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Oruc A, Ersoy A, Ozkalemkas F, Gul CB, Yigit E, Yildiz A. Utilization and importance of timing of therapeutic plasma exchange in kidney transplantation: A single-center experience. Ther Apher Dial 2025; 29:516-524. [PMID: 40037344 DOI: 10.1111/1744-9987.70002] [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: 12/17/2024] [Revised: 02/06/2025] [Accepted: 02/17/2025] [Indexed: 03/06/2025]
Abstract
INTRODUCTION Therapeutic plasma exchange (TPE) is a prominent approach for specific conditions among renal transplant candidates and recipients. The indications of TPE, those related to kidney transplantation, are limited, and knowledge and utilization strategies are blurred. Herein, we aimed to review our clinical experience of TPE among renal transplant recipients. METHODS A total of 69 (40.22 ± 12.29 years, 40 males, 63.8% deceased donor) ABO blood type-compatible kidney transplant recipients who underwent TPE were evaluated between January 2013 and December 2019. RESULTS A median of 5 (IQR 4-7) TPE sessions was administered at a median duration of 31 (IQR 3-564) days after transplantation. The main indication was a rejection episode. A total of 61 (39.44 ± 12.22 years, 24 living donor, 10 re-transplant, 37 male) recipients were successfully discharged with a serum creatinine of 1.39 (IQR 1-1.91) mg/dL, and eGFR of 62 (IQR 39-94) ml/min. Comparing the recipients according to TPE timing, early administered 32 (52.5%) recipients with a median of 4 (IQR 4-7) days after transplantation had better graft survival (62.5% vs. 17.2%, p < 0.001), despite higher mortality rates (25% vs.10%, p < 0.001). The rate of graft loss was higher (62.1% vs. 9.4%, p < 0.001) among the recipients who required TPE during the late post-transplant period (756 [IQR 272-1307] days). CONCLUSION According to our findings, TPE could provide beneficial effects on graft and patient outcomes, and the timing of TPE could influence its efficiency. Further studies are needed to support our findings.
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Affiliation(s)
- Aysegul Oruc
- Division of Nephrology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
| | - Alparslan Ersoy
- Division of Nephrology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
| | - Fahir Ozkalemkas
- Division of Haematology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
| | - Cuma Bulent Gul
- Division of Nephrology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
| | - Elif Yigit
- Department of Internal Medicine, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
| | - Abdulmecit Yildiz
- Division of Nephrology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
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Kirn G, Chandran S, Rajalingam R, Feng S. Efficacy of Steroid Pulse to Treat Borderline T-Cell Mediated Rejection on Protocol Kidney Allograft Biopsy. Clin Transplant 2025; 39:e70171. [PMID: 40329132 DOI: 10.1111/ctr.70171] [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: 01/06/2025] [Revised: 04/12/2025] [Accepted: 04/17/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND Borderline T-cell mediated rejection (bTCMR) is the most common renal allograft rejection phenotype within 1-year post-transplant and is associated with allograft failure. There is substantial heterogeneity in bTCMR management; steroid pulse therapy is commonly used but data regarding efficacy are lacking. METHODS To determine whether steroid pulse improved allograft histology and/or function, we conducted a single-center retrospective cohort study of 201 patients diagnosed with bTCMR on protocol biopsy treated with either steroid pulse therapy (n = 138) or no specific therapy (n = 63). RESULTS Baseline characteristics were similar between groups, including Banff i- and t-scores. At follow-up, bTCMR resolved in 62% overall without any differences between the groups. More patients receiving steroid pulse therapy showed worsened interstitial fibrosis (30% vs. 10%; p = 0.020) and tubular atrophy (27% vs. 0%; p < 0.001). Longitudinal eGFR trajectory was lower (8.9 mL/min/1.73 m2 below predicted; 95%CI -15.56 to -2.16; p = 0.009) in steroid-treated individuals. Graft loss or mortality did not differ between groups at median 3.5-year follow-up. CONCLUSIONS Steroid therapy for bTCMR identified on protocol biopsy was not associated with histological resolution, reduced fibrosis, or improved graft function, potentially reflecting subtle differences in disease severity among the patients who were treated. Further research is needed to elucidate optimal bTCMR management strategies, considering patient-specific factors and the potential need for more intensive therapies.
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Affiliation(s)
- Georgia Kirn
- Department of Surgery, University of California, San Francisco, California, USA
| | - Sindhu Chandran
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Raja Rajalingam
- Department of Surgery, University of California, San Francisco, California, USA
| | - Sandy Feng
- Department of Surgery, University of California, San Francisco, California, USA
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Chou-Wu E, Niemann M, Youngs D, Gimferrer I. De Novo donor-specific anti-HLA antibody risk stratification in kidney transplantation using a combination of B cell and T cell molecular mismatch assessment. Front Immunol 2025; 16:1508796. [PMID: 40070832 PMCID: PMC11893832 DOI: 10.3389/fimmu.2025.1508796] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 02/04/2025] [Indexed: 03/14/2025] Open
Abstract
Introduction The presence of de novo donor-specific antibody (dnDSA) has detrimental effect on allograft outcomes in kidney transplantation. As humoral responses in transplantation are elicited targeting non-self-epitopes on donor HLA proteins, assessing HLA mismatches at the molecular level provides a refined means for immunological risk stratification. Methods In the present study, we utilized three HLA molecular mismatch assessment algorithms, Snow, HLAMatchmaker, and PIRCHE-II, to evaluate the independent and synergistic association of B cell and T cell epitope mismatches with dnDSA development in a cohort of 843 kidney transplant recipients. Results Our results demonstrated that B cell and T cell epitope mismatches at HLA Class I and DRB1/DQB1 loci are remarkably increased in dnDSA-positive recipients, even after normalization by allele mismatch numbers in individual study subjects. Furthermore, elevated Snow, verified eplet mismatches, and PIRCHE-II scores are significantly associated with dnDSA occurrence individually and in combination. Conclusion Our findings highlight the value of utilizing B cell and T cell epitope mismatch evaluation in living donor selection and immunological risk stratification to improve transplant outcomes.
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Affiliation(s)
- Elaine Chou-Wu
- Immunogenetics/HLA Laboratory, Bloodworks Northwest, Seattle, WA, United States
| | | | - Danny Youngs
- Immunogenetics/HLA Laboratory, Bloodworks Northwest, Seattle, WA, United States
| | - Idoia Gimferrer
- Immunogenetics/HLA Laboratory, Bloodworks Northwest, Seattle, WA, United States
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Ramalhete L, Araújo R, Vieira MB, Vigia E, Aires I, Ferreira A, Calado CRC. Integration of FTIR Spectroscopy and Machine Learning for Kidney Allograft Rejection: A Complementary Diagnostic Tool. J Clin Med 2025; 14:846. [PMID: 39941517 PMCID: PMC11818318 DOI: 10.3390/jcm14030846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/21/2025] [Accepted: 01/25/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Kidney transplantation is a life-saving treatment for end-stage kidney disease, but allograft rejection remains a critical challenge, requiring accurate and timely diagnosis. The study aims to evaluate the integration of Fourier Transform Infrared (FTIR) spectroscopy and machine learning algorithms as a minimally invasive method to detect kidney allograft rejection and differentiate between T Cell-Mediated Rejection (TCMR) and Antibody-Mediated Rejection (AMR). Additionally, the goal is to discriminate these rejection types aiming to develop a reliable decision-making support tool. Methods: This retrospective study included 41 kidney transplant recipients and analyzed 81 serum samples matched to corresponding allograft biopsies. FTIR spectroscopy was applied to pre-biopsy serum samples, and Naïve Bayes classification models were developed to distinguish rejection from non-rejection and classify rejection types. Data preprocessing involved, e.g., atmospheric compensation, second derivative, and feature selection using Fast Correlation-Based Filter for spectral regions 600-1900 cm-1 and 2800-3400 cm-1. Model performance was assessed via area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and accuracy. Results: The Naïve Bayes model achieved an AUC-ROC of 0.945 in classifying rejection versus non-rejection and AUC-ROC of 0.989 in distinguishing TCMR from AMR. Feature selection significantly improved model performance, identifying key spectral wavenumbers associated with rejection mechanisms. This approach demonstrated high sensitivity and specificity for both classification tasks. Conclusions: The integration of FTIR spectroscopy with machine learning may provide a promising, minimally invasive method for early detection and precise classification of kidney allograft rejection. Further validation in larger, more diverse populations is needed to confirm these findings' reliability.
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Affiliation(s)
- Luís Ramalhete
- Blood and Transplantation Center of Lisbon, Instituto Português do Sangue e da Transplantação, Alameda das Linhas de Torres, No. 117, 1769-001 Lisbon, Portugal
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- iNOVA4Health—Advancing Precision Medicine, RG11: Reno-Vascular Diseases Group, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal
| | - Rúben Araújo
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
| | - Miguel Bigotte Vieira
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, 1049-001 Lisbon, Portugal
| | - Emanuel Vigia
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- Centro Hospitalar Universitário de Lisboa Central, Hepatobiliopancreatic and Transplantation Center—Curry Cabral Hospital, 1069-166 Lisbon, Portugal
| | - Inês Aires
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, 1049-001 Lisbon, Portugal
| | - Aníbal Ferreira
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal; (R.A.)
