.
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Affiliation(s)
- Zhe Yang
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Minrui Zhang
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Xianduo Li
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Zhipeng Xu
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Yi Chen
- Shandong Medical College, Jinan 250000, China
| | - Xiaoyu Xu
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Dongdong Chen
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Lingquan Meng
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Xiaoqing Si
- Department of dermatology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China.
| | - Jianning Wang
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China.
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15
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Wiśnicki K, Donizy P, Hałoń A, Wawrzonkowski P, Janczak D, Krajewska M, Banasik M. Indoleamine 2,3-Dioxygenase 1 (IDO1) in Kidney Transplantation: A Guardian against Rejection. J Clin Med 2023; 12:7531. [PMID: 38137602 PMCID: PMC10743959 DOI: 10.3390/jcm12247531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/27/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
Kidney transplantation is a crucial treatment for end-stage kidney disease, with immunosuppressive drugs helping to reduce acute rejection rates. However, kidney graft longevity remains a concern. This study explores the role of indoleamine 2,3-dioxygenase 1 (IDO1) in kidney transplant immunology. IDO1 breaks down tryptophan, affecting immune cell behavior, primarily T-cells. The research focuses on both cellular and antibody-mediated immune responses, often causing graft damage. The study assessed IDO1 expression in renal transplant biopsies from patients with graft function decline, examining its connection to clinical parameters. A total of 121 biopsy samples were evaluated for IDO1 expression using immunohistochemistry. Patients were categorized as IDO1(+) positive or IDO1(-) negative based on immunoreactivity in tubular epithelium. Results showed a significant link between IDO1 expression and rejection incidence. IDO1(+) positive patients had lower rejection rates (32.9%) compared to IDO1(-) negative ones (62.2%) [p = 0.0017], with substantial differences in antibody-mediated rejection (AMR) (5.2% vs. 20%) [p = 0.0085] and T-cell mediated rejection (TCMR) (31.6% vs. 57.8%). These associations suggest that IDO1 may play a protective role in kidney transplant rejection. IDO1 modulation could offer novel therapeutic avenues to enhance graft survival. The study underscores IDO1 as a potential marker for rejection risk assessment, with its potential applications in personalized interventions and improved patient outcomes. Further research is needed to fully comprehend the mechanisms behind IDO1's immunomodulatory functions and its potential clinical translation.
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Affiliation(s)
- Krzysztof Wiśnicki
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.W.); (M.K.)
| | - Piotr Donizy
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.D.); (A.H.)
| | - Agnieszka Hałoń
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.D.); (A.H.)
| | - Patryk Wawrzonkowski
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.W.); (M.K.)
| | - Dariusz Janczak
- Department of Vascular, General and Transplantation Surgery, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.W.); (M.K.)
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (P.W.); (M.K.)
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16
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Castelein J, Pamplona C, Armstrong Junior R, Vidal dos Santos M, Sack I, Dierckx R, Moers C, Borra R. Effects of kidney perfusion on renal stiffness and tissue fluidity measured with tomoelastography in an MRI-compatible ex vivo model. Front Bioeng Biotechnol 2023; 11:1236949. [PMID: 38026891 PMCID: PMC10665518 DOI: 10.3389/fbioe.2023.1236949] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Stiffness plays a vital role in diagnosing renal fibrosis. However, perfusion influences renal stiffness in various chronic kidney diseases. Therefore, we aimed to characterize the effect of tissue perfusion on renal stiffness and tissue fluidity measured by tomoelastography based on multifrequency magnetic resonance elastography in an ex vivo model. Five porcine kidneys were perfused ex vivo in an MRI-compatible normothermic machine perfusion setup with adjusted blood pressure in the 50/10-160/120 mmHg range. Simultaneously, renal cortical and medullary stiffness and fluidity were obtained by tomoelastography. For the cortex, a statistically significant (p < 0.001) strong positive correlation was observed between both perfusion parameters (blood pressure and resulting flow) and stiffness (r = 0.95, 0.91), as well as fluidity (r = 0.96, 0.92). For the medulla, such significant (p < 0.001) correlations were solely observed between the perfusion parameters and stiffness (r = 0.88, 0.71). Our findings demonstrate a strong perfusion dependency of renal stiffness and fluidity in an ex vivo setup. Moreover, changes in perfusion are rapidly followed by changes in renal mechanical properties-highlighting the sensitivity of tomoelastography to fluid pressure and the potential need for correcting mechanics-derived imaging biomarkers when addressing solid structures in renal tissue.
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Affiliation(s)
- Johannes Castelein
- Department of Radiology & Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, Netherlands
- Department for Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carolina Pamplona
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | | | | | - Ingolf Sack
- Department of Radiology, Charité University Medicine Berlin, Berlin, Germany
| | - Rudi Dierckx
- Department of Radiology & Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, Netherlands
| | - Cyril Moers
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Ronald Borra
- Department of Radiology & Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, Netherlands
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17
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Schnuelle P. Renal Biopsy for Diagnosis in Kidney Disease: Indication, Technique, and Safety. J Clin Med 2023; 12:6424. [PMID: 37835066 PMCID: PMC10573674 DOI: 10.3390/jcm12196424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
Renal biopsies are the gold standard for diagnosis, staging, and prognosis of underlying parenchymal kidney disease. This article provides an overview of the current indications and highlights ways to reduce bleeding complications in order to achieve optimal diagnostic yield with minimal risk to the patient. Novel indications have emerged from the increasing use of new molecularly targeted oncologic therapies in recent years, which often induce immune-mediated renal disease. On the other hand, the detection of specific antibodies against target antigens on podocytes in the sera of patients with new-onset nephrotic syndrome has now relativized the indication for biopsy in membranous nephropathy. The use of semi-automatic spring-loaded biopsy devices and real-time ultrasound considerably declined the complication rate and is the current standard. Percutaneous renal biopsies are overall a safe procedure if contraindications are considered. A coagulation disorder needs to be excluded beforehand, and an elevated blood pressure must be reduced to the normotensive range with medications. A laparoscopic approach or a radiology interventional procedure through the internal jugular vein may be considered for obtaining a kidney tissue sample if there is an urgent indication and a bleeding tendency cannot be adequately corrected. Major bleeding after a percutaneous renal biopsy can usually be managed with selective arterial embolization of the injured renal vessel. The use of a 16-gauge needle is the most reasonable compromise between diagnostic benefit and risk of complication. In the routine diagnostic, the biopsy specimen is examined with light microscopy, immunohistochemistry, and electron microscopy. Combination with modern molecular pathology techniques will contribute to more precise insights into the development and progression of kidney disease, which will likely refine future treatments in nephrology.
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Affiliation(s)
- Peter Schnuelle
- Center for Renal Diseases Weinheim, Academic Teaching Practice of the University Medical Center Mannheim, University of Heidelberg, D-69469 Weinheim, Germany
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18
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Cheng P, Wang R, He S, Yan P, Huang H, Chen J, Shen J, Pu K. Artificial Urinary Biomarkers for Early Diagnosis of Acute Renal Allograft Rejection. Angew Chem Int Ed Engl 2023; 62:e202306539. [PMID: 37431650 DOI: 10.1002/anie.202306539] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/12/2023]
Abstract
Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near-infrared fluorescence signals to report cell-mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros-based urinalysis discriminates allograft rejection against other non-alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.
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Affiliation(s)
- Penghui Cheng
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore, Singapore
| | - Rending Wang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, P. R. China
- Organ Donation and Coordination Office, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, P. R. China
| | - Shasha He
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore, Singapore
| | - Pengpeng Yan
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, P. R. China
| | - Hongfeng Huang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, P. R. China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, P. R. China
| | - Jia Shen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, P. R. China
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, Singapore, 636921, Singapore
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19
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Aoki Y, Kawamura T, Shiraga N, Yonekura T, Maeda M, Kurihara S, Sekine Y, Shishido S, Sakai K. Arteriovenous fistula in a renal allograft with gross hematuria and subsequent acute kidney injury due to urinary tract obstruction: a case report. BMC Nephrol 2023; 24:156. [PMID: 37277729 DOI: 10.1186/s12882-023-03183-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/26/2023] [Indexed: 06/07/2023] Open
Abstract
BACKGROUND Arteriovenous fistula (AVF) due to renal allograft biopsy is mechanical trauma resulting from the penetration of small arteries and veins by a core needle. Most AVFs are reported to resolve asymptomatically and spontaneously. This report presents a patient with acute kidney injury (AKI) due to urinary tract obstruction caused by a bleeding AVF in a renal allograft. CASE PRESENTATION A 22-year-old Japanese woman who underwent living-donor kidney transplantation (KT) at 3 years due to end-stage renal disease caused by focal segmental glomerulosclerosis (FSGS) presented with a renal transplant AVF (gourd-shaped; 42 × 19 × 20 mm). The AVF was unexpectedly discovered by ultrasound before a surveillance biopsy at 10 years after KT. The patient had a history of recurrent FSGS, had undergone several renal allograft biopsies after KT, and did not experience symptoms or growth of the AVF for years. Nineteen years after KT, the patient developed AKI with sudden, asymptomatic, gross hematuria and anuria. Plain computed tomography revealed a hematoma in the pelvis of the renal allograft and bladder tamponade. The AVF was successfully treated by coil embolization. Hemodialysis was performed for AKI, and graft function was gradually recovered. CONCLUSIONS Unexpected bleeding from a renal transplant AVF may lead to transplant dysfunction. Angiographic embolization against the ruptured renal transplant AVF may prevent rebleeding and rescue the renal allograft.