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, 1049-001 Lisbon, Portugal
| | - Cecília R. C. Calado
- ISEL—Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro 1, 1959-007 Lisbon, Portugal;
- Institute for Bioengineering and Biosciences (iBB), The Associate Laboratory Institute for Health and Bioeconomy–i4HB, Instituto Superior Técnico (IST), Universidade de Lisboa (UL), Av. Rovisco Pais, 1049-001 Lisbon, Portugal
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Kumar D, Raju N, Tanriover B, Azzouz L, Moinuddin I, Philogene M, Kamal L, McDougan F, Massey HD, Muthusamy S, Lee I, Halloran P, Gupta G. Tissue-based Gene Expression Diagnosis of Mild and Moderate T-cell-mediated Rejection to Guide Therapy in Kidney Transplants. Transplantation 2024:00007890-990000000-00962. [PMID: 39710875 DOI: 10.1097/tp.0000000000005296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
BACKGROUND Mild histologic lesions of tubulo-interstitial inflammation could represent a "response-to-wounding" rather than allorecognition. Tissue gene expression may complement histopathology for T-cell-mediated rejection (TCMR) diagnostics. METHODS We report on the incorporation of tissue gene expression testing using a Molecular Microscope Diagnostic System into the management of kidney transplant biopsies with suspected TCMR. Patients (N = 209) were divided into 3 groups based upon diagnosis and TCMR therapy (with high-dose steroids and/or anti-thymocyte globulin): Group 1: Untreated histologic TCMR with molecular quiescence (H+M-); Group 2: Treated histologic and molecular TCMR (H+M+); and Group 3: Controls, with no histologic or molecular (H-M-) rejection. RESULTS At biopsy, estimated glomerular filtration rate was worse (P = 0.006) in H+M+ (N = 35; 33 ± 22 mL/min/1.73 m2) and H+M- (N = 30; 40 ± 18 mL/min/1.73 m2) groups; compared with H-M- (N = 144; 47 ± 24 mL/min/1.73 m2) group. In H+M- biopsies, mean molecular acute kidney injury scores (0.33 versus 0.10; P = 0.03) were higher than in H-M-; while molecular TCMR was lower compared with H+M+ (0.04 versus 0.54; P < 0.001). At 12 m postbiopsy estimated glomerular filtration rate remained low (P < 0.001) in H+M+ (38 ± 22 mL/min/1.73 m2) but improved in untreated H+M- (44 ± 22 mL/min/1.73 m2) and H-M- (50 ± 23 mL/min/1.73 m2) groups. At a mean follow-up of 2.1 ± 1.2 y post-index biopsy, death-censored graft survival was lower in H+M+ (74%) than in H+M- (90%) and H-M- (92%; P = 0.001). H+M+ cases had numerically higher rejection on follow-up biopsy (20%) than H+M- (7%) (P = 0.12) and de novo donor-specific antibody formation (H+M+ 24%; H+M- 10%; P = 0.13). CONCLUSIONS In this large single-center study, biopsies with untreated histological TCMR and molecular quiescence had comparable clinical outcomes to cases with no rejection, whereas those with histologic and tissue gene expression confirmed TCMR had inferior outcomes.
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Affiliation(s)
- Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Nihar Raju
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | | | - Louiza Azzouz
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Irfan Moinuddin
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Mary Philogene
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Layla Kamal
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Felecia McDougan
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Hugh Davis Massey
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | | | - Inkoo Lee
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | | | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
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Ettenger RB, Seifert ME, Blydt-Hansen T, Briscoe DM, Holman J, Weng PL, Srivastava R, Fleming J, Malekzadeh M, Pearl M. Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices. Pediatr Transplant 2024; 28:e14836. [PMID: 39147695 DOI: 10.1111/petr.14836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024]
Abstract
INTRODUCTION The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION ClinicalTrials.gov: NCT03719339.
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Affiliation(s)
- Robert B Ettenger
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michael E Seifert
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Tom Blydt-Hansen
- Multi-Organ Transplant Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - David M Briscoe
- Division of Nephrology, Department of Pediatrics Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John Holman
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Patricia L Weng
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Rachana Srivastava
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - James Fleming
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Mohammed Malekzadeh
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Meghan Pearl
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Palmisano A, D'Angelo M, Gandolfini I, Delsante M, Rossi GM, Gentile M, Fiaccadori E, Cravedi P, Maggiore U. Borderline rejection: To treat or not to treat? Transpl Immunol 2024; 84:102047. [PMID: 38641147 DOI: 10.1016/j.trim.2024.102047] [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: 02/17/2024] [Revised: 04/16/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
INTRODUCTION It is unclear whether kidney transplant recipients with a biopsy diagnosis as a "borderline" acute T-cell mediated rejection (TCMR) requires the treatment with intravenous (iv) steroids pulse plus/minus intensification of the maintenance therapy (TRT) in comparison with the simple clinical follow-up (F-UP). METHODS We retrospectively followed a consecutive series of kidney transplant recipients diagnosed with a borderline acute TCMR at biopsy by surveillance or clinical indication for 12 months and compared TRT and F-UP groups. We evaluated trends in renal function by measuring estimated glomerular filtration rate (eGFR) using multiple regression models. Repeated eGFR measures (REML) were adjusted for potential confounding factors for 12 months. The difference in 12-month eGFR values were observed in the TRT vs F-UP groups, type of biopsy, as well as the surveillance vs. clinical outcomes. RESULTS Out of 59 included patients, 37% of them were in the TRT group and remaining 63% in the F-UP group. As expected, the TRT group had, at the time of biopsy, lower eGFR value of 39.0 ml/min/m2 [16.5] in comparison to 49.6 [19.6] ml/min/m2 in the F-UP group (P = 0.043), Similarly, the TRT group required more frequent clinical biopsies vs. F-UP group (68% vs. 32%; P = 0.014). However, the TRT group recovered kidney function reaching the eGFR values of the F-UP group at 12 months; the increase being significant only in patients who received indication biopsies (P < 0.001). The estimated adjusted TRT effect on 12-month eGFR change after indication biopsy was improved by +15.8 ml/min/1.73m2 (95%CI: +0.1 to +31.4 ml/min/1.73 m2; P = 0.048 by three-way interaction term) compared to the F-UP group. CONCLUSION Our preliminary study supports the indication for the treatment of acute borderline TCMR only in cases with biopsies performed by clinical indication.
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Affiliation(s)
- Alessandra Palmisano
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Marta D'Angelo
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Ilaria Gandolfini
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Marco Delsante
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Giovanni Maria Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Micaela Gentile
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Enrico Fiaccadori
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Paolo Cravedi
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Umberto Maggiore
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy.
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Mengel M, Adam BA. Emerging phenotypes in kidney transplant rejection. Curr Opin Organ Transplant 2024; 29:97-103. [PMID: 38032262 DOI: 10.1097/mot.0000000000001130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
PURPOSE OF REVIEW This review focuses on more recently emerging rejection phenotypes in the context of time post transplantation and the resulting differential diagnostic challenges. It also discusses how novel ancillary diagnostic tools can potentially increase the accuracy of biopsy-based rejection diagnosis. RECENT FINDINGS With advances in reducing immunological risk at transplantation and improved immunosuppression treatment renal allograft survival improved. However, allograft rejection remains a major challenge and represent a frequent course for allograft failure. With prolonged allograft survival, novel phenotypes of rejection are emerging, which can show complex overlap and transition between cellular and antibody-mediated rejection mechanisms as well as mixtures of acute/active and chronic diseases. With the emerging complexity in rejection phenotypes, it is crucial to achieve diagnostic accuracy in the individual patient. SUMMARY The prospective validation and adoption of novel molecular and computational diagnostic tools into well defined and appropriate clinical context of uses will improve our ability to accurately diagnose, stage, and grade allograft rejection.
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Affiliation(s)
- Michael Mengel
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta, Canada
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López Del Moral C, Wu K, Naik M, Osmanodja B, Akifova A, Lachmann N, Stauch D, Hergovits S, Choi M, Bachmann F, Halleck F, Schrezenmeier E, Schmidt D, Budde K. Predictors of graft failure after first detection of de novo donor-specific HLA antibodies in kidney transplant recipients. Nephrol Dial Transplant 2023; 39:84-94. [PMID: 37410616 DOI: 10.1093/ndt/gfad149] [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: 03/06/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. METHODS All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000-31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. RESULTS During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5-5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4-2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6-4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8-3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. CONCLUSIONS Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints.
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Affiliation(s)
- Covadonga López Del Moral
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Nephrology, Marqués de Valdecilla University Hospital-IDIVAL, Santander, Spain
| | - Kaiyin Wu
- Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Marcel Naik
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Bilgin Osmanodja
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Aylin Akifova
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nils Lachmann
- Institute for Transfusion Medicine, HLA-Laboratory, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Diana Stauch
- Institute for Transfusion Medicine, HLA-Laboratory, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sabine Hergovits
- Institute for Transfusion Medicine, HLA-Laboratory, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Mira Choi
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Friederike Bachmann
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Charité - Universitätsmedizin Berlin, BIH Academy, Berlin, Germany
| | - Danilo Schmidt
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Wiebe C, Balshaw R, Gibson IW, Ho J, Shaw J, Karpinski M, Trachtenberg A, Pochinco D, Goldberg A, Birk P, Pinsk M, Rush DN, Nickerson PW. A rational approach to guide cost-effective de novo donor-specific antibody surveillance with tacrolimus immunosuppression. Am J Transplant 2023; 23:1882-1892. [PMID: 37543094 DOI: 10.1016/j.ajt.2023.07.025] [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: 05/12/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/07/2023]
Abstract
De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.
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Affiliation(s)
- Chris Wiebe
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Shared Health Services Manitoba, Winnipeg, Manitoba, Canada.
| | - Rob Balshaw
- George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ian W Gibson
- Shared Health Services Manitoba, Winnipeg, Manitoba, Canada; Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Julie Ho
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Shared Health Services Manitoba, Winnipeg, Manitoba, Canada
| | - Jamie Shaw
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Martin Karpinski
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Aaron Trachtenberg
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Aviva Goldberg
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Patricia Birk
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Maury Pinsk
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David N Rush
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Shared Health Services Manitoba, Winnipeg, Manitoba, Canada
| | - Peter W Nickerson
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Shared Health Services Manitoba, Winnipeg, Manitoba, Canada
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11
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Alves TA, Nascimento E, de Castro LB, Fabreti-Oliveira RA. Impact of HLA eplet mismatch load in immunological outcomes after living donor kidney transplantation. Transpl Immunol 2023; 80:101908. [PMID: 37536379 DOI: 10.1016/j.trim.2023.101908] [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: 05/01/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/05/2023]
Abstract
INTRODUCTION HLA eplets mismatches (eMM) have been associated with negative kidney outcomes after transplantation, such as the development of de novo donor-specific antibody (dnDSA), antibody-mediated rejection (ABMR), and early graft loss. This study aimed to evaluate the clinical effects of the HLA eMM load on dnDSA development, ABMR, renal function, allograft survival and graft loss. MATERIAL AND METHODS This retrospective study involved 159 living donor kidney transplant patients categorized into groups based on antigen HLA mismatches assessed traditionally and HLA eMM load. Patients had followed for at least one year. The EpViX online program was used to evaluate the HLA eMM load. Cox models were constructed to assess the risk of graft loss. Kaplan-Meier survival curves were carried out. The analyses had performed using the R program and p < 0.05 was considered significant. RESULTS From all 159 patients, 28 (17.6%) lost their allografts. Rejection episodes occurred in 37.1% of patients, 13.6% of whom were ABMR. Patients with rejection episodes had higher HLA-AB (p = 0.032) and HLA-DR (p = 0.008) HLA eMM load, HLA-AB (p = 0.006) and HLA-DR (p = 0.009) antigens mismatches, and higher proportions of the following eMM in the HLA-DR locus: 70R eMM (p = 0.015), 70RE (p = 0.015), 74E (p = 0.015) and 48Q (p = 0.047). In multiple models, the presence of HLA-DR 70qq eMM (HR 3.75, 95% CI 1.47; 9.55) add an increase in creatinine levels at 1-year (HR 3.87, 95% CI 2.30, 6.53) were associated with the risk of graft loss. CONCLUSION The HLA eMM load was related to episodes of rejection and allograft loss. The HLA-DR eMM was most strongly associated with a worse immunologic outcome than eMM mismatches for HLA-AB.