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Affiliation(s)
- Yujiro Aoki
- Department of Nephrology, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan.
| | - Takeshi Kawamura
- Department of Nephrology, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Nobuyuki Shiraga
- Department of Diagnostic Radiology, Toho University Omori Medical Center, Tokyo, Japan
| | - Takashi Yonekura
- Department of Nephrology, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Maho Maeda
- Department of Nephrology, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Sota Kurihara
- Department of Urology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Yoshitaka Sekine
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Seiichiro Shishido
- Department of Nephrology, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Ken Sakai
- Department of Nephrology, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
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20
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Shin SH, Wendland MF, Wang J, Velasquez M, Vandsburger MH. Noninvasively differentiating acute and chronic nephropathies via multiparametric urea-CEST, nuclear Overhauser enhancement-CEST, and quantitative magnetization transfer MRI. Magn Reson Med 2023; 89:774-786. [PMID: 36226662 PMCID: PMC11027791 DOI: 10.1002/mrm.29477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/26/2022] [Accepted: 09/14/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE Standardized blood tests often lack adequate sensitivity and specificity to capture the gradual progression of renal injuries. We suggest a multiparametric molecular MRI approach as a noninvasive tool for monitoring renal function loss and distinguishing different types of renal injuries. METHODS CEST and quantitative magnetization transfer (qMT) imaging were performed on cisplatin (n = 16) and aristolochic acid (AA)-induced nephropathy (n = 22) mouse models at 7T with an infusion of either saline or urea. Seven-pool Lorentzian fitting was applied for the analysis of CEST Z-spectra, and the T1 -corrected CEST contrast apparent exchange-dependent relaxation (AREX) from urea (+1 ppm) and two nuclear Overhauser enhancement (NOE) pools (-1.6 and -3.5 ppm) were measured. Similarly, qMT spectra were fitted into two-pool Ramani equation and the relative semi-solid macromolecular pool-size ratio was measured. Histology of mouse kidneys was performed to validate the MR findings. RESULTS AA model showed disrupted spatial gradients of urea in the kidney and significantly decreased NOE CEST and qMT contrast. The cisplatin model showed slightly decreased qMT contrast only. The orrelation of MR parameters to histological features showed that NOE CEST and qMT imaging are sensitive to both acute and chronic injuries, whereas urea CEST shows a significant correlation only to acute injuries. CONCLUSION These results indicate that our multiparametric approach allows comprehensive and totally noninvasive monitoring of renal function and histological changes for distinguishing different nephropathies.
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Affiliation(s)
- Soo Hyun Shin
- Department of Bioengineering, University of California, Berkeley, Berkeley, CA
| | - Michael F. Wendland
- Berkeley Preclinical Imaging Core (BPIC), University of California, Berkeley, Berkeley, CA
| | - Jingshen Wang
- Department of Biostatistics, University of California, Berkeley, Berkeley, CA
| | - Mark Velasquez
- Department of Bioengineering, University of California, Berkeley, Berkeley, CA
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21
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Llinàs-Mallol L, Raïch-Regué D, Pascual J, Crespo M. Alloimmune risk assessment for antibody-mediated rejection in kidney transplantation: A practical proposal. Transplant Rev (Orlando) 2023; 37:100745. [PMID: 36572001 DOI: 10.1016/j.trre.2022.100745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 12/07/2022] [Accepted: 12/11/2022] [Indexed: 12/24/2022]
Abstract
Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although an improvement in graft survival has been observed in the last decades with the use of different immunosuppressive drugs, this is still limited in time with antibody-mediated rejection being a main cause of graft-loss. Immune monitoring and risk assessment of antibody-mediated rejection before and after kidney transplantation with useful biomarkers is key to tailoring treatments to achieve the best outcomes. Here, we provide a review of the rationale and several accessible tools for immune monitoring, from the most classic to the modern ones. Finally, we end up discussing a practical proposal for alloimmune risk assessment in kidney transplantation, including histocompatibility leukocyte antigen (HLA) and non-HLA antibodies, HLA molecular mismatch analysis and characterization of peripheral blood immune cells.
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Affiliation(s)
- Laura Llinàs-Mallol
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Dàlia Raïch-Regué
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Julio Pascual
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
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22
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Pang Q, Chen H, Wu H, Wang Y, An C, Lai S, Xu J, Wang R, Zhou J, Xiao H. N6-methyladenosine regulators-related immune genes enable predict graft loss and discriminate T-cell mediate rejection in kidney transplantation biopsies for cause. Front Immunol 2022; 13:1039013. [PMID: 36483557 PMCID: PMC9722771 DOI: 10.3389/fimmu.2022.1039013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/01/2022] [Indexed: 11/23/2022] Open
Abstract
Objective The role of m6A modification in kidney transplant-associated immunity, especially in alloimmunity, still remains unknown. This study aims to explore the potential value of m6A-related immune genes in predicting graft loss and diagnosing T cell mediated rejection (TCMR), as well as the possible role they play in renal graft dysfunction. Methods Renal transplant-related cohorts and transcript expression data were obtained from the GEO database. First, we conducted correlation analysis in the discovery cohort to identify the m6A-related immune genes. Then, lasso regression and random forest were used respectively to build prediction models in the prognosis and diagnosis cohort, to predict graft loss and discriminate TCMR in dysfunctional renal grafts. Connectivity map (CMap) analysis was applied to identify potential therapeutic compounds for TCMR. Results The prognostic prediction model effectively predicts the prognosis and survival of renal grafts with clinical indications (P< 0.001) and applies to both rejection and non-rejection situations. The diagnostic prediction model discriminates TCMR in dysfunctional renal grafts with high accuracy (area under curve = 0.891). Meanwhile, the classifier score of the diagnostic model, as a continuity index, is positively correlated with the severity of main pathological injuries of TCMR. Furthermore, it is found that METTL3, FTO, WATP, and RBM15 are likely to play a pivotal part in the regulation of immune response in TCMR. By CMap analysis, several small molecular compounds are found to be able to reverse TCMR including fenoldopam, dextromethorphan, and so on. Conclusions Together, our findings explore the value of m6A-related immune genes in predicting the prognosis of renal grafts and diagnosis of TCMR.
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Affiliation(s)
- Qidan Pang
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Chen
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hang Wu
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Yong Wang
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Changyong An
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Suhe Lai
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jia Xu
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Ruiqiong Wang
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Juan Zhou
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, China,*Correspondence: Hanyu Xiao, ; Juan Zhou,
| | - Hanyu Xiao
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China,*Correspondence: Hanyu Xiao, ; Juan Zhou,
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23
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Intravoxel Incoherent Motion-Diffusion-Weighted MRI for Investigation of Delayed Graft Function Immediately after Kidney Transplantation. BIOMED RESEARCH INTERNATIONAL 2022; 2022:2832996. [PMID: 36303584 PMCID: PMC9596237 DOI: 10.1155/2022/2832996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/02/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022]
Abstract
Purpose A non-invasive way of assessing post-transplant renal graft function has been needed. This study aimed to assess the micro-structural and micro-functional status of graft kidneys by using intravoxel incoherent motion- (IVIM-) diffusion-weighted imaging (DWI) to investigate delayed graft function (DGF) immediately after transplantation. Method A prospective study was conducted on 37 patients, 14 with early graft function (EGF) and 23 with DGF (9 with complication, 14 without) who underwent IVIM-DWI, most often within 1-7 days after kidney transplantation. A total of 37 cases were collected and all the participants have been well-informed and signed their consents. In addition, the study conducted in this paper was approved by the Ethics Committee of Clinical Research, Taichung Veterans General Hospital (IRB number: CE14065). Using biexponential analysis of slow diffusion coefficient (Dslow), fast diffusion coefficient (Dfast), and perfusion fraction was performed. The apparent diffusion coefficient (ADC) was calculated by use of a monoexponential model. All parameters were measured from three different regions-of-interest (ROI), covering the entire renal parenchyma, cortex, and medulla. Results Dslow, perfusion fraction, and ADC were significantly higher in patients with EGF than DGF (all p values values <0.001). Especially, ADC measured from ROI covering the entire kidney parenchyma had the best cut-off value (1.93μm2/msec) with the highest area under the receiver operating characteristic curve (AUC 0.943) in differentiating EGF from DGF. For analysis of pair-wise differences, only the perfusion fraction values, measured from the ROI covering the renal cortex, were significantly higher in 14 DGF patients with no complications than in the 9 DGF patients with complications, with the best cut-off value of 12.3% and the AUC of 0.844. Conclusion Noninvasive IVIM-DWI reliably differentiates DGF from EGF after kidney transplantation, and it may aid in identifying posttransplant complications and indications for renal biopsy.