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Affiliation(s)
- Thiago Abramo Alves
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil; University Hospital of the Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil.
| | - Evaldo Nascimento
- IMUNOLAB - Laboratory of Histocompatibility, Belo Horizonte, Minas Gerais, Brazil; Institute of Research and Education of the Hospital Santa Casa, Belo Horizonte, Minas Gerais, Brazil.
| | | | - Raquel Aparecida Fabreti-Oliveira
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil; IMUNOLAB - Laboratory of Histocompatibility, Belo Horizonte, Minas Gerais, Brazil.
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12
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Mubarak M, Raza A, Rashid R, Shakeel S. Evolution of human kidney allograft pathology diagnostics through 30 years of the Banff classification process. World J Transplant 2023; 13:221-238. [PMID: 37746037 PMCID: PMC10514746 DOI: 10.5500/wjt.v13.i5.221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 09/15/2023] Open
Abstract
The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide. This activity was, however, accompanied by many issues and challenges. An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are, a big challenge. Kidney allograft biopsy played a vital role in addressing the above challenge. However, its interpretation was not standardized for many years until, in 1991, the Banff process was started to fill this void. Thereafter, regular Banff meetings took place every 2 years for the past 30 years. Marked changes have taken place in the interpretation of kidney allograft biopsies, diagnosis, and classification of rejection and other non-rejection pathologies from the original Banff 93 classification. This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process. It will interest the transplant surgeons, physicians, pathologists, and allied professionals associated with the care of kidney transplant patients.
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Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Amber Raza
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Rahma Rashid
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Shaheera Shakeel
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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13
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Alasfar S, Kodali L, Schinstock CA. Current Therapies in Kidney Transplant Rejection. J Clin Med 2023; 12:4927. [PMID: 37568328 PMCID: PMC10419508 DOI: 10.3390/jcm12154927] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Despite significant advancements in immunosuppressive therapies, kidney transplant rejection continues to pose a substantial challenge, impacting the long-term survival of grafts. This article provides an overview of the diagnosis, current therapies, and management strategies for acute T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). TCMR is diagnosed through histological examination of kidney biopsy samples, which reveal the infiltration of mononuclear cells into the allograft tissue. Corticosteroids serve as the primary treatment for TCMR, while severe or steroid-resistant cases may require T-cell-depleting agents, like Thymoglobulin. ABMR occurs due to the binding of antibodies to graft endothelial cells. The most common treatment for ABMR is plasmapheresis, although its efficacy is still a subject of debate. Other current therapies, such as intravenous immunoglobulins, anti-CD20 antibodies, complement inhibitors, and proteasome inhibitors, are also utilized to varying degrees, but their efficacy remains questionable. Management decisions for ABMR depend on the timing of the rejection episode and the presence of chronic changes. In managing both TCMR and ABMR, it is crucial to optimize immunosuppression and address adherence. However, further research is needed to explore newer therapeutics and evaluate their efficacy.
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Affiliation(s)
- Sami Alasfar
- Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA;
| | - Lavanya Kodali
- Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA;
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14
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Ho J, Schaub S, Jackson AM, Balshaw R, Carroll R, Cun S, De Serres SA, Fantus D, Handschin J, Hönger G, Jevnikar AM, Kleiser M, Lee JH, Li Y, Nickerson P, Pei R, Pochinco D, Shih R, Trinh M, Wang J, Nguyen J, Knechtle S. Multicenter Validation of a Urine CXCL10 Assay for Noninvasive Monitoring of Renal Transplants. Transplantation 2023; 107:1630-1641. [PMID: 36949034 DOI: 10.1097/tp.0000000000004554] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
BACKGROUND Urine CXCL10 (C-X-C motif chemokine ligand 10, interferon gamma-induced protein 10 [IP10]) outperforms standard-of-care monitoring for detecting subclinical and early clinical T-cell-mediated rejection (TCMR) and may advance TCMR therapy development through biomarker-enriched trials. The goal was to perform an international multicenter validation of a CXCL10 bead-based immunoassay (Luminex) for transplant surveillance and compare with an electrochemiluminescence-based (Meso Scale Discovery [MSD]) assay used in transplant trials. METHODS Four laboratories participated in the Luminex assay development and evaluation. Urine CXCL10 was measured by Luminex and MSD in 2 independent adult kidney transplant trial cohorts (Basel and TMCT04). In an independent test and validation set, a linear mixed-effects model to predict (log 10 -transformed) MSD CXCL10 from Luminex CXCL10 was developed to determine the conversion between assays. Net reclassification was determined after mathematical conversion. RESULTS The Luminex assay was precise, with an intra- and interassay coefficient of variation 8.1% and 9.3%; showed modest agreement between 4 laboratories (R 0.96 to 0.99, P < 0.001); and correlated with known CXCL10 in a single- (n = 100 urines, R 0.94 to 0.98, P < 0.001) and multicenter cohort (n = 468 urines, R 0.92, P < 0.001) but the 2 assays were not equivalent by Passing-Bablok regression. Linear mixed-effects modeling demonstrated an intercept of -0.490 and coefficient of 1.028, showing Luminex CXCL10 are slightly higher than MSD CXCL10, but the agreement is close to 1.0. After conversion of the biopsy thresholds, the decision to biopsy would be changed for only 6% (5/85) patients showing acceptable reclassification. CONCLUSIONS These data demonstrate this urine CXCL10 Luminex immunoassay is robust, reproducible, and accurate, indicating it can be readily translated into clinical HLA laboratories for serial posttransplant surveillance.
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Affiliation(s)
- Julie Ho
- Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, Canada
- Transplant Manitoba, Shared Health Manitoba, Winnipeg, Canada
| | - Stefan Schaub
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | | | - Robert Balshaw
- George and Fay Yee Center for Healthcare Innovation, Manitoba, Canada
| | - Robert Carroll
- Royal Adelaide Hospital, University of Adelaide, SA, Australia
| | - Sylvia Cun
- Thermo Fisher Scientific, Los Angeles, CA
| | | | - Daniel Fantus
- Division of Nephrology, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM) and Centre de Recherche du CHUM (CRCHUM), Montréal, Québec, Canada
| | - Joelle Handschin
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gideon Hönger
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Anthony M Jevnikar
- Department of Medicine, Western University and Multiorgan Transplant Program, London, ON, Canada
| | - Marc Kleiser
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | | | - Yan Li
- Department of Surgery and Immunology, Duke University, Durham, NC
| | - Peter Nickerson
- Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, Canada
- Transplant Manitoba, Shared Health Manitoba, Winnipeg, Canada
- Canadian Blood Services HLA Laboratory, Diagnostic Services of Manitoba, Canada
| | - Rui Pei
- Thermo Fisher Scientific, Los Angeles, CA
| | - Denise Pochinco
- Canadian Blood Services HLA Laboratory, Diagnostic Services of Manitoba, Canada
| | - Remi Shih
- Terasaki Innovation Center, Los Angeles, CA
| | | | - Jason Wang
- Thermo Fisher Scientific, Los Angeles, CA
| | | | - Stuart Knechtle
- Department of Surgery and Immunology, Duke University, Durham, NC
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15
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Cherukuri A, Abou-Daya KI, Chowdhury R, Mehta RB, Hariharan S, Randhawa P, Rothstein DM. Transitional B cell cytokines risk stratify early borderline rejection after renal transplantation. Kidney Int 2023; 103:749-761. [PMID: 36436679 PMCID: PMC10038876 DOI: 10.1016/j.kint.2022.10.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 11/27/2022]
Abstract
Borderline rejection (BL) in renal transplantation is associated with decreased allograft survival, yet many patients with BL maintain stable graft function. Identifying patients with early BL at risk for shortened allograft survival would allow for timely targeted therapeutic intervention aimed at improving outcomes. 851/1187 patients transplanted between 2013-18 underwent early biopsy (0-4 mos). 217/851 (25%) had BL and were compared to 387/851 without significant inflammation (NI). Serial surveillance and for-cause biopsies and seven-year follow-up were used to evaluate histological and clinical progression. To identify high-risk patients, we examined clinical/histological parameters using regression and non-linear dimensionality reduction (tSNE) and a biomarker based on peripheral blood transitional-1 B cell (T1B) IL-10/TNFα ratio. Compared to NI, early BL was associated with increased progression to late acute rejection (AR; 5-12 mos), premature interstitial fibrosis and tubular atrophy (IFTA) and decreased seven-year graft survival. However, decreased graft survival was limited to BL patients who progressed to late AR or IFTA, and was not influenced by treatment. Although tSNE clustered patients into groups based on clinical factors, the ability of these factors to risk stratify BL patients was modest. In contrast, a low T1B IL-10/TNFα ratio at 3 months identified BL patients at high risk for progression to AR (ROC AUC 0.87) and poor 7-yr graft survival (52% vs. 92%, p=0.003), while BL patients with a high ratio had similar graft survival to patients with NI (91%, p=NS). Thus, progressive early allograft inflammation manifested as BL that progresses to late AR in the first post-transplant year represents a high-risk clinical state for poor allograft outcomes. Such high-risk status can be predicted by the T1B IL-10/TNFα ratio before irreversible scarring sets in, thus allowing timely risk stratification.
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Affiliation(s)
- Aravind Cherukuri
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
| | - Khodor I Abou-Daya
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Raad Chowdhury
- Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rajil B Mehta
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sundaram Hariharan
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Parmjeet Randhawa
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Division of Transplantation Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - David M Rothstein
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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16
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The Histological Spectrum and Clinical Significance of T Cell-mediated Rejection of Kidney Allografts. Transplantation 2022; 107:1042-1055. [PMID: 36584369 DOI: 10.1097/tp.0000000000004438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
T cell-mediated rejection (TCMR) remains a significant cause of long-term kidney allograft loss, either indirectly through induction of donor-specific anti-HLA alloantibodies or directly through chronic active TCMR. Whether found by indication or protocol biopsy, Banff defined acute TCMR should be treated with antirejection therapy and maximized maintenance immunosuppression. Neither isolated interstitial inflammation in the absence of tubulitis nor isolated tubulitis in the absence of interstitial inflammation results in adverse outcomes, and neither requires antirejection treatment. RNA gene expression analysis of biopsy material may supplement conventional histology, especially in ambiguous cases. Lesser degrees of tubular and interstitial inflammation (Banff borderline) may portend adverse outcomes and should be treated when found on an indication biopsy. Borderline lesions on protocol biopsies may resolve spontaneously but require close follow-up if untreated. Following antirejection therapy of acute TCMR, surveillance protocol biopsies should be considered. Minimally invasive blood-borne assays (donor-derived cell-free DNA and gene expression profiling) are being increasingly studied as a means of following stable patients in lieu of biopsy. The clinical benefit and cost-effectiveness require confirmation in randomized controlled trials. Treatment of acute TCMR is not standardized but involves bolus corticosteroids with lymphocyte depleting antibodies for severe, refractory, or relapsing cases. Arteritis may be found with acute TCMR, active antibody-mediated rejection, or mixed rejections and should be treated accordingly. The optimal treatment ofchronic active TCMR is uncertain. Randomized controlled trials are necessary to optimally define therapy.
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17
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Mehta RB, Melgarejo I, Viswanathan V, Zhang X, Pittappilly M, Randhawa P, Puttarajappa C, Sood P, Wu C, Sharma A, Molinari M, Hariharan S. Long-term immunological outcomes of early subclinical inflammation on surveillance kidney allograft biopsies. Kidney Int 2022; 102:1371-1381. [PMID: 36049641 DOI: 10.1016/j.kint.2022.07.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 07/07/2022] [Accepted: 07/26/2022] [Indexed: 01/12/2023]
Abstract
The long-term impact of early subclinical inflammation (SCI) through surveillance biopsy has not been well studied. To do this, we recruited a prospective observational cohort that included 1000 sequential patients who received a kidney transplant from 2013-2017 at our center. A total of 586 patients who underwent a surveillance biopsy in their first year post-transplant were included after excluding those with clinical rejections, and those who were unable to undergo a surveillance biopsy. Patients were classified based on their biopsy findings: 282 with NSI (No Significant Inflammation) and 304 with SCI-T (SCI and Tubulitis) which was further subdivided into 182 with SC-BLR (Subclinical Borderline Changes) and 122 with SC-TCMR (Subclinical T Cell Mediated Rejection, Banff 2019 classification of 1A or more). We followed the clinical and immunological events including Clinical Biopsy Proven Acute Rejection [C-BPAR], long-term kidney function and death-censored graft loss over a median follow-up of five years. Episodes of C-BPAR were noted at a median of two years post-transplant. Adjusted odds of having a subsequent C-BPAR was significantly higher in the SCI-T group [SC-BLR and SC-TCMR] compared to NSI 3.8 (2.1-7.5). The adjusted hazard for death-censored graft loss was significantly higher with SCI-T compared to NSI [1.99 (1.04-3.84)]. Overall, SCI detected through surveillance biopsy within the first year post-transplant is a harbinger for subsequent immunological events and is associated with a significantly greater hazard for subsequent C-BPAR and death-censored graft loss. Thus, our study highlights the need for identifying patients with SCI through surveillance biopsy and develop strategies to prevent further alloimmune injuries.
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Affiliation(s)
- Rajil B Mehta
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
| | - Ivy Melgarejo
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Vignesh Viswanathan
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Xingyu Zhang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Matthew Pittappilly
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Parmjeet Randhawa
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Chethan Puttarajappa
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Puneet Sood
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Christine Wu
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Akhil Sharma
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Michele Molinari
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Sundaram Hariharan
- Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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18
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Wiebe C, Nickerson PW, Kosmoliaptsis V. Molecular Mismatch and the Risk for T Cell-Mediated Rejection. Am J Kidney Dis 2022; 80:704-706. [PMID: 36057468 DOI: 10.1053/j.ajkd.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/27/2022] [Indexed: 02/02/2023]
Affiliation(s)
- Chris Wiebe
- Department of Medicine, University of Manitoba, Winnipeg, Canada; Shared Health Services Manitoba; Department of Immunology, University of Manitoba, Winnipeg, Canada.
| | - Peter W Nickerson
- Department of Medicine, University of Manitoba, Winnipeg, Canada; Shared Health Services Manitoba; Department of Immunology, University of Manitoba, Winnipeg, Canada
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom, and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at the University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
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19
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The Current State of Donor-Derived Cell-Free DNA Use in Allograft Monitoring in Kidney Transplantation. J Pers Med 2022; 12:jpm12101700. [PMID: 36294839 PMCID: PMC9605518 DOI: 10.3390/jpm12101700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/21/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022] Open
Abstract
Renal transplantation is the definitive therapy for patients suffering from end-stage renal disease. Though there have been significant advances in immunosuppression in these patients, there is still up to 30% acute and subclinical rejection. Current standards employ lab markers of renal function and biopsy results for accurate diagnosis. However, donor derived cell-free DNA has been identified as a measurable lab test that may be able to adequately diagnose rejection at early stages, precluding the need for invasive procedures like biopsy. We obtained published data directly from companies that offer ddcfDNA assay tests and additionally conducted a literature review using databases like PUBMED and NIH U.S. National Library of Medicine. We comprehensively compare the most used ddcfDNA assays, delineate their respective limitations, and further explore future directions in the utility of ddcfDNA in renal transplant patients.
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20
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López del Moral C, Wu K, Naik M, Osmanodja B, Akifova A, Lachmann N, Stauch D, Hergovits S, Choi M, Bachmann F, Halleck F, Schrezenmeier E, Schmidt D, Budde K. The natural history of de novo donor-specific HLA antibodies after kidney transplantation. Front Med (Lausanne) 2022; 9:943502. [PMID: 36186822 PMCID: PMC9523126 DOI: 10.3389/fmed.2022.943502] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/19/2022] [Indexed: 11/24/2022] Open
Abstract
Background De novo donor-specific HLA antibodies (dnDSA) are key factors in the diagnosis of antibody-mediated rejection (ABMR) and related to graft loss. Methods This retrospective study was designed to evaluate the natural course of dnDSA in graft function and kidney allograft survival and to assess the impact of mean fluorescence intensity (MFI) evolution as detected by annual Luminex® screening. All 400 kidney transplant recipients with 731 dnDSA against the last graft (01/03/2000-31/05/2021) were included. Results During 8.3 years of follow-up, ABMR occurred in 24.8% and graft loss in 33.3% of the cases, especially in patients with class I and II dnDSA, and those with multiple dnDSA. We observed frequent changes in MFI with 5-year allograft survivals post-dnDSA of 74.0% in patients with MFI reduction ≥ 50%, 62.4% with fluctuating MFI (MFI reduction ≥ 50% and doubling), and 52.7% with doubling MFI (log-rank p < 0.001). Interestingly, dnDSA in 168 (24.3%) cases became negative at some point during follow-up, and 38/400 (9.5%) patients became stable negative, which was associated with better graft survival. Multivariable analysis revealed the importance of MFI evolution and rejection, while class and number of dnDSA were not contributors in this model. Conclusion In summary, we provide an in-depth analysis of the natural course of dnDSA after kidney transplantation, first evidence for the impact of MFI evolution on graft outcomes, and describe a relevant number of patients with a stable disappearance of dnDSA, related to better allograft survival.
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Affiliation(s)
- Covadonga López del Moral
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Valdecilla Biomedical Research Institute (IDIVAL), Santander, Spain
- *Correspondence: Covadonga López del Moral,
| | - Kaiyin Wu
- Department of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Marcel Naik
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Bilgin Osmanodja
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Aylin Akifova
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nils Lachmann
- Institute for Transfusion Medicine, HLA-Laboratory, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Diana Stauch
- Institute for Transfusion Medicine, HLA-Laboratory, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Sabine Hergovits
- Institute for Transfusion Medicine, HLA-Laboratory, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Mira Choi
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Friederike Bachmann
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Charité – Universitätsmedizin Berlin, BIH Academy, Berlin, Germany
| | - Danilo Schmidt
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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21
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Betjes MGH, Peereboom ETM, Otten HG, Spierings E. The number of donor HLA-derived T cell epitopes available for indirect antigen presentation determines the risk for vascular rejection after kidney transplantation. Front Immunol 2022; 13:973968. [PMID: 36110856 PMCID: PMC9468767 DOI: 10.3389/fimmu.2022.973968] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
The role of the indirect T-cell recognition pathway of allorecognition in acute T cell-mediated rejection (aTCMR) is not well defined. The amount of theoretical T-cell epitopes available for indirect allorecognition can be quantified for donor-recipient combinations by the Predicted Indirectly ReCognizable HLA Epitopes algorithm (PIRCHE-II). The PIRCHE-II score was calculated for 688 donor kidney-recipient combinations and associated with the incidence of first-time diagnosed cases of TCMR. A diagnosis of TCMR was made in 182 cases; 121 cases of tubulo-interstitial rejection cases (79 cases of borderline TCMR, 42 cases of TCMR IA-B) and 61 cases of vascular TCMR (TCMR II-III). The PIRCHE-II score for donor HLA-DR/DQ (PIRCHE-II DR/DQ) was highly associated with vascular rejection. At one year after transplantation, the cumulative percentage of recipients with a vascular rejection was 12.7%, 8.6% and 2.1% within respectively the high, medium and low tertile of the PIRCHE-II DR/DQ score (p<0.001). In a multivariate regression analysis this association remained significant (p<0.001 for PIRCHE-II DR/DQ tertiles). The impact of a high PIRCHE-II DR/DQ score was mitigated by older recipient age and a living donor kidney. In conclusion, indirect antigen presentation of donor HLA-peptides may significantly contribute to the risk for acute vascular rejection.