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24
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Role of the Immune System in Renal Transplantation, Types of Response, Technical Approaches and Current Challenges. IMMUNO 2022. [DOI: 10.3390/immuno2040035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Advances over the last decades have made renal transplantation an important therapy for patients with end-stage renal disease, as the incidences of acute rejection and short-term transplant loss have been significantly reduced. However, long-term transplant survival remains a challenge in the renal transplantation community. The main causes of long-term graft loss are acute and chronic rejection, as well as the complications related to immunosuppression therapy. In spite of the breakthroughs achieved in recent years, histology is the gold standard technique to confirm the activation of the immune system against the graft with all the ensuing problems that taking biopsies brings to immunosuppressed patients. For this reason, several assays have been developed to try to monitor the immune function, but they show serious constraints owing to the fact that they require substantial laboratory work, they are not clinically available and they provide controversial results, so the combination of multiple assays is often needed to obtain a reliable diagnosis. Thus, the aim of this review is to perform a retrospective study of the immune system in renal transplantation, with special emphasis on the cutting-edge technological developments for monitoring, classification and early detection of rejection episodes in order to contribute to a better adjustment of immunosuppressive therapies and, hence, to a more personalized medicine that improves the quality of life of patients.
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25
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Liu SJ, Ma K, Liu LS, Wang K, Zhang YA, Bi ZR, Chen YX, Chen KZ, Wang CX, Qiao SL. Point-of-care non-invasive enzyme-cleavable nanosensors for acute transplant rejection detection. Biosens Bioelectron 2022; 215:114568. [PMID: 35850041 DOI: 10.1016/j.bios.2022.114568] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/24/2022] [Accepted: 07/09/2022] [Indexed: 12/28/2022]
Abstract
Accurate and non-invasive monitoring of allograft posttransplant is essential for early detection of acute cellular rejection and determines the long-term survival of the graft. Clinically, tissue biopsy is the most effective approach for diagnosing transplant rejection. Nonetheless, the procedure is invasive and potentially triggers organ failure. This work aims to design and apply GzmB-responsive nanosensors (GBRNs) that can readily size-change in graft tissues. Subsequently, we investigate the activity of serine protease granzyme B by generating a direct colorimetric urinary readout for non-invasive detection of transplant rejection in under 1 h. In preclinical heart graft mice models of transplant rejection, GBRNs were cleaved by GzmB and excreted by the kidneys via accurate nanometre-size glomerular filtration. By exploiting the catalytic activity of ultrasmall gold nanoclusters, GBRNs urinalysis promotes ultrasensitive surveillance of rejection episodes with a receiver operator characteristic curve area under the curve of 0.896 as well as a 95% confidence interval of about 0.7701-1.000. Besides, the catalytic activity of gold nanoclusters in urine can be detected at point-of-care testing to predict the immunity responses in mice with insufficient immunosuppressive therapy. Therefore, this non-invasive, sensitive, and quantitative method is a robust and informative approach for rapid and routine monitoring of transplant allografts without invasive biopsy.
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Affiliation(s)
- Shi-Jie Liu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, PR China
| | - Ke Ma
- Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology (QUST), Qingdao, 266042, PR China
| | - Long-Shan Liu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, PR China
| | - Ke Wang
- Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology (QUST), Qingdao, 266042, PR China
| | - Ying-Ao Zhang
- Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology (QUST), Qingdao, 266042, PR China
| | - Zi-Rong Bi
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, PR China
| | - Yan-Xu Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, PR China
| | - Ke-Zheng Chen
- Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology (QUST), Qingdao, 266042, PR China.
| | - Chang-Xi Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, PR China.
| | - Sheng-Lin Qiao
- Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology (QUST), Qingdao, 266042, PR China.
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26
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Ho QY, Lim CC, Tan HZ, Sultana R, Kee T, Htay H. Complications of Percutaneous Kidney Allograft Biopsy: Systematic Review and Meta-analysis. Transplantation 2022; 106:1497-1506. [PMID: 35019898 DOI: 10.1097/tp.0000000000004033] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Kidney biopsy is important to guide the management of allograft dysfunction but has a risk of complications. This review aimed to determine the incidence and risk factors of complications after kidney allograft biopsy. METHODS This is a systematic review and meta-analysis of randomized controlled trials, cohort studies, or case-control studies indexed on PubMed, Embase, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry, and ClinicalTrials.gov, limited to the English language, from January 2000 to December 2020, including adult and pediatric kidney allograft biopsies. Primary outcomes were gross hematuria, bleeding requiring transfusion, and major complications (requiring interventions such as blood transfusion or surgical or radiological interventions). RESULTS The review included 72 studies (40 082 biopsies). The quality of included studies was suboptimal. Pooled rates of gross hematuria, bleeding requiring transfusion, and major complications were 3.18% [95% confidence interval (95% CI), 2.31-4.19], 0.31% (95% CI, 0.15-0.52) and 0.89% (95% CI, 0.61-1.22), respectively. Gross hematuria rates were lower in high-income compared with middle-income countries (2.59% versus 6.44%, P < 0.01) and biopsies performed by radiology as compared with nephrology departments (1.25% versus 3.71%, P < 0.01). Blood transfusion rates were lower in pediatrics than adults (0.0% versus 0.65%, P < 0.01). Major complications were lower in biopsies performed by specialists as compared with trainees (0.02% versus 3.64%, P < 0.01). Graft loss and mortality were extremely rare. Limitations included missing data, few randomized controlled trials, and possible publication bias. CONCLUSIONS The risk of complications after kidney allograft biopsy was low. Given the low quality of included studies, risk factors for complications should be further examined in future studies.
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Affiliation(s)
- Quan Yao Ho
- Department of Renal Medicine, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Transplant Centre, Singapore
| | | | - Hui Zhuan Tan
- Department of Renal Medicine, Singapore General Hospital, Singapore
| | | | - Terence Kee
- Department of Renal Medicine, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Transplant Centre, Singapore
| | - Htay Htay
- Department of Renal Medicine, Singapore General Hospital, Singapore
- Duke-NUS Medical School, Singapore
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27
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Molecular Markers of Kidney Transplantation Outcome: Current Omics Tools and Future Developments. Int J Mol Sci 2022; 23:ijms23116318. [PMID: 35682996 PMCID: PMC9181061 DOI: 10.3390/ijms23116318] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 02/04/2023] Open
Abstract
Purpose of review: The emerging field of molecular predictive medicine is aiming to change the traditional medical approach in renal transplantation. Many studies have explored potential biomarker molecules with predictive properties in renal transplantation, issued from omics research. Herein, we review the biomarker molecules of four technologies (i.e., Genomics, Transcriptomics, Proteomics, and Metabolomics) associated with favorable kidney transplant outcomes. Recent findings: Several panels of molecules have been associated with the outcome that the majority of markers are related to inflammation and immune response; although. other molecular ontologies are also represented, such as proteasome, growth, regeneration, and drug metabolism. Throughout this review, we highlight the lack of properly validated statistical demonstration. Indeed, the most preeminent molecular panels either remain at the limited size study stage or are not confirmed during large-scale studies. At the core of this problem, we identify the methodological shortcomings and propose a comprehensive workflow for discovery and validation of molecular biomarkers that aims to improve the relevance of these tools in the future. Summary: Overall, adopting a patient management through omics approach could bring remarkable improvement to transplantation success. An increased effort and investment between scientists, medical biologists, and clinicians seem to be the path toward a proper solution.
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28
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Oblak M, Mlinšek G, Kojc N, Frelih M, Buturović-Ponikvar J, Arnol M. Spot Urine Protein Excretion in the First Year Following Kidney Transplantation Associates With Allograft Rejection Phenotype at 1-Year Surveillance Biopsies: An Observational National-Cohort Study. Front Med (Lausanne) 2021; 8:781195. [PMID: 34869503 PMCID: PMC8635090 DOI: 10.3389/fmed.2021.781195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/13/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: Urine protein excretion is routinely measured to assess kidney allograft injury, but the diagnostic value of this measurement for kidney transplant pathology remains unclear. Here we investigated whether spot urine protein excretion in the first year following transplantation associates with allograft rejection phenotype at 1-year surveillance biopsies and de-novo occurrence of donor-specific antibodies (DSA). Patients and Methods: This prospective, observational national-cohort study included 139 non-sensitized patients who received a deceased donor kidney transplant between December 2014 and 2018. All patients received basiliximab induction and tacrolimus-based immunosuppression. Estimated protein excretion rate (ePER) was calculated monthly from spot urine protein-to-creatinine ratios. At 1-year, all recipients underwent surveillance graft biopsy and were screened for de-novo DSA. Screening-positive sera were subjected to single antigen bead (SAB) testing. The occurrence of de-novo DSA was determined based on SAB reactivity patterns using a mean fluorescence intensity threshold >1,000. Results: Among the 139 study patients, 27 patients (19%) had histologic evidence of T cell-mediated rejection (TCMR), and 9 patients (7%) had histologic evidence of antibody-mediated rejection (AMR) at 1-year surveillance biopsy. One year after transplant, 19 patients (14%) developed de-novo DSA. Compared with patients without rejection and no de-novo DSA, mixed-effects linear regression analysis showed a significant difference in slope of ePER during the first year in patients with AMR and de-novo DSA at 1-year (46, 95% CI 25-68 mg/day/1.73 m2 per month and 34, 95% CI 20-49 mg/day/1.73 m2 per month, respectively). Patients with vascular TCMR also showed a significant difference in ePER slope over time compared with patients with non-rejection findings (31, 95% CI 9-52 mg/day/1.73 m2 per month). The discriminatory power of ePER for intragraft rejection processes was better in patients with AMR (AUC 0.95, 95% CI 0.90-0.99; P < 0.001) than in those with TCMR (AUC 0.68, 95% CI 0.59-0.79; P = 0.002), with 89% sensitivity and 93% specificity for proteinuria >550 mg/day/1.73m2. Conclusions: An increase in ePER in the first year following kidney transplantation associates with AMR, vascular TCMR and de-novo DSA at 1-year and may be used as a non-invasive clinical marker of intragraft endothelial cell injury.