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Affiliation(s)
- Michiel G. H. Betjes
- Department of Internal Medicine, Section of Nephrology and Transplantation, Erasmus Medical Center (MC), University Medical Center, Rotterdam, Netherlands
- *Correspondence: Michiel G. H. Betjes,
| | - Emma T. M. Peereboom
- Center for Translational Immunology, University Medical Center, Utrecht, Netherlands
| | - Henny G. Otten
- Center for Translational Immunology, University Medical Center, Utrecht, Netherlands
| | - Eric Spierings
- Center for Translational Immunology, University Medical Center, Utrecht, Netherlands
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22
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Li Y, Nieuwenhuis LM, Keating BJ, Festen EA, de Meijer VE. The Impact of Donor and Recipient Genetic Variation on Outcomes After Solid Organ Transplantation: A Scoping Review and Future Perspectives. Transplantation 2022; 106:1548-1557. [PMID: 34974452 PMCID: PMC9311456 DOI: 10.1097/tp.0000000000004042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/16/2021] [Accepted: 11/25/2021] [Indexed: 11/25/2022]
Abstract
At the outset of solid organ transplantation, genetic variation between donors and recipients was recognized as a major player in mechanisms such as allograft tolerance and rejection. Genome-wide association studies have been very successful in identifying novel variant-trait associations, but have been difficult to perform in the field of solid organ transplantation due to complex covariates, era effects, and poor statistical power for detecting donor-recipient interactions. To overcome a lack of statistical power, consortia such as the International Genetics and Translational Research in Transplantation Network have been established. Studies have focused on the consequences of genetic dissimilarities between donors and recipients and have reported associations between polymorphisms in candidate genes or their regulatory regions with transplantation outcomes. However, knowledge on the exact influence of genetic variation is limited due to a lack of comprehensive characterization and harmonization of recipients' or donors' phenotypes and validation using an experimental approach. Causal research in genetics has evolved from agnostic discovery in genome-wide association studies to functional annotation and clarification of underlying molecular mechanisms in translational studies. In this overview, we summarize how the recent advances and progresses in the field of genetics and genomics have improved the understanding of outcomes after solid organ transplantation.
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Affiliation(s)
- Yanni Li
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lianne M. Nieuwenhuis
- Department of Surgery, section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Brendan J. Keating
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Eleonora A.M. Festen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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23
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Immune checkpoint inhibitors in kidney transplant recipients: a multicentre, single-arm, phase 1 study. Lancet Oncol 2022; 23:1078-1086. [DOI: 10.1016/s1470-2045(22)00368-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 12/15/2022]
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24
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Senev A, Lerut E, Coemans M, Callemeyn J, Copley HC, Claas F, Koshy P, Kosmoliaptsis V, Kuypers D, Sprangers B, Van Craenenbroeck A, Van Loon E, Van Sandt V, Emonds MP, Naesens M. Association of HLA Mismatches and Histology Suggestive of Antibody-Mediated Injury in the Absence of Donor-Specific Anti-HLA Antibodies. Clin J Am Soc Nephrol 2022; 17:1204-1215. [PMID: 35649719 PMCID: PMC9435985 DOI: 10.2215/cjn.00570122] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 05/12/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND OBJECTIVES The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA-derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy. RESULTS In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell-mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies. CONCLUSIONS The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.
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Affiliation(s)
- Aleksandar Senev
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross Flanders, Mechelen, Belgium
| | - Evelyne Lerut
- Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Maarten Coemans
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jasper Callemeyn
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Hannah Charlotte Copley
- Department of Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom,National Institute for Health and Care Research Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, United Kingdom,National Institute for Health and Care Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Frans Claas
- Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Priyanka Koshy
- Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom,National Institute for Health and Care Research Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, United Kingdom,National Institute for Health and Care Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Dirk Kuypers
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Ben Sprangers
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Amaryllis Van Craenenbroeck
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Elisabet Van Loon
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Vicky Van Sandt
- Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross Flanders, Mechelen, Belgium
| | - Marie-Paule Emonds
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross Flanders, Mechelen, Belgium
| | - Maarten Naesens
- KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
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25
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Roufosse C, Becker JU, Rabant M, Seron D, Bellini MI, Böhmig GA, Budde K, Diekmann F, Glotz D, Hilbrands L, Loupy A, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation. Transpl Int 2022; 35:10140. [PMID: 35669973 PMCID: PMC9163810 DOI: 10.3389/ti.2022.10140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/03/2022] [Indexed: 12/15/2022]
Abstract
Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.
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Affiliation(s)
- Candice Roufosse
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Marion Rabant
- Department of Pathology, Hôpital Necker-Enfants Malades, Paris, France
| | - Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d'Hebrón University Hospital, Barcelona, Spain
| | | | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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26
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Becker JU, Seron D, Rabant M, Roufosse C, Naesens M. Evolution of the Definition of Rejection in Kidney Transplantation and Its Use as an Endpoint in Clinical Trials. Transpl Int 2022; 35:10141. [PMID: 35669978 PMCID: PMC9163319 DOI: 10.3389/ti.2022.10141] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 12/11/2022]
Abstract
This article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT’s opinion, the use of “biopsy-proven acute rejection” as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build.
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Affiliation(s)
- Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
| | - Marion Rabant
- Department of Pathology, Hôpital Necker–Enfants Malades, Paris, France
| | - Candice Roufosse
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- *Correspondence: Maarten Naesens,
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27
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Seron D, Rabant M, Becker JU, Roufosse C, Bellini MI, Böhmig GA, Budde K, Diekmann F, Glotz D, Hilbrands L, Loupy A, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation. Transpl Int 2022; 35:10135. [PMID: 35669975 PMCID: PMC9163314 DOI: 10.3389/ti.2022.10135] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 12/14/2022]
Abstract
The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.
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Affiliation(s)
- Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
| | - Marion Rabant
- Department of Pathology, Hôpital Necker–Enfants Malades, Paris, France
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Candice Roufosse
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | | | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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28
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Rampersad C, Balshaw R, Gibson IW, Ho J, Shaw J, Karpinski M, Goldberg A, Birk P, Rush DN, Nickerson PW, Wiebe C. The negative impact of T cell-mediated rejection on renal allograft survival in the modern era. Am J Transplant 2022; 22:761-771. [PMID: 34717048 PMCID: PMC9299170 DOI: 10.1111/ajt.16883] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 01/25/2023]
Abstract
The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.
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Affiliation(s)
| | - Robert Balshaw
- George and Fay Yee Centre for Healthcare InnovationUniversity of ManitobaWinnipegManitobaCanada
| | - Ian W. Gibson
- Shared Health Services ManitobaWinnipegManitobaCanada,Department of PathologyUniversity of ManitobaWinnipegManitobaCanada
| | - Julie Ho
- Department of MedicineUniversity of ManitobaWinnipegManitobaCanada,Shared Health Services ManitobaWinnipegManitobaCanada,Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | - Jamie Shaw
- Department of MedicineUniversity of ManitobaWinnipegManitobaCanada
| | - Martin Karpinski
- Department of MedicineUniversity of ManitobaWinnipegManitobaCanada
| | - Aviva Goldberg
- Department of Pediatrics and Child HealthUniversity of ManitobaWinnipegManitobaCanada
| | - Patricia Birk
- Department of Pediatrics and Child HealthUniversity of ManitobaWinnipegManitobaCanada
| | - David N. Rush
- Department of MedicineUniversity of ManitobaWinnipegManitobaCanada,Shared Health Services ManitobaWinnipegManitobaCanada
| | - Peter W. Nickerson
- Department of MedicineUniversity of ManitobaWinnipegManitobaCanada,Shared Health Services ManitobaWinnipegManitobaCanada,Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | - Chris Wiebe
- Department of MedicineUniversity of ManitobaWinnipegManitobaCanada,Shared Health Services ManitobaWinnipegManitobaCanada,Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
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29
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Ho J, Okoli GN, Rabbani R, Lam OLT, Reddy V, Askin N, Rampersad C, Trachtenberg A, Wiebe C, Nickerson P, Abou‐Setta AM. Effectiveness of T cell-mediated rejection therapy: A systematic review and meta-analysis. Am J Transplant 2022; 22:772-785. [PMID: 34860468 PMCID: PMC9300092 DOI: 10.1111/ajt.16907] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/22/2021] [Accepted: 11/26/2021] [Indexed: 01/25/2023]
Abstract
The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised, and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), and Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with the National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2 statistic. From 2875 screened citations, we included 12 studies (1255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95% CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.
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Affiliation(s)
- Julie Ho
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - George N. Okoli
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Rasheda Rabbani
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada,Department of Community Health SciencesMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Otto L. T. Lam
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Viraj K. Reddy
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Nicole Askin
- Neil John Maclean Health Sciences LibraryUniversity of ManitobaWinnipegManitobaCanada
| | - Christie Rampersad
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Aaron Trachtenberg
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Chris Wiebe
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Peter Nickerson
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Ahmed M. Abou‐Setta
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada,Department of Community Health SciencesMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
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30
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Lezoeva E, Nilsson J, Wüthrich R, Mueller TF, Schachtner T. High PIRCHE Scores May Allow Risk Stratification of Borderline Rejection in Kidney Transplant Recipients. Front Immunol 2022; 13:788818. [PMID: 35250973 PMCID: PMC8894244 DOI: 10.3389/fimmu.2022.788818] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Background The diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury. Methods We identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes. Results Total PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003). Conclusions High PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.
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Affiliation(s)
- Ekaterina Lezoeva
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Jakob Nilsson
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Rudolf Wüthrich
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Thomas F. Mueller
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Schachtner
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
- *Correspondence: Thomas Schachtner, ; orcid.org/0000-0001-5549-4798
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31
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Yeung MY. Histocompatibility Assessment in Precision Medicine for Transplantation: Towards a Better Match. Semin Nephrol 2022; 42:44-62. [DOI: 10.1016/j.semnephrol.2022.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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32
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Callemeyn J, Lamarthée B, Koenig A, Koshy P, Thaunat O, Naesens M. Allorecognition and the spectrum of kidney transplant rejection. Kidney Int 2021; 101:692-710. [PMID: 34915041 DOI: 10.1016/j.kint.2021.11.029] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 10/05/2021] [Accepted: 11/08/2021] [Indexed: 12/18/2022]
Abstract
Detection of mismatched human leukocyte antigens by adaptive immune cells is considered as the main cause of transplant rejection, leading to either T-cell mediated rejection or antibody-mediated rejection. This canonical view guided the successful development of immunosuppressive therapies and shaped the diagnostic Banff classification for kidney transplant rejection that is used in clinics worldwide. However, several observations have recently emerged that question this dichotomization between T-cell mediated rejection and antibody-mediated rejection, related to heterogeneity in the serology, histology, and prognosis of the rejection phenotypes. In parallel, novel insights were obtained concerning the dynamics of donor-specific anti-human leukocyte antigen antibodies, the immunogenicity of donor-recipient non-human leukocyte antigen mismatches, and the autoreactivity against self-antigens. Moreover, the potential of innate allorecognition was uncovered, as exemplified by natural killer cell-mediated microvascular inflammation through missing self, and by the emerging evidence on monocyte-driven allorecognition. In this review, we highlight the gaps in the current classification of rejection, provide an overview of the expanding insights into the mechanisms of allorecognition, and critically appraise how these could improve our understanding and clinical approach to kidney transplant rejection. We argue that consideration of the complex interplay of various allorecognition mechanisms can foster a more integrated view of kidney transplant rejection and can lead to improved risk stratification, targeted therapies, and better outcome after kidney transplantation.