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Affiliation(s)
- Manca Oblak
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gregor Mlinšek
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nika Kojc
- Faculty of Medicine, Institute of Pathology, University of Ljubljana, Ljubljana, Slovenia
| | - Maja Frelih
- Faculty of Medicine, Institute of Pathology, University of Ljubljana, Ljubljana, Slovenia
| | - Jadranka Buturović-Ponikvar
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Miha Arnol
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Shi H, Gong Y, Liang Q, Li J, Xiang Y, Li G. Target-Initiated Great Change in Electrochemical Steric Hindrance for an Assay of Granzyme B Activity. Anal Chem 2021; 93:13382-13388. [PMID: 34549940 DOI: 10.1021/acs.analchem.1c03188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
To improve long-term graft patient outcomes and develop more effective antirejection therapies, noninvasive monitoring of acute cellular rejection (ACR) after organ transplantation is urgently needed. As a biomarker of ACR, Granzyme B (GrB) is expected to be applied in the noninvasive monitoring of ACR. Herein, we have developed a method for detecting the GrB activity based on the target-initiated great change in electrochemical steric hindrance by designing a nanoprobe. The nanoprobe is prepared by conjugating a specific peptide, which is responsive to GrB cleavage activity, to gold nanoparticles (AuNPs). Meanwhile, a piece of DNA sequence with G-quadruplex (G4) is attached at the distal end of the peptide. Upon exposure to GrB, the peptide substrate is cleaved to eliminate the steric hindrance between inter-nanoprobes as well as nanoprobe and DNA tetrahedron (TDN), allowing the released DNA strand to hybridize with TDN, giving sensitive signal output. The method can also be used to detect GrB activity in complex biological settings, so it has a great potential for monitoring GrB activity in the blood or urine of graft patients.
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Affiliation(s)
- Hai Shi
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Youjing Gong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Qizhi Liang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Jinlong Li
- The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P. R. China
| | - Yang Xiang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Genxi Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China.,Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, P. R. China
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30
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Phillips BL, Ibrahim M, Greenhall GHB, Mumford L, Dorling A, Callaghan CJ. Effect of delayed graft function on longer-term outcomes after kidney transplantation from donation after circulatory death donors in the United Kingdom: A national cohort study. Am J Transplant 2021; 21:3346-3355. [PMID: 33756062 DOI: 10.1111/ajt.16574] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/16/2021] [Accepted: 03/14/2021] [Indexed: 01/25/2023]
Abstract
Kidneys from donation after circulatory death (DCD) donors are utilized variably worldwide, in part due to high rates of delayed graft function (DGF) and putative associations with adverse longer-term outcomes. We aimed to determine whether the presence of DGF and its duration were associated with poor longer-term outcomes after kidney transplantation from DCD donors. Using the UK transplant registry, we identified 4714 kidney-only transplants from controlled DCD donors to adult recipients between 2006 and 2016; 2832 recipients (60·1%) had immediate graft function and 1882 (39·9%) had DGF. Of the 1847 recipients with DGF duration recorded, 926 (50·1%) had DGF < 7 days, 576 (31·2%) had DGF 7-14 days, and 345 (18·7%) had DGF >14 days. After risk adjustment, the presence of DGF was not associated with inferior long-term graft or patient survivals. However, DGF duration of >14 days was associated with an increased risk of death-censored graft failure (hazard ratio 1·7, p = ·001) and recipient death (hazard ratio 1·8, p < ·001) compared to grafts with immediate function. This study suggests that shorter periods of DGF have no adverse influence on graft or patient survival after DCD donor kidney transplantation and that DGF >14 days is a novel early biomarker for significantly worse longer-term outcomes.
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Affiliation(s)
- Benedict L Phillips
- Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Maria Ibrahim
- Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Department of Statistics and Clinical Studies, National Health Service Blood and Transplant (NHSBT), Bristol, UK
| | - George H B Greenhall
- Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK.,Department of Statistics and Clinical Studies, National Health Service Blood and Transplant (NHSBT), Bristol, UK
| | - Lisa Mumford
- Department of Statistics and Clinical Studies, National Health Service Blood and Transplant (NHSBT), Bristol, UK
| | - Anthony Dorling
- Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Chris J Callaghan
- Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK
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Nassar M, Nso N, Ariyaratnam J, Sandhu J, Mohamed M, Baraka B, Ibrahim A, Alfishawy M, Zheng D, Bhangoo H, Soliman KM, Li M, Rizzo V, Daoud A. Coronavirus disease 2019 and renal transplantation. World J Clin Cases 2021; 9:7986-7997. [PMID: 34621855 PMCID: PMC8462194 DOI: 10.12998/wjcc.v9.i27.7986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/17/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Ever since the severe acute respiratory syndrome virus causing coronavirus disease 2019 (COVID-19) struck the world, global health strategies have changed significantly. According to the Centers for Disease Control and Prevention, kidney transplant recipients are stratified as being high risk of developing fatal illness from COVID-19 infection. Kidney transplant is the gold-standard treatment for end-stage kidney disease subjects. During the pandemic, significant concerns have emerged regarding continuation of kidney transplant surgeries and management of kidney transplant recipients post-transplant. The added risk of immunosuppression in this cohort was and remains a theoretical concern, posing a potential risk of transplantation rather than benefit. This comprehensive review aims to cover most of the faced challenges in kidney transplantation in different stages of the pandemic. In addition, it will elucidate the epidemiology, nature, course of the disease, surgical consideration in donors and recipients as well as role of immunosuppression and management of COVID-19 infected kidney transplant recipients during these extraordinary circumstances.
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Affiliation(s)
- Mahmoud Nassar
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Nso Nso
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Jonathan Ariyaratnam
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Jasmine Sandhu
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Mahmoud Mohamed
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Bahaaeldin Baraka
- Department of Oncology, Southend University Hospital, NHS Foundation Trust, Essex SS0 0RY, United Kingdom
| | - Atif Ibrahim
- Renal Division, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Mostafa Alfishawy
- Infectious Diseases, Infectious Diseases Consultants and Academic Researchers of Egypt IDCARE, Cairo 0000, Egypt
| | - David Zheng
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Harangad Bhangoo
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Karim M Soliman
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Matthew Li
- Department of Clinical Pharmacy, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 10029, United States
| | - Vincent Rizzo
- Department of Medicine, Icahn School of Medicine at Mount Sinai (NYC Health and Hospitals: Queens), New York, NY 11373, United States
| | - Ahmed Daoud
- Department of Medicine, Kasr Alainy Medical School, Cairo University, Cairo 11562, Egypt
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Goyal A, Hemachandran N, Kumar A, Sharma R, Shamim SA, Bansal VK, Das CJ, Kandasamy D, Agarwal SK, Dinda AK, Seenu V. Evaluation of the Graft Kidney in the Early Postoperative Period: Performance of Contrast-Enhanced Ultrasound and Additional Ultrasound Parameters. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2021; 40:1771-1783. [PMID: 33184930 DOI: 10.1002/jum.15557] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/19/2020] [Accepted: 10/05/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVES To evaluate the various quantitative parameters of Doppler ultrasound, contrast-enhanced ultrasound (CEUS), and shear wave elastography (SWE) of graft kidneys in the early postoperative period and to explore their utility in the diagnosis of parenchymal causes of graft dysfunction. METHODS In this ethically approved study, consecutive patients who underwent renal transplantation from March 2017 to August 2018 were recruited, and those with urologic or vascular complications and those who denied consent were excluded. All patients underwent ultrasound with Doppler, SWE, CEUS (using sulfur hexafluoride), and renal scintigraphic examinations 3 to 10 days after transplantation. A composite reference standard was used, including the clinical course, renal function test results, urine output, and histopathologic results for graft dysfunction. Cortical SWE values, quantitative CEUS parameters (generated from a time-intensity curve), and their ratios were analyzed to identify graft dysfunction and differentiate acute tubular necrosis (ATN) from acute rejection (AR). RESULTS Of the 105 patients included, 19 developed graft dysfunction (18.1%; 12 ATN, 5 AR, and 2 drug toxicity) in the early postoperative period. The peak systolic velocity in the interpolar artery showed a significant difference between control and graft dysfunction groups (P < .001) as well as between ATN and AR (P = .019). Resistive indices and SWE did not show significant differences. Ratios of the time to peak showed a significant difference between control and graft dysfunction groups (P < .05). The rise time and fall time of the large subcapsular region of interest and the rise time ratio were significantly different between ATN and AR (P = .03). CONCLUSIONS Contrast-enhanced ultrasound can be used to diagnose parenchymal causes of early graft dysfunction with reasonable diagnostic accuracy.