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Affiliation(s)
- Jasper Callemeyn
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Necker-Enfants Malades Institute, French National Institute of Health and Medical Research (INSERM) Unit 1151, Paris, France
| | - Alice Koenig
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France; Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Priyanka Koshy
- Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France; Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Maarten Naesens
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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33
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Role of HLA molecular mismatch in clinical practice. Hum Immunol 2021; 83:219-224. [PMID: 34887099 DOI: 10.1016/j.humimm.2021.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/29/2021] [Accepted: 11/13/2021] [Indexed: 11/20/2022]
Abstract
To date, traditional pre-transplant risk factors have failed to provide accurate risk stratification in transplantation. As a result, the practice of precision medicine remains elusive, resulting in a one-size-fits-all therapeutic approach for most patients. However, recent advancements in the understanding of HLA molecules at the molecular level have revitalized interest in HLA mismatch assessment. This review discusses HLA molecular mismatch as a potential prognostic and predictive biomarker available at the time of transplantation and answers some of the common questions and critiques of this approach. We highlight the retrospective data that supports single molecule risk categorization and explore the next steps required to evaluate its potential in clinical practice.
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34
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Loupy A, Mengel M, Haas M. 30 years of the International Banff Classification for Allograft Pathology: The Past, Present and Future of Kidney Transplant Diagnostics. Kidney Int 2021; 101:678-691. [DOI: 10.1016/j.kint.2021.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/06/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
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35
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Park S, Guo K, Heilman RL, Poggio ED, Taber DJ, Marsh CL, Kurian SM, Kleiboeker S, Weems J, Holman J, Zhao L, Sinha R, Brietigam S, Rebello C, Abecassis MM, Friedewald JJ. Combining Blood Gene Expression and Cellfree DNA to Diagnose Subclinical Rejection in Kidney Transplant Recipients. Clin J Am Soc Nephrol 2021; 16:1539-1551. [PMID: 34620649 PMCID: PMC8499014 DOI: 10.2215/cjn.05530421] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/11/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVES Subclinical acute rejection is associated with poor outcomes in kidney transplant recipients. As an alternative to surveillance biopsies, noninvasive screening has been established with a blood gene expression profile. Donor-derived cellfree DNA (cfDNA) has been used to detect rejection in patients with allograft dysfunction but not tested extensively in stable patients. We hypothesized that we could complement noninvasive diagnostic performance for subclinical rejection by combining a donor-derived cfDNA and a gene expression profile assay. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a post hoc analysis of simultaneous blood gene expression profile and donor-derived cfDNA assays in 428 samples paired with surveillance biopsies from 208 subjects enrolled in an observational clinical trial (Clinical Trials in Organ Transplantation-08). Assay results were analyzed as binary variables, and then, their continuous scores were combined using logistic regression. The performance of each assay alone and in combination was compared. RESULTS For diagnosing subclinical rejection, the gene expression profile demonstrated a negative predictive value of 82%, a positive predictive value of 47%, a balanced accuracy of 64%, and an area under the receiver operating curve of 0.75. The donor-derived cfDNA assay showed similar negative predictive value (84%), positive predictive value (56%), balanced accuracy (68%), and area under the receiver operating curve (0.72). When both assays were negative, negative predictive value increased to 88%. When both assays were positive, positive predictive value increased to 81%. Combining assays using multivariable logistic regression, area under the receiver operating curve was 0.81, significantly higher than the gene expression profile (P<0.001) or donor-derived cfDNA alone (P=0.006). Notably, when cases were separated on the basis of rejection type, the gene expression profile was significantly better at detecting cellular rejection (area under the receiver operating curve, 0.80 versus 0.62; P=0.001), whereas the donor-derived cfDNA was significantly better at detecting antibody-mediated rejection (area under the receiver operating curve, 0.84 versus 0.71; P=0.003). CONCLUSIONS A combination of blood-based biomarkers can improve detection and provide less invasive monitoring for subclinical rejection. In this study, the gene expression profile detected more cellular rejection, whereas donor-derived cfDNA detected more antibody-mediated rejection.
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Affiliation(s)
- Sookhyeon Park
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois,Division of Nephrology, Department of Medicine, Northwestern University, Chicago, Illinois
| | - Kexin Guo
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois,Department of Preventive Medicine, Biostatistics Collaboration Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Raymond L. Heilman
- Department of Medicine, Mayo Clinic College of Medicine and Science, Mayo Clinic, Phoenix, Arizona
| | - Emilio D. Poggio
- Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio
| | - David J. Taber
- Division of Transplant Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Christopher L. Marsh
- Department of Medicine and Surgery, Scripps Clinic and Green Hospital, La Jolla, California
| | - Sunil M. Kurian
- Bio-Repository and Bio-Informatics Core, Scripps Health, La Jolla, California
| | | | - Juston Weems
- Eurofins US Clinical Diagnostics, Lee’s Summit, Missouri
| | - John Holman
- Transplant Genomics, Inc., Mansfield, Massachusetts
| | - Lihui Zhao
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois,Department of Preventive Medicine, Biostatistics Collaboration Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Rohita Sinha
- Eurofins US Clinical Diagnostics, Lee’s Summit, Missouri
| | - Susan Brietigam
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Christabel Rebello
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Michael M. Abecassis
- Department of Surgery, University of Arizona College of Medicine, Tucson, Arizona,Department of Immunobiology, University of Arizona College of Medicine, Tucson, Arizona
| | - John J. Friedewald
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois,Division of Nephrology, Department of Medicine, Northwestern University, Chicago, Illinois
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36
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Khilnani C, Heeger PS. Two Can Be Better Than One: Improving Noninvasive Diagnostics in Kidney Transplantation. Clin J Am Soc Nephrol 2021; 16:1462-1463. [PMID: 34620644 PMCID: PMC8499010 DOI: 10.2215/cjn.10630821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Calla Khilnani
- Renal Division, Department of Medicine, Translational Transplant Research Center and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Peter S. Heeger
- Renal Division, Department of Medicine, Translational Transplant Research Center and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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37
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Doberer K, Haupenthal F, Nackenhorst M, Bauernfeind F, Dermuth F, Eigenschink M, Schiemann M, Kläger J, Görzer I, Eskandary F, Reindl-Schwaighofer R, Kikić Ž, Böhmig G, Strassl R, Regele H, Puchhammer-Stöckl E, Bond G. Torque Teno Virus Load Is Associated With Subclinical Alloreactivity in Kidney Transplant Recipients: A Prospective Observational Trial. Transplantation 2021; 105:2112-2118. [PMID: 33587432 PMCID: PMC8376270 DOI: 10.1097/tp.0000000000003619] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Nonpathogenic torque teno viruses (TTVs) are highly prevalent in transplant recipients and associated with immunosuppression. Studies in kidney transplant patients have proposed assessment of TTV load for risk stratification of clinically overt graft rejection. The value of TTV quantification in the context of subclinical rejection has not been evaluated. METHODS In this prospective trial, 307 consecutive kidney transplant recipients were subjected to per-protocol monitoring of plasma TTV. TTV was analyzed in the context of protocol biopsies (n = 82), scheduled 1 year posttransplantation. RESULTS TTV load at the time of biopsy was lower in recipients with rejection (n = 19; according to Banff, including borderline changes suspicious for acute T cell-mediated rejection) than those without rejection (n = 63) whereby each log increase in TTV copies/mL decreased the risk for rejection by 9% (risk ratio 0.91, 95% confidence interval, 0.85-0.97; P = 0.004). Development of chronic lesions (cg, cv, ci, ct, ah, ptcml) was associated with the number of days with a TTV load <1 × 106 copies/mL between months 3 and 12 posttransplant (β 0.07, 95% confidence interval, 0.01-0.14; P = 0.02). CONCLUSIONS This trial demonstrates an association between TTV and subclinical graft rejection in kidney transplant recipients. A TTV load <1 × 106 copies/mL suggests suboptimal immunosuppression.
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Affiliation(s)
- Konstantin Doberer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Frederik Haupenthal
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maja Nackenhorst
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Florian Bauernfeind
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Florentina Dermuth
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Eigenschink
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Martin Schiemann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Johannes Kläger
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Irene Görzer
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Farsad Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Željko Kikić
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Georg Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Robert Strassl
- Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Heinz Regele
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Gregor Bond
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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38
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Senn L, Wehmeier C, Hönger G, Geiger I, Amico P, Hirt-Minkowski P, Steiger J, Dickenmann M, Schaub S. Outcome of Husband-to-Wife Kidney Transplantation With Mutual Children: Single Center Experience Using T Cell-Depleting Induction and Review of the Literature. Front Med (Lausanne) 2021; 8:724851. [PMID: 34409057 PMCID: PMC8365247 DOI: 10.3389/fmed.2021.724851] [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: 06/14/2021] [Accepted: 07/08/2021] [Indexed: 11/13/2022] Open
Abstract
Few data on husband-to-wife transplantations with mutual children (H2W) exist in the current era. We investigated the outcome of H2W transplantations (n = 25) treated with T cell-depleting induction compared to women with prior pregnancies also receiving their first HLA-mismatched kidney transplant, but from a different donor source: (i) other living donor (n = 52) and (ii) deceased donor (n = 120). Seventy-four percent of the women had ≥2 pregnancies; median follow-up time was 5 years. Death-censored allograft survival was significantly lower in the H2W group compared to the other two groups (p = 0.03). Three of four graft losses in the H2W group were due to rejection. 5-year patient survival in the H2W group was high and similar compared to the other living donor group (100 vs. 98%; p = 0.28). The incidence of (sub)clinical antibody-mediated rejection was higher in the H2W group (36 vs. 20 vs. 18%) (p = 0.10). The frequency of infections was similar among the three groups. No immunological parameter was predictive for rejection or graft loss in H2W transplantations. In conclusion, H2W transplantation is a valuable option, but associated with a higher risk for allograft loss due to rejection despite T cell-depleting induction. Further research is required for better risk prediction on an individual patient level.