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Affiliation(s)
- Ankur Goyal
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Naren Hemachandran
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Atin Kumar
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Raju Sharma
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Shamim Ahmed Shamim
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Virinder Kumar Bansal
- Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
| | - Chandan Jyoti Das
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sanjay Kumar Agarwal
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Amit Kumar Dinda
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - V Seenu
- Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
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Ali AA, Almukhtar SE, Abd KH, Saleem ZSM, Sharif DA, Hughson MD. The causes and frequency of kidney allograft failure in a low-resource setting: observational data from Iraqi Kurdistan. BMC Nephrol 2021; 22:272. [PMID: 34364378 PMCID: PMC8349141 DOI: 10.1186/s12882-021-02486-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 07/28/2021] [Indexed: 12/18/2022] Open
Abstract
Background In the developing world, transplantation is the most common long-term treatment for patients with end-stage renal disease, but rates and causes of graft failure are uncertain. Methods This was a retrospective outcomes study of renal transplant patients seen in Iraqi Kurdistan nephrology clinics in the year 2019. In 2019, 871 renal transplant patients were registered and outcomes followed through 12/31/2020. Indicated renal biopsies were obtained on 431 patients at 1 day to 18 years post-transplantation. Outcomes were compared with United States Renal Data System (USRDS) living donor reports. Results All donors were living. The recipient age was 38.5 ± 13.3 years, 98.2% were < 65 years old, 3.7% had previous transplants, and 2.8% had pretransplant donor-specific antibodies (DSA). Gehan-Breslow estimated failure rates for all-cause, return to HD, and death with functional graft were 6.0, 4.2, and 1.9% at 1 year and 18.1, 13.7, and 5.1% at 5 years post-engraftment (USRDS 2000; 1 year: 7.0, 5.0, 2.6%; 5 year: 22.3, 15.2, 10.6%. USRDS 2010; 1 year: 3.7, 2.4, 1.4%; 5 year: 15.3, 9.6, 7.3%). The median graft survival was 15 years. Acute tubular injury (ATI), infarction, and acute T cell-mediated rejection accounted for 22.2% of graft loss, with > 75% of these failures taking place in the first year. Most graft failures occurred late, at a median post-transplant time of 1125 (interquartile range, 365–2555) days, and consisted of interstitial fibrosis and tubular atrophy (IF/TA) (23.8%), transplant glomerulopathy (13.7%), and acquired active antibody-mediated rejection (12.0%). The significant predictors of graft loss were C4d + biopsies (P < 0.01) and advanced IF/TA (P < 0.001). Conclusions Kurdistan transplant patients had graft failure rates similar to living donors reported by the USRDS for the year 2000 but higher than reported for 2010. Compared to USRDS 2010, Kurdistan patients had a moderate excess of HD failures at one and 5 years post-engraftment. Nevertheless, prolonged survival is the norm, with chronic disorders and acquired DSA being the leading causes of graft loss.
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Affiliation(s)
- Alaa Abbas Ali
- University of Sulaimani College of Medicine, Quirga Road, Sulaimani, Iraq
| | | | - Kais H Abd
- University of Dohuk College of Medicine, Dohuk, Iraq
| | | | - Dana A Sharif
- University of Sulaimani College of Medicine, Quirga Road, Sulaimani, Iraq
| | - Michael D Hughson
- University of Sulaimani College of Medicine, Quirga Road, Sulaimani, Iraq.
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Abstract
PURPOSE OF REVIEW Fibrosis is an important biomarker of chronic kidney injury, and a powerful predictor of renal outcome. Currently, the only method for measuring fibrotic burden is histologic analysis, which requires a kidney biopsy in humans, or kidney removal in animal models. These requirements have not only hindered our ability to manage patients effectively, but have also prevented a full understanding of renal fibrosis pathogenesis, and slowed the translation of new antifibrotic agents. The development of noninvasive fibrosis imaging tools could thus transform both clinical care and renal fibrosis research. RECENT FINDINGS Conventional imaging modalities have historically failed to image fibrosis successfully. However, recent exciting technological advances have greatly enhanced their capabilities. New techniques, for example, may allow imaging of the physical consequences of scarring, as surrogate measures of renal fibrosis. Similarly, other groups have developed ways to directly image extracellular matrix, either with the use of contrast-enhanced probes, or using matrix components as endogenous contrast agents. SUMMARY New developments in imaging technology have the potential to transform our ability to visualize renal fibrosis and to monitor its progression. In doing so, these advances could have major implications for kidney disease care, the development of new antiscarring agents, and our understanding of renal fibrosis in general.
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Teng Y, Huang Z, Yao L, Wang Y, Li T, Guo J, Wei R, Xia L, Wu Q. Emerging roles of long non-coding RNAs in allotransplant rejection. Transpl Immunol 2021; 70:101408. [PMID: 34015462 DOI: 10.1016/j.trim.2021.101408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/09/2021] [Accepted: 05/14/2021] [Indexed: 01/10/2023]
Abstract
Allotransplantation has extensively been employed for managing end-stage organ failure and malignant tumors. Acute and chronic post-transplant rejections are major causes of late morbidity and mortality after allotransplantation. However, there are no objective diagnostic criteria and specific therapy for post-transplant rejections. Owing to key advances in high-throughput RNA sequencing techniques, a wealth of studies have disclosed that long noncoding RNA (lncRNA) expression increased or decreased evidently in biopsies, blood, plasma, urine and specific cells of rejecting patients, and the dysregulated lncRNAs affected the cellular functions and differentiation of the immune system. Hence, we present an overview of the functions of lncRNAs expressed in various immune cells related to allotransplant rejection. Moreover, our review explores the regulatory interplay of relevant lncRNAs and recipients with or without allograft rejection after solid organ transplantations or hematopoietic stem cell transplantation, then discuss whether these relevant lncRNAs can be molecular biomarkers for diagnosis and new therapeutic targets in the management of post-transplanted patients.
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Affiliation(s)
- Yao Teng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenli Huang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lan Yao
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajun Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingjing Guo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruowen Wei
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linghui Xia
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Qiuling Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Fecal Metabolomics Reveals Distinct Profiles of Kidney Transplant Recipients and Healthy Controls. Diagnostics (Basel) 2021; 11:diagnostics11050807. [PMID: 33946812 PMCID: PMC8145417 DOI: 10.3390/diagnostics11050807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/14/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023] Open
Abstract
Monitoring graft recipients remains dependent on traditional biomarkers and old technologies lacking specificity, sensitivity, or accuracy. Recently, metabolomics is becoming a promising approach that may offer to kidney transplants a more effective and specific monitoring. Furthermore, emerging evidence suggested a fundamental role of gut microbiota as an important determinant of patients’ metabolomes. In the current study, we enrolled forty stable renal allografts recipients compared to twenty healthy individuals. Samples were taken at different time points from patient to patient following transplantation surgery, which varied from 3 months to 22 years post-graft. All patients started the immunosuppression therapy immediately following kidney graft (Day 0). Gas chromatography–mass spectrometry (GC–MS) was employed to perform untargeted analysis of fecal metabolites. Globally, the fecal metabolic signature was significantly different between kidney transplants and the control group. Fecal metabolome was dominated by lipids (sterols and fatty acids) in the stable transplant group compared to the controls (p < 0.05). Overall, 18 metabolites were significantly altered within kidney transplant recipients. Furthermore, the most notable altered metabolic pathways in kidney transplants include ubiquinone and other terpenoid-quinone biosynthesis, tyrosine metabolism, tryptophan biosynthesis, and primary bile acid biosynthesis. Fecal metabolites could effectively distinguish stable transplant recipients from controls, supporting the potential utility of metabolomics in rapid and non-invasive diagnosis to produce relevant biomarkers and to help clinicians in monitoring kidney transplants. Further investigations are needed to clarify the physiological relevance of fecal metabolome and to assess the impact of microbiota modulation.