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Affiliation(s)
- Lisa Senn
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Caroline Wehmeier
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Gideon Hönger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,HLA-Diagnostics and Immungenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Irene Geiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patrizia Amico
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patricia Hirt-Minkowski
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Michael Dickenmann
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,HLA-Diagnostics and Immungenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
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39
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Bestard O, Meneghini M, Crespo E, Bemelman F, Koch M, Volk HD, Viklicky O, Giral M, Banas B, Ruiz JC, Melilli E, Hu L, van Duivenvoorden R, Nashan B, Thaiss F, Otto NM, Bold G, Stein M, Sefrin A, Lachmann N, Hruba P, Stranavova L, Brouard S, Braudeau C, Blancho G, Banas M, Irure J, Christakoudi S, Sanchez-Fueyo A, Wood KJ, Reinke P, Grinyó JM. Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation: Results of the CELLIMIN trial. Am J Transplant 2021; 21:2833-2845. [PMID: 33725408 DOI: 10.1111/ajt.16563] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/08/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
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Affiliation(s)
- Oriol Bestard
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.,Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
| | - Maria Meneghini
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.,Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
| | - Elena Crespo
- Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
| | - Frederike Bemelman
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands
| | - Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans D Volk
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.,Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Magali Giral
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France
| | - Bernhard Banas
- Department of Nephrology, University Medical Center Regensburg, Regensburg, Germany
| | - Juan C Ruiz
- Department of Nephrology, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL, Santander, Spain
| | - Edoardo Melilli
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain
| | - Liu Hu
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands
| | - Raphael van Duivenvoorden
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands
| | - Björn Nashan
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friedrich Thaiss
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalie M Otto
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Gantuja Bold
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Maik Stein
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Anett Sefrin
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Nils Lachmann
- HLA-Laboratory, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.,Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Lucia Stranavova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.,Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Sophie Brouard
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France
| | - Cécile Braudeau
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France.,CHU Nantes, Laboratoire d'immunologie, CIMNA, Nantes, France
| | - Gilles Blancho
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France
| | - Miriam Banas
- Department of Nephrology, University Medical Center Regensburg, Regensburg, Germany
| | - Juan Irure
- Immunology Department, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Sophia Christakoudi
- Institute of Liver Studies, MRC Centre for Transplantation, Department of Inflammation Biology, Faculty of Sciences & Medicine, King's College London, London, UK
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, MRC Centre for Transplantation, Department of Inflammation Biology, Faculty of Sciences & Medicine, King's College London, London, UK
| | - Kathryn J Wood
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Petra Reinke
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Josep M Grinyó
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.,Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
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Abstract
PURPOSE OF REVIEW The clinical significance and treatment of borderline changes are controversial. The lowest detectable margin for rejection on histology is unclear. We review recent evidence about borderline changes and related biomarkers. RECENT FINDINGS Borderline change (Banff ≥ t1i1) is associated with progressive fibrosis, a greater propensity to form de-novo DSA, and reduced graft survival. Isolated tubulitis appears to have similar kidney allograft outcomes with normal controls, but this finding should be validated in a larger, diverse population. When borderline change was treated, a higher chance of kidney function recovery and better clinical outcomes were observed. However, spontaneous borderline changes resolution without treatment was also observed. Various noninvasive diagnostic biomarkers have been developed to diagnose subclinical acute rejection, including borderline changes and ≥ Banff 1A TCMR. Biomarkers using gene expression and donor-derived cell-free DNA, and HLA DR/DQ eplet mismatch show potential to diagnose subclinical acute rejection (borderline change and ≥Banff 1A TCMR), to avoid surveillance biopsy, or to predict poor kidney allograft outcomes. SUMMARY Borderline changes are associated with poor kidney allograft outcomes, but it remains unclear if all cases of borderline changes should be treated. Novel biomarkers may inform physicians to aid in the diagnosis and treatment.
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Borderline Changes in Renal Transplantation: Are We Aware of the Real Impact in Graft Survival? Transplant Proc 2021; 53:1514-1518. [PMID: 33994188 DOI: 10.1016/j.transproceed.2021.03.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/17/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Borderline changes suspicious for acute T-cell-mediated rejection (BC) are frequently seen on biopsy specimens, but their clinical significance and clinical management are still controversial. Our goal was to compare clinical outcomes of kidney transplant recipients with biopsy-proven BC vs acute T-cell-mediated rejection (aTCMR) and the influence of treating BC on graft outcomes. METHODS A retrospective cohort study was performed in all kidney transplant recipients with biopsy-proven BC and aTCMR between January 2012 and December 2018, according to Banff 2017 criteria; patients with concomitant antibody-mediated rejection were excluded. RESULTS We included 85 patients, 30 with BC (35.3%) and 55 with aTCMR (64.7%). There was no difference between groups regarding demographics, HLA matching and sensitization, immunosuppression, or time of transplant. Treatment with steroids was started in 15 patients with BC (50%) and in all patients with aTCMR, with 4 of the latter additionally receiving thymoglobulin (7.2%). At 1 year post biopsy, overall graft survival was 71%, and despite presenting better estimated glomerular filtration rate (eGFR) at biopsy (33.3 ± 23.4 vs 19.9 ± 13.2 mL/min/1.73 m2, P = .008), patients in the BC group presented the same graft survival as the aTCMR group according to Kaplan-Meyer survival curves. When analyzing the BC group (n = 30) and comparing the patients who were treated (n = 15) vs a conservative approach (n = 15), graft survival at 1 year was 87% for treated patients and 73% for nontreated patients (P = .651), with no difference in eGFR for patients with functioning graft. However, at longer follow-up, survival curves showed a trend for better graft survival in treated patients (70.2 ± 9.2 vs 38.4 ± 8.4 months, P = .087). CONCLUSION Our study showed that patients with BC did not present better graft survival or graft function at 1 year after biopsy or at follow-up compared with the aTCMR group, despite better eGFR at diagnosis. We found a trend for better graft survival in patients with BC treated with steroids compared with a conservative approach. These results reinforce the importance of borderline changes in graft outcomes and that the decision to treat can influence long-term outcomes.
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Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients. J Clin Med 2021; 10:jcm10091934. [PMID: 33947168 PMCID: PMC8125522 DOI: 10.3390/jcm10091934] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/20/2021] [Accepted: 04/27/2021] [Indexed: 01/17/2023] Open
Abstract
The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.
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Donor-specific ELISPOT assay for predicting acute rejection and allograft function after kidney transplantation: A systematic review and meta-analysis. Clin Biochem 2021; 94:1-11. [PMID: 33882287 DOI: 10.1016/j.clinbiochem.2021.04.011] [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: 03/04/2021] [Revised: 04/05/2021] [Accepted: 04/08/2021] [Indexed: 12/29/2022]
Abstract
Acute rejection remains an important problem after kidney transplantation. Enzyme-linked immunosorbent spot (ELISPOT) assay has been investigated extensively and has shown promising results as a predictor of allograft rejection. The objective of this study was to systematically review and analyze the predictive value of the donor-specific ELISPOT assay to identify recipients at risk for acute rejection. Electronic databases were searched for studies reporting donor-specific ELISPOT and kidney transplantation outcomes. Odds ratio (OR) for acute rejection was calculated, along with standardized mean difference (SMD) of cytokine producing-cells between recipients with and without acute rejection. Pooled estimates were calculated using random-effect models. The positive ELISPOT cutoff frequencies were extracted from each study. From 665 articles found, 32 studies were included in the meta-analysis. IFN-γ was the most investigated cytokine (30 out of 32 studies). Patients with positive pre-transplantation donor-reactive IFN-γ ELISPOT had an OR of 3.3 for acute rejection (95%-CI 2.1 to 5.1), and OR of 6.8 (95%-CI 2.5 to 18.9) for post-transplantation ELISPOT. Recipients with rejection had significantly higher frequencies of pre- and post-transplantation cytokine producing-cells (SMD 0.47, 95%-CI 0.07 to 0.87 and SMD 3.68, 95%-CI 1.04 to 6.32, respectively). Pre-transplantation ELISPOT had a positive predictive value of 43% and a negative predictive value of 81% for acute rejection. A positive ELISPOT result was associated with a lower estimated glomerular filtration rate (SMD -0.59, 95%-CI -0.83 to -0.34). In conclusion, patients with a high frequency of donor-reactive IFN-γ ELISPOT are at higher risk for acute rejection. The donor-specific IFN-γ ELISPOT assay can serve as an immune-monitoring tool in kidney transplantation.
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Blydt-Hansen TD, Sharma A, Gibson IW, Wiebe C, Sharma AP, Langlois V, Teoh CW, Rush D, Nickerson P, Wishart D, Ho J. Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients. Am J Transplant 2021; 21:1545-1555. [PMID: 33034126 DOI: 10.1111/ajt.16336] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/26/2020] [Accepted: 09/20/2020] [Indexed: 02/06/2023]
Abstract
Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66-0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66-0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = -0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.
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Affiliation(s)
- Tom D Blydt-Hansen
- Pediatric Nephrology, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Atul Sharma
- Biostatistical Consulting Unit, George, Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ian W Gibson
- Pathology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Chris Wiebe
- Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada.,Transplant/Immunology Lab, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ajay P Sharma
- Pediatric Nephrology, University of Western Ontario, London, Ontario, Canada
| | - Valerie Langlois
- Pediatric Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - Chia W Teoh
- Pediatric Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - David Rush
- Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Peter Nickerson
- Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada.,Transplant/Immunology Lab, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David Wishart
- Computing Science, University of Alberta, Edmonton, Alberta, Canada.,The Metabolomics Innovation Center, Edmonton, Alberta, Canada
| | - Julie Ho
- Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada.,Manitoba Centre for Proteomics & Systems Biology, Winnipeg, Manitoba, Canada
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Nickerson PW, Balshaw R, Wiebe C, Ho J, Gibson IW, Bridges ND, Rush DN, Heeger PS. A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation. Am J Transplant 2021; 21:1503-1512. [PMID: 32956576 PMCID: PMC8048676 DOI: 10.1111/ajt.16311] [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: 05/14/2020] [Revised: 08/03/2020] [Accepted: 09/04/2020] [Indexed: 01/25/2023]
Abstract
Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.