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Caliskan Y, Karahan G, Akgul SU, Mirioglu S, Ozluk Y, Yazici H, Demir E, Dirim AB, Turkmen A, Edwards J, Savran FO, Sever MS, Kiryluk K, Gharavi A, Lentine KL. LIMS1 Risk Genotype and T-Cell Mediated Rejection in Kidney Transplant Recipients. Nephrol Dial Transplant 2021; 36:2120-2129. [PMID: 33909908 DOI: 10.1093/ndt/gfab168] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND This study aims to examine the association of LIM Zinc Finger Domain Containing 1 (LIMS1) genotype with allograft rejection in an independent kidney transplant cohort. METHODS We genotyped 841 kidney transplant recipients for LIMS1 rs893403 variant by Sanger sequencing followed by PCR confirmation of the deletion. Recipients who were homozygous for LIMS1 rs893403 genotype GG were compared to AA/AG genotypes. The primary outcome was T-cell mediated (TCMR) or antibody mediated rejection (ABMR) and secondary outcome was allograft loss. RESULTS After a median follow-up of 11.4 years, the rate of TCMR was higher in recipients with the GG (n = 200) compared to AA/AG (n = 641) genotypes [25 (12.5%) vs 35 (5.5%); p = 0.001] while ABMR did not differ by genotype [18 (9.0%) vs 62 (9.7%)]. Recipients with GG genotype had 2.4-times higher risk of TCMR than those who did not have this genotype (adjusted hazard ratio (aHR), 1.442.434.12, p = 0.001). A total of 189 (22.5%) recipients lost their allografts during follow up. Kaplan-Meier estimates of 5-year (94.3% vs. 94.4%, p = 0.99) and 10-year graft survival rates (86.9% vs. 83.4%, p = 0.31) did not differ significantly in those with GG compared to AA/AG groups. CONCLUSIONS Our study demonstrates that recipient LIMS1 risk genotype is associated with increased risk of TCMR after kidney transplantation, confirming the role of LIMS1 locus in allograft rejection. These findings may have clinical implications for the prediction and clinical management of kidney transplant rejection by pretransplant genetic testing of recipients and donors for LIMS1 risk genotype.
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Affiliation(s)
- Yasar Caliskan
- Division of Nephrology, Saint Louis University, Saint Louis, MO, USA.,Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Gonca Karahan
- Department of Medical Biology, Istanbul University School of Medicine, Turkey.,Leiden University Medical Center, Leiden, The Netherlands
| | - Sebahat Usta Akgul
- Department of Medical Biology, Istanbul University School of Medicine, Turkey
| | - Safak Mirioglu
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Yasemin Ozluk
- Department of Pathology, Istanbul University School of Medicine, Turkey
| | - Halil Yazici
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Erol Demir
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Ahmet B Dirim
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Aydin Turkmen
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - John Edwards
- Division of Nephrology, Saint Louis University, Saint Louis, MO, USA
| | - Fatma Oguz Savran
- Department of Medical Biology, Istanbul University School of Medicine, Turkey
| | - Mehmet S Sever
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | | | - Ali Gharavi
- Division of Nephrology, Columbia University Medical Center, NY, USA
| | - Krista L Lentine
- Division of Nephrology, Saint Louis University, Saint Louis, MO, USA
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Abstract
Interstitial fibrosis with tubule atrophy (IF/TA) is the response to virtually any sustained kidney injury and correlates inversely with kidney function and allograft survival. IF/TA is driven by various pathways that include hypoxia, renin-angiotensin-aldosterone system, transforming growth factor (TGF)-β signaling, cellular rejection, inflammation and others. In this review we will focus on key pathways in the progress of renal fibrosis, diagnosis and therapy of allograft fibrosis. This review discusses the role and origin of myofibroblasts as matrix producing cells and therapeutic targets in renal fibrosis with a particular focus on renal allografts. We summarize current trends to use multi-omic approaches to identify new biomarkers for IF/TA detection and to predict allograft survival. Furthermore, we review current imaging strategies that might help to identify and follow-up IF/TA complementary or as alternative to invasive biopsies. We further discuss current clinical trials and therapeutic strategies to treat kidney fibrosis.Supplemental Visual Abstract; http://links.lww.com/TP/C141.
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Chan CK, Chan KKJ, Liu N, Chan W. Quantitation of Protein Adducts of Aristolochic Acid I by Liquid Chromatography-Tandem Mass Spectrometry: A Novel Method for Biomonitoring Aristolochic Acid Exposure. Chem Res Toxicol 2021; 34:144-153. [PMID: 33410325 DOI: 10.1021/acs.chemrestox.0c00454] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Emerging evidence suggests that chronic exposure to aristolochic acids (AAs) is one of the etiological pathways leading to chronic kidney disease (CKD). Due to the traditional practice of herbal medicine and AA-containing plants being used extensively as medicinal herbs, over 100 million East Asians are estimated to be at risk of AA poisoning. Given that the chronic nephrotoxicity of AAs only manifests itself after decades of exposure, early diagnosis of AA exposure could allow for timely intervention and disease risk reduction. However, an early detection method is not yet available, and diagnosis can only be established at the end stage of CKD. The goal of this study was to develop a highly sensitive and selective method to quantitate protein adducts of aristolochic acid I (AAI) as a biomarker of AA exposure. The method entails the release of protein-bound aristolactam I (ALI) by heat-assisted alkaline hydrolysis, extraction of ALI, addition of internal standard, and quantitation by liquid chromatography-tandem mass spectrometric analysis. Accuracy and precision of the method were critically evaluated using a synthetic ALI-containing glutathione adduct. The validated method was subsequently used to detect dose-dependent formation of ALI-protein adducts in human serum albumin exposed to AAI and in proteins isolated from the tissues and sera of AAI-exposed rats. Our time-dependent study showed that ALI-protein adducts remained detectable in rats even at 28 days postdosing. It is anticipated that the developed method will fill the technical gap in diagnosing AA intoxication and facilitate the biomonitoring of human exposures to AAs.
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Affiliation(s)
- Chi-Kong Chan
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
| | - Kwan-Kit Jason Chan
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
| | - Ning Liu
- Central Laboratory, The Second Hospital of Jilin University, Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China
| | - Wan Chan
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
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Sahay M, Kunthara M, Hussain H, Ismal K, Vali PS, Kavadi A, Kumar BV. Posttransplant renal allograft dysfunction – A retrospective observational study. INDIAN JOURNAL OF TRANSPLANTATION 2021. [DOI: 10.4103/ijot.ijot_129_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Wu J, Zhang F, Zhang J, Sun Z, Wang W. Advances of miRNAs in kidney graft injury. Transplant Rev (Orlando) 2020; 35:100591. [PMID: 33309915 DOI: 10.1016/j.trre.2020.100591] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/14/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022]
Abstract
Kidney transplantation is the preferred treatment for patients with end-stage renal disease. However, various types of kidney graft injury after transplantation are still key factors that affect the survival of the kidney graft. Therefore, exploring the underlying mechanisms involved is very important. Current diagnostic measures for kidney graft injury (including needle biopsy, blood creatinine, eGFR, etc.) have many limiting factors such as invasiveness, insufficient sensitivity and specificity, so they cannot provide timely and effective information to clinicians. As for kidney grafts that have occurred injury, the traditional treatment has a little efficacy and many side effects. Therefore, there is an urgent need for developing new biomarkers and targeted treatment for kidney graft injury. Recently, studies have found that miRNAs are involved in the regulation of the progression of kidney graft injury. At the same time, it has high stability in blood, urine, and other body fluids, so it is suggested to have the potential as a biomarker and therapeutic target for kidney graft injury. Here, we reviewed the miRNAs involved in the pathophysiology of kidney graft injury such as ischemia/reperfusion injury, acute rejection, drug-induced nephrotoxicity, chronic allograft dysfunction, BK virus infection, and the latest advances of miRNAs as biomarkers and therapeutic targets of kidney graft injury, then summarized the specific data of miRNAs expression level in kidney graft injury, which aims to provide a reference for subsequent basic research and clinical transformation.
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Affiliation(s)
- Jiyue Wu
- Institute of Urology, Beijing Chaoyang Hospital, Capital Medical Unversity, China
| | - Feilong Zhang
- Institute of Urology, Beijing Chaoyang Hospital, Capital Medical Unversity, China
| | - Jiandong Zhang
- Institute of Urology, Beijing Chaoyang Hospital, Capital Medical Unversity, China
| | - Zejia Sun
- Institute of Urology, Beijing Chaoyang Hospital, Capital Medical Unversity, China
| | - Wei Wang
- Institute of Urology, Beijing Chaoyang Hospital, Capital Medical Unversity, China.
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Dattani R, Corbett RW, Galliford J, Hill P, Cairns T, Cook HT, Roufosse C, Ashby DR. The Effect of Kidney Biopsy on Glomerular Filtration Rate: A Frequent Patient Concern. Am J Nephrol 2020; 51:1-4. [PMID: 33311026 DOI: 10.1159/000511798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 09/24/2020] [Indexed: 11/19/2022]
Abstract
The effect of percutaneous kidney biopsy on glomerular filtration rate has never been identified, though it is frequently a concern raised by patients. Following a clinical interaction with an inquisitive patient undergoing her fifth biopsy, we attempted to estimate the effect using retrospective data. In a cohort of patients with stable kidney function undergoing transplant biopsy without clinical indication (as part of a surveillance programme) the effect of biopsy was observed as a step change in glomerular filtration rate. Reassuringly, the loss of glomerular filtration rate resulting from a biopsy, has a 1-sided 95% confidence interval of <1.4 mL/min.
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Affiliation(s)
- Rakesh Dattani
- Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom,
| | - Richard W Corbett
- Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Jack Galliford
- Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Peter Hill
- Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Tom Cairns
- Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - H Terence Cook
- Department of Immunology and Inflammation, Centre for Inflammatory Diseases, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Candice Roufosse
- Department of Immunology and Inflammation, Centre for Inflammatory Diseases, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Damien R Ashby
- Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
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Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts. J Nephrol 2020; 34:861-874. [PMID: 33275196 PMCID: PMC8192319 DOI: 10.1007/s40620-020-00886-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 10/08/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND In kidney transplantation, fibrosis represents the final and irreversible consequence of the pathogenic mechanisms that lead to graft failure, and in the late stages it irremediably precedes the loss of renal function. The invasiveness of kidney biopsy prevents this condition from being frequently monitored, while clinical data are rather unspecific. The objective of this study was to find noninvasive biomarkers of kidney rejection. METHODS We carried out proteomic analysis of the urinary Extracellular Vesicles (uEVs) from a cohort of kidney transplant recipients (n = 23) classified according to their biopsy-based diagnosis and clinical parameters as interstitial fibrosis and tubular atrophy (IFTA), acute cellular rejection (ACR), calcineurin inhibitors toxicity (CNIT) and normal kidney function (NKF). RESULTS Shotgun mass spectrometry of uEV-proteins identified differential expression of several proteins among these different groups. Up to 23 of these proteins were re-evaluated using targeted proteomics in a new independent cohort of patients (n = 41) classified in the same diagnostic groups. Among other results, we found a differential expression of vitronectin (VTN) in patients displaying chronic interstitial and tubular lesions (ci and ct mean > 2 according to Banff criteria). These results were further confirmed by a pilot study using enzyme-linked immunosorbent assay (ELISA). CONCLUSION Urinary vitronectin levels are a potential stand-alone biomarker to monitor fibrotic changes in kidney transplant recipients in a non-invasive fashion.
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Murray SL, Fennelly NK, Doyle B, Lynch SA, Conlon PJ. Integration of genetic and histopathology data in interpretation of kidney disease. Nephrol Dial Transplant 2020; 35:1113-1132. [PMID: 32777081 DOI: 10.1093/ndt/gfaa176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Indexed: 12/22/2022] Open
Abstract
For many years renal biopsy has been the gold standard for diagnosis in many forms of kidney disease. It provides rapid, accurate and clinically useful information in most individuals with kidney disease. However, in recent years, other diagnostic modalities have become available that may provide more detailed and specific diagnostic information in addition to, or instead of, renal biopsy. Genomics is one of these modalities. Previously prohibitively expensive and time consuming, it is now increasingly available and practical in a clinical setting for the diagnosis of inherited kidney disease. Inherited kidney disease is a significant cause of kidney disease, in both the adult and paediatric populations. While individual inherited kidney diseases are rare, together they represent a significant burden of disease. Because of the heterogenicity of inherited kidney disease, diagnosis and management can be a challenge and often multiple diagnostic modalities are needed to arrive at a diagnosis. We present updates in genomic medicine for renal disease, how genetic testing integrates with our knowledge of renal histopathology and how the two modalities may interact to enhance patient care.
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Affiliation(s)
- Susan L Murray
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.,Department of Medicine, Royal College of Surgeons, Dublin, Ireland
| | | | - Brendan Doyle
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
| | - Sally Ann Lynch
- National Rare Disease Office Mater Hospital Dublin, Dublin, Ireland
| | - Peter J Conlon
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.,Department of Medicine, Royal College of Surgeons, Dublin, Ireland
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Shin SH, Wendland MF, Vandsburger MH. Delayed urea differential enhancement CEST (dudeCEST)-MRI with T 1 correction for monitoring renal urea handling. Magn Reson Med 2020; 85:2791-2804. [PMID: 33180343 DOI: 10.1002/mrm.28583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE We demonstrate a method of delayed urea differential enhancement CEST for probing urea recycling action of the kidney using expanded multi-pool Lorentzian fitting and apparent exchange-dependent relaxation compensation. METHODS T1 correction of urea CEST contrast by apparent exchange-dependent relaxation was tested in phantoms. Nine mice were scanned at 7 Tesla following intraperitoneal injection of 2M 150 μL urea, and later saline. T1 maps and Z-spectra were acquired before and 20 and 40 min postinjection. Z-spectra were fit to a 7-pool Lorentzian model for CEST quantification and compared to urea assay of kidney homogenate. Renal injury was induced by aristolochic acid in 7 mice, and the same scan protocol was performed. RESULTS Apparent exchange-dependent relaxation corrected for variable T1 times in phantoms. Urea CEST contrast at +1 ppm increased significantly at both time points following urea injection in the inner medulla and papilla. When normalizing the postinjection urea CEST contrast to the corresponding baseline value, both urea and saline injection resulted in identical fold changes in urea CEST contrast. Urea assay of kidney homogenate showed a significant correlation to both apparent exchange-dependent relaxation (R2 = 0.4687, P = .0017) and non-T1 -corrected Lorentzian amplitudes (R2 = 0.4964, P = .0011). Renal injury resulted in increased T1 time in the cortex and reduced CEST contrast change upon urea and saline infusion. CONCLUSION Delayed urea enhancement following infusion can provide insight into renal urea handling. In addition, changes in CEST contrast at 1.0 ppm following saline infusion may provide insight into renal function.
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Affiliation(s)
- Soo Hyun Shin
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
| | - Michael F Wendland
- Berkeley Preclinical Imaging Core (BPIC), University of California, Berkeley, Berkeley, California, USA
| | - Moriel H Vandsburger
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
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Wang JH, Liu XL, Sun JM, Yang JH, Xu DH, Yan SS. Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review. World J Stem Cells 2020; 12:879-896. [PMID: 32952864 PMCID: PMC7477661 DOI: 10.4252/wjsc.v12.i8.879] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/02/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been reported to possess immune regulatory effects in innate and adaptive immune reactions. MSCs can mediate intercellular communications by releasing extracellular vesicles (EVs), which deliver functional molecules to targeted cells. MSC derived EVs (MSC-EVs) confer altering effects on many immune cells, including T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages. A large number of studies have suggested that MSC-EVs participate in regulating autoimmunity related diseases. This characteristic of MSC-EVs makes them be potential biomarkers for the diagnosis and treatment of autoimmunity related diseases.
AIM To verify the potential of MSC-EVs for molecular targeted therapy of autoimmunity related diseases.
METHODS Literature search was conducted in PubMed to retrieve the articles published between 2010 and 2020 in the English language. The keywords, such as “MSCs,” “EVs,” “exosome,” “autoimmunity,” “tumor immunity,” and “transplantation immunity,” and Boolean operator “AND” and “NOT” coalesced admirably to be used for searching studies on the specific molecular mechanisms of MSC-EVs in many immune cell types and many autoimmunity related diseases. Studies that did not investigate the molecular mechanisms of MSC-EVs in the occurrence and development of autoimmune diseases were excluded.
RESULTS A total of 96 articles were chosen for final reference lists. After analyzing those publications, we found that it had been well documented that MSC-EVs have the ability to induce multiple immune cells, like T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages, to regulate immune responses in innate immunity and adaptive immunity. Many validated EVs-delivered molecules have been identified as key biomarkers, such as proteins, lipids, and nucleotides. Some EVs-encapsulated functional molecules can serve as promising therapeutic targets particularly for autoimmune disease.
CONCLUSION MSC-EVs play an equally important part in the differentiation, activation, and proliferation of immune cells, and they may become potential biomarkers for diagnosis and treatment of autoimmunity related diseases.