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Affiliation(s)
- Peter W. Nickerson
- Department of Internal MedicineMax Rady College of MedicineUniversity of ManitobaWinnipegCanada,Health Sciences CentreShared Health Services ManitobaWinnipegCanada,Department of ImmunologyMax Rady College of MedicineUniversity of ManitobaWinnipegCanada
| | - Robert Balshaw
- George and Fay Yee Centre for Healthcare InnovationUniversity of ManitobaWinnipegCanada
| | - Chris Wiebe
- Department of Internal MedicineMax Rady College of MedicineUniversity of ManitobaWinnipegCanada,Health Sciences CentreShared Health Services ManitobaWinnipegCanada,Department of ImmunologyMax Rady College of MedicineUniversity of ManitobaWinnipegCanada
| | - Julie Ho
- Department of Internal MedicineMax Rady College of MedicineUniversity of ManitobaWinnipegCanada,Health Sciences CentreShared Health Services ManitobaWinnipegCanada,Department of ImmunologyMax Rady College of MedicineUniversity of ManitobaWinnipegCanada
| | - Ian W. Gibson
- Health Sciences CentreShared Health Services ManitobaWinnipegCanada,Department of PathologyMax Rady College of MedicineUniversity of ManitobaWinnipegCanada
| | - Nancy D. Bridges
- Division of AllergyImmunology and TransplantationNational Institute of Allergy and Infectious DiseaseBethesdaMaryland
| | - David N. Rush
- Department of Internal MedicineMax Rady College of MedicineUniversity of ManitobaWinnipegCanada,Health Sciences CentreShared Health Services ManitobaWinnipegCanada
| | - Peter S. Heeger
- Translational Transplant Research CenterDepartment of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew York
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Meneghini M, Crespo E, Niemann M, Torija A, Lloberas N, Pernin V, Fontova P, Melilli E, Favà A, Montero N, Manonelles A, Cruzado JM, Palou E, Martorell J, Grinyó JM, Bestard O. Donor/Recipient HLA Molecular Mismatch Scores Predict Primary Humoral and Cellular Alloimmunity in Kidney Transplantation. Front Immunol 2021; 11:623276. [PMID: 33776988 PMCID: PMC7988214 DOI: 10.3389/fimmu.2020.623276] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 12/31/2020] [Indexed: 12/28/2022] Open
Abstract
Donor/recipient molecular human leukocyte antigen (HLA) mismatch predicts primary B-cell alloimmune activation, yet the impact on de novo donor-specific T-cell alloimmunity (dnDST) remains undetermined. The hypothesis of our study is that donor/recipient HLA mismatches assessed at the molecular level may also influence a higher susceptibility to the development of posttransplant primary T-cell alloimmunity. In this prospective observational study, 169 consecutive kidney transplant recipients without preformed donor-specific antibodies (DSA) and with high resolution donor/recipient HLA typing were evaluated for HLA molecular mismatch scores using different informatic algorithms [amino acid mismatch, eplet MM, and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II)]. Primary donor-specific alloimmune activation over the first 2 years posttransplantation was assessed by means of both dnDSA and dnDST using single antigen bead (SAB) and IFN-γ ELISPOT assays, respectively. Also, the predominant alloantigen presenting pathway priming DST alloimmunity and the contribution of main alloreactive T-cell subsets were further characterized in vitro. Pretransplantation, 78/169 (46%) were DST+ whereas 91/169 (54%) DST−. At 2 years, 54/169 (32%) patients showed detectable DST responses: 23/54 (42%) dnDST and 31/54 (57%) persistently positive (persistDST+). 24/169 (14%) patients developed dnDSA. A strong correlation was observed between the three distinct molecular mismatch scores and they all accurately predicted dnDSA formation, in particular at the DQ locus. Likewise, HLA molecular incompatibility predicted the advent of dnDST, especially when assessed by PIRCHE-II score (OR 1.014 95% CI 1.001–1.03, p=0.04). While pretransplant DST predicted the development of posttransplant BPAR (OR 5.18, 95% CI=1.64–16.34, p=0.005) and particularly T cell mediated rejection (OR 5.33, 95% CI=1.45–19.66, p=0.012), patients developing dnDST were at significantly higher risk of subsequent dnDSA formation (HR 2.64, 95% CI=1.08–6.45, p=0.03). In vitro experiments showed that unlike preformed DST that is predominantly primed by CD8+ direct pathway T cells, posttransplant DST may also be activated by the indirect pathway of alloantigen presentation, and predominantly driven by CD4+ alloreactive T cells in an important proportion of patients. De novo donor-specific cellular alloreactivity seems to precede subsequent humoral alloimmune activation and is influenced by a poor donor/recipient HLA molecular matching.
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Affiliation(s)
- Maria Meneghini
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.,Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Elena Crespo
- Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | | | - Alba Torija
- Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Nuria Lloberas
- Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Vincent Pernin
- Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.,Department of Nephrology, Dialysis and Transplantation, Montpellier University Hospital, Montpellier, France.,Institute for Regenerative Medicine & Biotherapy (IRMB), University of Montpellier, INSERM, Montpellier, France
| | - Pere Fontova
- Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Edoardo Melilli
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Alexandre Favà
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.,Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Nuria Montero
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Anna Manonelles
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Josep Maria Cruzado
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.,Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Eduard Palou
- Laboratory of Immunology and Histocompatibility, Hospital Clinic, Barcelona, Spain
| | - Jaume Martorell
- Laboratory of Immunology and Histocompatibility, Hospital Clinic, Barcelona, Spain
| | - Josep Maria Grinyó
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.,Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Oriol Bestard
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.,Translational Transplantation and Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
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Hoffmann AJ, Gibson IW, Ho J, Nickerson P, Rush D, Sharma A, Wishart D, Blydt-Hansen TD. Early surveillance biopsy utilization and management of pediatric renal allograft acute T cell-mediated rejection in Canadian centers: Observations from the PROBE multicenter cohort study. Pediatr Transplant 2021; 25:e13870. [PMID: 33026135 DOI: 10.1111/petr.13870] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/31/2020] [Accepted: 09/07/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Early TCMR surveillance with protocol kidney biopsy is used differentially among pediatric kidney transplant centers. Little has been reported about actual center-based differences, and this variability may influence TCMR ascertainment, treatment, and monitoring more broadly. METHODS Data from the PROBE multicenter study were used to identify patients from centers conducting ESB or LSIB. ESB was defined as >50% of patients having at least 1 surveillance biopsy in the first 9 months. Patients were compared for number of biopsies, rejection episodes, treatment, and follow-up monitoring. RESULTS A total of 261 biopsies were performed on 97 patients over 1-2 years of follow-up. A total of 228 (87%) of biopsies were performed in ESB centers. Compared to LSIB centers, ESB centers had 7-fold more episodes of TCMR diagnosed on any biopsy [0.8 ± 1.2 vs 0.1 ± 0.4; P < .001] and a 3-fold higher rate from indication biopsies [0.3 ± 0.9 vs 0.1 ± 0.3; P = .04]. The proportion of rejection treatment varied based on severity: Banff borderline i1t1 (40%);>i1t1 and < Banff 1A (86%); and ≥ Banff 1A (100%). Biopsies for follow-up were performed after treatment in 80% of cases (n = 28) of rejection almost exclusively at ESB centers, with 17 (61%) showing persistence of TCMR (≥i1t1). CONCLUSIONS Practice variation exists across Canadian pediatric renal transplant centers with ESB centers identifying more episodes of rejection. Additionally, treatment of Banff borderline is not universal and varies with severity regardless of center type. Lastly, follow-up biopsies are performed inconsistently and invariably show persistence of rejection.
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Affiliation(s)
| | - Ian W Gibson
- Department of Pathology, University of Manitoba, Winnipeg, MB, Canada
| | - Julie Ho
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Peter Nickerson
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.,Shared Health Services Manitoba, Transplant/Immunology Lab, Winnipeg, MB, Canada
| | - David Rush
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Atul Sharma
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
| | - David Wishart
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, Canada
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48
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Landsberg A, Riazy M, Blydt-Hansen TD. Yield and utility of surveillance kidney biopsies in pediatric kidney transplant recipients at various time points post-transplant. Pediatr Transplant 2021; 25:e13869. [PMID: 33073499 DOI: 10.1111/petr.13869] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/29/2020] [Accepted: 09/09/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Due to a lack of consensus on SB for pediatric kidney transplant recipients, we evaluated the yield and clinical utility of SB findings at various time points post-transplant. METHODS Patients transplanted at a single institution between 2014 and 2020 with at least one SB at 1.5, 3, 6, 12, and 24 months post-transplant were included. Additional biopsies were done for indication (IB). TCMR was classified by Banff criteria (score ≥i1t1). RESULTS Forty-seven patients had 142 biopsies (SB = 113, IB = 29); 19 (40.4%) of whom experienced at least one TCMR episode in the first-year post-transplant. The greatest SB yield of any pathologic abnormality was at 6 months (57.1%; P < .001). Six months also had the highest yield for TCMR (42.9%), compared with 3.3%, 20.8%, 15.0%, and 9.1% at 1.5, 3, 12 months, and 24 months, respectively (P = .003). SB instigated intensification of immunosuppression (28.3% cases), reduction of immunosuppression (2.7% cases), and other non-immunosuppressant changes (1.8% cases). The 6-month SB led to the greatest number of changes in management (53.6%), compared with 1.5, 3, 12, and 24 months (13.3, 20.8, 25.0, and 36.4%, respectively; P = .012). There were no major biopsy-related complications. CONCLUSIONS SBs identify an important burden of subclinical rejection and other pathology leading to changes in clinical management. The greatest yield was at 6 months, whereas the least utility was at the 1.5 months. Selection of SB timing may be tailored such that the optimal yield is balanced against the procedural risk.
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Affiliation(s)
- Adina Landsberg
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Maziar Riazy
- Department of Pathology, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Tom D Blydt-Hansen
- Division of Nephrology, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada
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Davis S, Wiebe C, Campbell K, Anobile C, Aubrey M, Stites E, Grafals M, Pomfret E, Nickerson P, Cooper JE. Adequate tacrolimus exposure modulates the impact of HLA class II molecular mismatch: a validation study in an American cohort. Am J Transplant 2021; 21:322-328. [PMID: 32888256 PMCID: PMC7821185 DOI: 10.1111/ajt.16290] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/07/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023]
Abstract
Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus <6 ng/ml versus >8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.
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Affiliation(s)
- Scott Davis
- Department of MedicineUniversity of ColoradoAuroraColoradoUSA
| | - Christopher Wiebe
- Department of MedicineRady Faculty of Health SciencesWinnipegManitobaUSA
| | | | | | | | - Erik Stites
- Department of MedicineUniversity of ColoradoAuroraColoradoUSA
| | - Monica Grafals
- Department of MedicineUniversity of ColoradoAuroraColoradoUSA
| | | | - Peter Nickerson
- Department of MedicineRady Faculty of Health SciencesWinnipegManitobaUSA
| | - James E. Cooper
- Department of MedicineUniversity of ColoradoAuroraColoradoUSA
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