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Affiliation(s)
- Jing-Hua Wang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Xiao-Ling Liu
- Department of Emergency Medicine, Yantai Shan Hospital, Yantai 264001, Shandong Province, China
| | - Jian-Mei Sun
- Department of Chemistry, School of Applied Chemistry, Food and Drug, Weifang Engineering Vocational College, Qingzhou 262500, Shandong Province, China
| | - Jing-Han Yang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Dong-Hua Xu
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Central Laboratory of the First Affiliated Hospital, Weifang 261000, Shandong Province, China
| | - Shu-Shan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
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47
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Zhang Y, Ou M, Lin H, Lai L, Chen H, Chen J, Sui W, Xue W, Zhang R, Gan Q, Tang D, Sun X, Dong J, Yan Q, Dai Y. Proteomic analysis of differentially expressed proteins in the serum of patients with acute renal allograft rejection using iTRAQ labelling technology. Mol Med Rep 2020; 22:2329-2341. [PMID: 32705285 PMCID: PMC7411402 DOI: 10.3892/mmr.2020.11299] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 04/07/2020] [Indexed: 12/24/2022] Open
Abstract
Transplantation is currently the best treatment for patients with end‑stage renal disease. However, acute rejection (AR) is the major source of failure in renal transplantation. The current best practice for the diagnosis of AR involves renal biopsy, but it is invasive, time‑consuming, costly and inconvenient. Sensitive and less invasive detection of AR episodes in renal transplant patients is essential to preserve allograft function. The present study applied isobaric tags for relative and absolute quantitation (iTRAQ) mass spectrometry to analyze serum protein expression in patients with AR and healthy controls. Overall, 1,399 proteins were identified. Using a cut‑off of Q<0.05 and a fold change of >1.2 for the variation in expression, 109 proteins were identified to be differentially expressed between the AR and control groups, 72 of which were upregulated and 37 were downregulated. Several proteins, including properdin, keratin 1, lipoprotein(a) and vitamin D‑binding protein, may have roles in the pathogenesis of AR. The present study focused on iTRAQ‑based proteomic profiling of serum samples in AR. Insight from the present study may help advance the understanding of the molecular mechanisms of AR and identify potential novel biomarkers of AR for further characterization.
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Affiliation(s)
- Yue Zhang
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Minglin Ou
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Hua Lin
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Liusheng Lai
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Huaizhou Chen
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Jiejing Chen
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Weiguo Sui
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Wen Xue
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Ruohan Zhang
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Qing Gan
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Donge Tang
- Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, P.R. China
| | - Xuyong Sun
- Department of Organ Transplantation, Institute of Transplant Medicine, No. 923 Hospital of People's Liberation Army, Guangxi Key Laboratory for Transplantation Medicine, Guangxi Transplantation Medicine Research Center of Engineering Technology, Nanning, Guangxi 530021, P.R. China
| | - Jianhui Dong
- Department of Organ Transplantation, Institute of Transplant Medicine, No. 923 Hospital of People's Liberation Army, Guangxi Key Laboratory for Transplantation Medicine, Guangxi Transplantation Medicine Research Center of Engineering Technology, Nanning, Guangxi 530021, P.R. China
| | - Qiang Yan
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
| | - Yong Dai
- Department of Nephrology, Guilin No. 924 Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Disease Research, Guilin, Guangxi 541002, P.R. China
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Di Stefano AB, Pappalardo M, Moschella F, Cordova A, Toia F. MicroRNAs in solid organ and vascularized composite allotransplantation: Potential biomarkers for diagnosis and therapeutic use. Transplant Rev (Orlando) 2020; 34:100566. [PMID: 32682704 DOI: 10.1016/j.trre.2020.100566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/23/2020] [Accepted: 06/30/2020] [Indexed: 12/24/2022]
Abstract
Nowadays, solid organ transplantation (SOT) is an established treatment for patients with end-organ dysfunction, which dramatically improves the quality-of-life. Vascularized composite allotransplants (VCAs) including hand and face have been reported worldwide over the last 20 years. However, VCAs, differently to SOT, are life-enhancing instead of life-saving and are not routinely performed due to the risk of immune rejection and the adverse effects of immunosuppression. Over the past decade, although considerable improvements in short-term outcomes after allotransplantation have been registered, these results have not been translated into major progress in long-term allograft acceptance and patient survival. Recently active researches in the field of biomarker discovery have been conducted to develop individualized therapies for allograft recipients. MicroRNAs (miRNAs) are a small noncoding RNAs functioning as critical regulators of gene and protein expression by RNA interference. They have been connected in numerous biological processes and diseases. Due to their immunomodulatory functions, miRNAs have been amended as potential diagnostic and prognostic biomarker for the detection of rejection in allotransplantation. Due to their specific circulating expression profile, they could act as noninvasive predictive tools for rejection that may help clinicians in an early adjustment of the immunosuppression protocol during acute rejections episodes. Indeed, specific anti-sense oligonucleotides suppressing miRNAs expressed in rejection could reduce the rejection rate in allografts and decrease the use of immunosuppressants. We present a literature review of the immunomodulatory properties and characteristics of miRNAs. We will summarize the current knowledge on miRNAs as potential biomarkers for allograft rejection and possible application in allotransplantation monitoring. Finally, we will discuss the advances in preclinical miRNA-based therapies for immunosuppression.
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Affiliation(s)
- Anna Barbara Di Stefano
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Marco Pappalardo
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Francesco Moschella
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Adriana Cordova
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
| | - Francesca Toia
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
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49
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Donor-derived Cell-free DNA in Infections in Kidney Transplant Recipients: Case Series. Transplant Direct 2020; 6:e568. [PMID: 32766423 PMCID: PMC7339327 DOI: 10.1097/txd.0000000000001019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/08/2020] [Accepted: 05/02/2020] [Indexed: 12/16/2022] Open
Abstract
Background. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive plasma biomarker to evaluate for transplant allograft rejection. The relationship between infectious complications in kidney allografts and dd-cfDNA has received cursory attention in prior publications. Methods. Retrospective review of all renal transplant recipients who underwent dd-cfDNA testing between November 2017 and August 2019. Results. We report on 7 cases in whom infections affecting the transplanted kidney were associated with elevation in dd-cfDNA without concomitant rejection or elevation in serum creatinine. Five patients had BK viremia, and 2 patients had urinary tract infection associated with elevated dd-cfDNA levels. Conclusions. These observations suggest that elevations in dd-cfDNA are not specific to kidney allograft rejection and can be associated with infections affecting the transplanted kidney. This biomarker may be valuable in evaluating infectious complications of kidney allografts.
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50
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Hysi E, He X, Fadhel MN, Zhang T, Krizova A, Ordon M, Farcas M, Pace KT, Mintsopoulos V, Lee WL, Kolios MC, Yuen DA. Photoacoustic imaging of kidney fibrosis for assessing pretransplant organ quality. JCI Insight 2020; 5:136995. [PMID: 32298239 DOI: 10.1172/jci.insight.136995] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Roughly 10% of the world's population has chronic kidney disease (CKD). In its advanced stages, CKD greatly increases the risk of hospitalization and death. Although kidney transplantation has revolutionized the care of advanced CKD, clinicians have limited ways of assessing donor kidney quality. Thus, optimal donor kidney-recipient matching cannot be performed, meaning that some patients receive damaged kidneys that function poorly. Fibrosis is a form of chronic damage often present in donor kidneys, and it is an important predictor of future renal function. Currently, no safe, easy-to-perform technique exists that accurately quantifies renal fibrosis. We describe a potentially novel photoacoustic (PA) imaging technique that directly images collagen, the principal component of fibrotic tissue. PA imaging noninvasively quantifies whole kidney fibrotic burden in mice, and cortical fibrosis in pig and human kidneys, with outstanding accuracy and speed. Remarkably, 3-dimensional PA imaging exhibited sufficiently high resolution to capture intrarenal variations in collagen content. We further show that PA imaging can be performed in a setting that mimics human kidney transplantation, suggesting the potential for rapid clinical translation. Taken together, our data suggest that PA collagen imaging is a major advance in fibrosis quantification that could have widespread preclinical and clinical impact.
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Affiliation(s)
- Eno Hysi
- Department of Physics, Ryerson University, Toronto, Canada.,Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael's Hospital, Toronto, Canada
| | - Xiaolin He
- Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael's Hospital, Toronto, Canada.,Division of Nephrology, Department of Medicine, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, Canada.,Keenan Research Centre for Biomedical Science and
| | - Muhannad N Fadhel
- Department of Physics, Ryerson University, Toronto, Canada.,Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael's Hospital, Toronto, Canada
| | - Tianzhou Zhang
- Division of Nephrology, Department of Medicine, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, Canada.,Keenan Research Centre for Biomedical Science and
| | - Adriana Krizova
- Keenan Research Centre for Biomedical Science and.,Department of Laboratory Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Canada
| | - Michael Ordon
- Keenan Research Centre for Biomedical Science and.,Department of Laboratory Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Canada.,Division of Urology, Department of Surgery, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, Ontario, Canada
| | - Monica Farcas
- Keenan Research Centre for Biomedical Science and.,Department of Laboratory Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Canada.,Division of Urology, Department of Surgery, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, Ontario, Canada
| | - Kenneth T Pace
- Keenan Research Centre for Biomedical Science and.,Department of Laboratory Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Canada.,Division of Urology, Department of Surgery, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, Ontario, Canada
| | - Victoria Mintsopoulos
- Keenan Research Centre for Biomedical Science and.,Interdepartmental Division of Critical Care Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Warren L Lee
- Keenan Research Centre for Biomedical Science and.,Interdepartmental Division of Critical Care Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Michael C Kolios
- Department of Physics, Ryerson University, Toronto, Canada.,Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael's Hospital, Toronto, Canada
| | - Darren A Yuen
- Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael's Hospital, Toronto, Canada.,Division of Nephrology, Department of Medicine, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, Canada.,Keenan Research Centre for Biomedical Science and
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